ML23156A040

PR-030, 035 - 55FR34513 - Authorization to Prepare Radiopharmaceutical Reagent Kits & Elute Radiopharmaceutical Generators Use of Radiopharmaceuticals for Therapy

ML23156A040
Person / Time
Issue date:	08/23/1990
From:	Chilk S NRC/SECY
To:
References
PR-030, PR-035, 55FR34513
Download: ML23156A040 (1)

Text

ADAMS Template: SECY-067 DOCUMENT DATE: 08/23/1990 TITLE: PR-030,035 - 55FR34513 -AUTHORIZATION TO PREPARE RADIOPHARMACEUTICAL REAGENT KITS & ELUTE RADIOPHARMACEUTICAL GENERATORS USE OF RADIOPHARMACEUTICALS FOR THERAPY CASE

REFERENCE:

PR-030,035 55FR34513 KEYWORD: RULEMAKING COMMENTS Document Sensitivity: Non-sensitive - SUNSI Review Complete

STATUS OF RULEMAKING PROPOSED RULE: PR-030,035 OPEN ITEM (Y/N) N RULE NAME: AUTHORIZATION TO PREPARE RADIOPHARMACEUTICAL REA-GENT KITS, ELUTE RADIOPHARMACEUTICAL GENERATORS:

USE OF RADIOPHARMACEUTICALS FOR THERAPY PROPOSED RULE FED REG CITE: 55FR34513 PROPOSED RULE PUBLICATION DATE: 08/23/90 NUMBER OF COMMENTS: 8 ORIGINAL DATE FOR COMMENTS: 10/23/93 EXTENSION DATE: I I FINAL RULE FED. REG. CITE: 59FR61767 FINAL RULE PUBLICATION DATE: 12/02/94 NOTES ON ISSUED AS INTERIM FINAL RULE. SEE PROPOSED RULE ON PR 30, 32 '35 TATUS PUBLISHED AT 58 FR 33396. ALSO SEE REVISED FR PUB. AT 60 FR 322 &

OF RULE WORKSHOP NOTICE PUB. AT 57 FR 48305. FILE LOCATED ON Pl.

TO FIND THE STAFF CONTACT OR VIEW THE RULEMAKING HISTORY PRESS PAGE DOWN KEY HISTORY OF THE RULE PART AFFECTED: PR-030,035 RULE TITLE: AUTHORIZATION TO PREPARE RADIOPHARMACEUTICAL REA-GENT KITS, ELUTE RADIOPHARMACEUTICAL GENERATORS:

USE OF RADIOPHARMACEUTICALS FOR THERAPY PROPOSED RULE PROPOSED RULE DATE PROPOSED RULE SECY PAPER: 90-193 SRM DATE: 07/25/90 SIGNED BY SECRETARY: 08/17/90 FINAL RULE FINAL RULE DATE FINAL RULE SECY PAPER: SRM DATE: I I SIGNED BY SECRETARY: 11/25/94 STAFF CONTACTS ON THE RULE CONTACTl: ANTHONY TSE MAIL STOP: NLS-129 PHONE: 492-3797 CONTACT2: MAIL STOP: PHONE:

DOCKET NO. PR-030,035 (55FR34513)

In the Matter of AUTHORIZATION TO PREPARE RADIOPHARMACEUTICAL REAGE NT KITS AND ELUTE RADIOPHARMACEUTICAL GENERATORS:

USE OF RADIOPHARMACEUTICALS FOR THERAPY DATE DATE OF TITLE OR DOCKETED DOCUMENT DESCRIPTION OF DOCUMENT 08/17/90 08/17/90 FEDERAL REGISTER NOTICE - PROPOSED RULE 09/24/90 09/20/90 COVER LETTER WITH PETITION FOR RECONSIDERATION 10/01/90 09/27/90 COMMENT OF JAMES A. PONTO, MS, RPH ( 1) 10/09/90 10/03/90 COMMENT OF RAYMOND N. DANSEREAU, PH.D. ( 2) 11/14/90 11/08/90 COMMENT OF NATIONAL ASSOCIATION OF BDS OF PHARMACY (C. A. CATIZONE, M.S., R.PH.) ( 3) 12/04/90 11/27/90 COMMENT OF UNIVERSITY OF CALIFORNIA, LOS ANGELES

{CAROLS. MARCUS, PH.D., M.D.) { 4) 03/13/91 09/21/90 COMMENT OF AMERICAN COLLEGE OF NUCLEAR PHYSICIANS (R. HENKIN, M.D. & N. ALAZRAKI, M.D.) ( 5) 03/13/91 02/27/91 COMMENT OF THE UNIVERSITY OF NEW MEXICO (DENNIS ESHIMA, RPH., BCNP, PH.D.) ( 6) 03/15/91 02/20/91 COMMENT OF DEPARTMENT OF VETERANS AFFAIRS (JESSE BALSEIRO, M.D.) ( 7) 04/09/91 04/08/91 COMMENT OF ACNP &SNM (TERENCE BEVIN, M.D., PRESIDENT) ( 8)

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U5NRC American The Society College of '91 APR -9 A\ 1 :25 of Nu?l~ar Nuclear Medicine Physicians April 8, 1991 Samuel J. Chilk Secretary U.S. Nuclear Regulatory Commission 11 555 Rockville PikE!

Rockville, MD 20852 AlTN : Chief, Docketing and Service Branch RE: Interim Final Rule and Petition for R<...:lemaking

Dear Mr. Chilk:

We are writing in response to the ongoing problems associated with the Immediately Effective Interim Final Rule (Federal Reg~ter 55(164):23 Aug. 90, pp. 34513-34518). As representatives of the American College of Nuclear Physicians (ACNP) and the Society of Nuclear Medicine (SNM), the organizations that petitioned for this rulemaking, we wish to recommend this rule be immediately withdrawn and remanded back to the Advisory Committee for the Medical Uses of Isotopes (ACMUI) for further consideration.

According to the notice, this rule was intended to "aliow licensees who elute generators

,and prepare reagent kits to depart from the manufacturr 's instructions for elution and preparation in the package insert nrovidHd the licensees meet certain conditions and limitn~ions." (emphasis added). The interpretation and subsequent implementation of the phrase emphasized is of great concern to the nuclear medicine community.

On page 34515 of the notice, departures are allowed if there is a "written directive (e.g.,

prescription) made by an authorized user physician directing a specific departure for a particular patient or patients, or for a radiopharmaceutical, and which includes (1) the specific nature of the departur~ (2) a p:-ecise description of the departure, and (3) a brief statement of the reasons why the de12arture from the manufacturers's instructions would obtain medical result5 not otherwise atta,nable or would reduce medical risks to particular patients because of their medical condition." (emphasis added) .

The rule mandates t,i e retention of all records of deviations for five years for inspection purposes. In no other medical specialty are pharmacists or physicians inspected by a federal agency for the appropriate use of pharmaceuticals.

APR 24 1 AcknowJedged by card .....................:..... .....

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Letter to Mr. Ch ilk April 8, 1991 Page 2 NRC staff maintains that these restrictions will not be time consuming or hinder the practice of medicine and pharmacy. We, as representatives of over 14,000 nuclear medicine physicians, pharmacists, technologists and scientists, are not comfortable with these assurances and respectfully recommend the complete withdrawal of the Interim Final Rule until an appropriate and reasonable response to the ACNP/SNM petition is developed by the ACMUI and the nuclear medicine community.

While under review we suggest that a memorand..Jm of understanding be created to protect the practice of nuclear medicine and pharmacy until a new rule can be negotiated.

We kindly request that this recommendation be debated at the May 9 and 10, 1991 ACMUI meeting. In the meantime, your consideration and attention is much appreciated.

Sincerely,

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President Society of Nuclear Medicine T~J2asCE 's,Ev8\J Terence Seven, M.D.

President American College of Nuclear Physicians

DOCKET NUMBER PR ,a 0 ~

PROPOSED RULE - 3 16,/ 3, DEPARTMENT OF VETERANS AFFAIRS( SS f--~  :)

Hunter Holmes McGuire Medical Center 1201 Broad Rock Boulevard Richmond VA 23249

'91 11 R \ 5 p 3 :36

• Dr.Anthony Tse Office of Nuc1ear Regu1atory Research U.S. Nuclear Regu1atory Commission Washington, D.C. 20555

Dear Sir:

We would appreciate your assistance in clarifying the item related to the interim rule.

a.) Under part 35.200 the on1y record a Nuc1ear Medicine department needs to maintain is the physician's written directive (see attached) as long as the doses are not prepared in house. We requested from the At1anta regional office an assurance statement but they referred us to the NRC Central Office in Washington. Since we are inspected by the Atlanta office and there seems to be some confusion on the issue we are requesting a written clarification.

b.) If the commercial radiopharmacy prepares the kit within the package insert 1 s guidelines and we use the material past it's expiration time {but within the time set by the physician's written directive), what are the record keeping requirements?

Thank you for your prompt attention to this matter.

J C airman, uclear Medi cine APR 2 4 1991 Acknowledged by card ...........................YIM..

U.S. UCLEAA REGULATORY CO Ml SION DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSI01 Oocumc,,t Stat1slfcs Post ark Date ~hvj "JI r /?5)

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TO : Syncor Pharmacy Manager FROM: Authorized User Physician RE: Written Directive for Eluting Generators and Preparing R;:idiopharmaceuticals As we discussed on __________ . I request that Syncor International Corporation prepare and dispense Radiopharmaceuticals according to the attached Kit Preparation Guidelines, dated November 1989. I have initialed the copy of Guidelines attached to indicate our review.

The attached guidelines satisfy the requirements of 1o CFR Part 35 .200 that I provide a written directive with the nature and precise description of departures from manufacturer's instructions in eluting generators and preparing diagnostic reagent kits.

!n my judgement, these departure~ from mar,'.Jfacturer's instn,ctions are justified for the following reasons:

0 Adjusting the activity used in reconstituting MAA is necessary for patient safety. Failure to make this compensation could result in administration of an improper number of particles to the patient, posing a significant risk to the patient in the event of pulmonary embolus.

o Times of use for Sulfur Colloid, MDP and MAA are extended to twelve hours to facilitate patient scheduling during the day, and to allow overnight use of doses for emergency cases.

o Times of use for Sulfur Colloid, MDP and MAA are extended to twelve hours, to allow for a practical delivery schedule from the pharmacy. Without the option of using the services of a radiopharmacy, this department would be forced to elute generators and prepare radiopharma-ceuticals in-house. Because of the widespread shortage of qualified Nuclear Medicine Technolo-gists, the time diverted to these activitie*s would result in a reduction in the quality and quantity of patient care delivered by this department. Further, we believe that using a centralized radiopharmacy allows this institution to take advantage of the experience and expertise of a licensed radiopharmacist which we would not otherwise have.

0 NOTE: Follow Package Insert Requirements for DTPA-Renal Exp Time This directive applies to all orders placed by this institution for these radiopharmaceuticals, unless you are specifically instructed otherwise at the time the order is placed. or until this directive is cancelled or replaced.

Sincerely yours,

MAR 1 a 1991 Dr. Jesse Balseiro, M.D.

Chairman, Radiaiton Safety Committee Nuclear Medicine Service (115)

Hunter Holmes McGuire Medical Center 1201 Broad Rock Boulevard Richmond, VA 23249

Dear Dr. Balseiro:

Thank you for your letter (Reference No. 652/115) requesting clarification of certain items related to the interim final rule entitled "Authorization to Prepare Radiopharmaceutical Reagent Kits and Elute Radiopharmaceutical Generators; Use of Radiopharmaceuticals for Therapy."

By copy of this letter, I am referring your letter and the attachment to our Office of Nuclear Material Safety and Safeguards (NMSS), which is responsible for these matters. NMSS will respond to your specific questions.

I am also fowarding your letter to our Office of the Secretary of the Commission to be docketed as a public comment on this rulemaking so th at your letter and the attachment will be considered when the interim final rule is reconsidered.

Sincerely, Anthony Tse Regulation Development Branch Division of Regulatory Applications Office of Nuclear Regulatory Research DISTRIBUTION: (Tse) subj-chron-circ ROB reading (SBahadur)

JTelford ATse (w/incoming):

DBHowe, NMSS LCamper, NMSS EJulian, SECY

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OFF: RDB/D~RA NAME: ATse DATE: 3/13/ 1

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'91 MAR 13 A1 1 :30 The University of New Mexico College of Pharmacy Radiopharmacy Albuquerque, NM 87131 Telephone 505: 277-6104 February 27, 1991 Dr. Anthony Tse Nuclear Regulatory Commission Office of Nuclear Regulatory Research Washington, DC 20555

Dear Dr. Tse:

This letter provides comments to the Nuclear Regulatory Commission interim final rule entitled "Authorization to Prepare Radiopharma-ceutical Reagent Kits and Elute Radiopharmaceutical Generators; Use of Radiopharmaceuticals for Therapy, " 10 CFR Parts 3 O and 3 5, Federal Register, Vol. 55, No. 164, Thursday, August 23, 1990, Rules and Regulations, pp. 34513 - 34518.

We at the University of New Mexico have carefully followed the rulemaking process surrounding these regulations and appreciate all the efforts the NRC has made in incorporating comments and suggestions submitted by various health care professional organizations. We feel inclined, therefore, to participate and comment on the proposed regulations because of our involvement in an active educational program as well as a functional centralized radiopharmacy that services the state of New Mexico.

In the past, we made comments through the American Society of Hospital Pharmacists (ASHP). There are several points outstanding (from our vantage point) that will significantly affect the operation of all centralized radiopharmacies in the United states and the career path for hospital-based nuclear pharmacists for years, issues that should be addressed specifically before any final rules are prepared.

We therefore respectfully request that the Nuclear Regulatory Commission fully consider the following comments regarding 10 CFR Parts 30 and 35, interim final rule:

A Place in Your Future

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Anthony Tse Page 2 of 4 February 27, 1991 COMMENT I Prior to the release of the interim final rule, a wide spectrum of cornmentors made strong arguments that it was in the interest of the national heal th, and good medical and pharmacy practice that physicians and pharmacists should be entrusted with the same authority to make discretionary professional judgements in nuclear practice as in the realm of traditional medical and pharmacy practice. That is, licensed physicians and pharmacists should be allowed a reasonable discretion to deviate from the package insert for NDA approved radiopharmaceuticals. Such has been the practice for generations outside the realm of nuclear p r actice in the fields of medicine and pharmacy. And the interim rules did recognize the appropriateness for a physician's comprehending needs for deviation from the package inserts of NOA approved radiopharmaceuticals.

The interim rules, however, recognized nothing regarding the pharmacist's ability to know and apply his professional knowledge to deviate from the package inserts, and thereby recognizes no area, even pharmaceutical preparation, for wh i ch a pharmacist's training supercedes a physician's training. Such a lack of recognition of the pharmacist's complex and intense training equates to a disenfranchisement of the profession of pharmacy from the practice of nuclear pharmacy.

That our profession for which we have worked so long and so diligently appears on the brink of disenfranchisement concerns us greatly. We plead that the Nuclear Regulatory Commission listen to our concerns and so change the interim regulations to fully recognize the substantial training and necessary professional judgement of nuclear pharmacists.

COMMENT I I The second comment regards the administrative process established in the interim final rule for documenting deviations from package inserts for NDA approved radiopharmaceuticals. The rule authorizes only physicians to make written directives --- a fitt i ng approach when the reason for the deviation is clinical and therefore part of the sphere of physician expertise.

However, when the need for deviation is pharmaceutically based, such as when research proves a formulation has better stability with the addition of a stabilizer that is not specified in the package insert, the pharmacist has no efficient means to document such a deviation. (Of course, the rules must first recognize the pharmacist as an appropriate professional to analyze pharmaceutical aspects of pharmaceutical preparations).

Anthony Tse Page 3 of 4 February 27, 1991 As the final interim rule stands, the pharmacist (centralized radiopharmacy) falls in the awkward position of, after recognizing the need for pharmaceutical deviations, to then educate all physicians, prepare boiler-plate documentation for physician authorization, develop a tracking system, transmit the documentation, and follow-up on non-responses ---- all this a potential administrative nightmare.

The efficient approach would be for the pharmacist to document the reasons for the deviations and then simply notify all the physicians, with time a.llowances for comments b ack from p hysicians.

In addition to fine-tuning the administrative process, the approach would reduce administrative expense and therefore reduce the cost of providing radiopharmaceuticals to the American public.

It should be noted that, because of the need for the control of radionuclidic materials, our described administrative approach goes far beyond the traditional practice, for which pharmacists make no notification whatsoever to physicians about particulars of compounding. These additional requirements would therefore be appropriate for efficient NRC oversight.

As further support of our mutual belief with the NRC for appropriate oversight and control, we would support a requirement from the NRC that the documentation for any deviations from the pharmacist's perspective be certified by a Board Certified Nuclear Pharmacist (BCNP) or a nuclear pharmacist with a graduate degree specializing in nuclear pharmacy or a nuclear pharmacist with a board quality certification from any other nationally recognized nuclear certifying bodies.

COMMENT I I I Our third comment addresses- the p oint that the fina l interim r ule does not even address the issue of extemporaneous radiolabeled compounding. There are times when a physician, in h i s/her practi ce of medicine recognizes a legitimate need for the radiolabeling of a compound, such as a monoclonal antibody. Upon recognition of such need, the physician should be able to write a prescription specifying the radio labeling of the compound, and the nuclear pharmacist should be able to compound and fill the prescri ption.

Under the final interim rule, none of these needed matters can be legally accomplished.

CONCLUS ION We believe the consideration and evaluation of these three comments, and the incorporation into the final regulations of changes that address and solve the problems described by these comments, to be critical to the good practice of nuclear medicine

Anthony Tse Page 4 of 4 February 27, 1991 and nuclear pharmacy in the United States for decades and, as well, to be critical to cost containment in the practice of nuclear medicine and nuclear pharmacy.

Thank you for the opportunity to comment on this important matter of public health concern. We look forward to your response.

Dennis Eshima, RPh., BCNP, PhD.

Assistant Professor Ga French, RPh.

M.S. Candidate and Nuclear Pharmacy Resident Hladik III, RPh., M.S.

rand Director of Radiopharmacy cy Resident y, RPh., Pharm D.

M.S. Nuclear Pharmacy Resident

~~t Nanc Wolf, RPh., M.S.

Nuclea Pharmacy Resident

t American College of Nuc lear Phvsicians September 21, 1990

____, John H. Glenn, Jr.

U.S. Nuclear Regulatory Commission Washington, DC 20555

Dear John:

We are writing with regard to the recently published interim final rule Fed. Reg. Vol. 55 No .

164 page 34513 in response to the Petition for Rulemaking filed by the American College of Nuclear Physicians (ACNP) and the Society of Nuclear Medicine (SNM). We appreciate the efforts that the NRC has made in response to the petition. In general, the items covered in the Federal Register notice represent a positive response to the petition. We note, as we had learned from a number of private discussions with NRC personnel that there are significant items in the petition that would not be responded to at the present time. We look forward to that response in the future.

There is however, some confusion that has resulted from the wording of the interim final rule. As worded, an "authorized user physician" may direct a "specific departure for a particular patient, or patients, or for a radiopharmaceutical," if he " includes the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manufacturer's instructions for preparing the radiopharmaceutical would obtain medical results not otherwise obtainable, or would reduce medical risk to particular patients because of their medical condition. If the authorized user physician determines that a delay in preparing the radiopharmaceutical in order to make a written direcfr:e would j~op~.rd;ze the- patient's health bc:=c2t:$e of t:be er!!erge~t n~t:Jre of the patient's medical condition, the radiopharmaceutical may be prepared first without making a written directive."

In the discussions held between the nuclear medicine community and the NRC, the nuclear medicine community understood that the criteria for deviation from package insert during

. the three years of this trial period, would be solely physician judgement. The physician would only be required to simply note the reason for his deviation. The wording that is cited above is considerably more restrictive in our opinion, than our discussions led to anticipate.

The rule could be construed to say that the only justification for going outside the package insert would be:

1. To obtain medical results not otherwise obtainable.

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• ' I APR 2 4 1991

2. Reduce risks to a particular patient.

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We believe this to be too restrictive and subsequent discussions with you have indicated that it was not NRC's intent to be this restrictive.

Since there appears to be wording that could be interpreted as restnct1ve, we request information on what enforcement actions would be associated with physicians who used a radiopharmaceutical other than as described in the package insert and did not satisfy the NRC criteria as listed above. Without going into detail, there are a number of clinical situations in which departure from the package insert would occur and might be difficult to fit into one of the two clinical categories. For that reason we would hope- that a prescription would serve as adequate documentation of the deviation and that physician judgement would be sufficient justification.

We agree with and understand the data gathering aims of the U.S.N.R.C.,however, in order that our membership be able to properly comply with the rule while exercising their best medical judgement, some clarification is required as to how this rule is interpreted by NRC.

If, in fact, the physician involved believes for reasons that he cannot define well, that his

• deviation from the package insert is in his patient's best interest, what would NRC's response be to this? Likewise, we hope that NRC will not consider the outcome of a procedure, that is it did not benefit the patient, as a lack of justification for having done it in the first place. Physicians are often forced to make judgements based on their best estimation and unable to predict the outcome. If an outcome is not more beneficial than the standard method, it should still be acceptable.

• These are very important issues in instructing our membership how they must comply with the interim final rule and what is and is not appropriate under that rule. We look forward to your response at the earliest possible date.

Sincerely,

/Z~~ a~,,,,k,. 'htb Robert E. Henkin, M.D. Naomi Al~ki, ~~D. -,

President President American College of Nuclear Physicians Society of Nuclear Medicine

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SUBJECT:

TWO PUBLIC COMMENT LETTERS TO BE DOCKETED.

Per our telephone conversation, enclosed are two public comment letters concerning the interim final rule for Parts 30 and 35 (55 .FR 34513, August 23, 1990).

Please docket both letter~.

Thanks.

Enclosures:

1. Ltr from Henkin and Alazraki dated 9/21/90.

2. Ltr from Eshima and others dated 2/27/91.

DO NOT UM this form as a RECORD of approvals. concurrences, disposals, cleaninces. and similar actions FROM: (Name. or,. symbol, Aseney/Post) Room No.-Bldg.

Anthony Tse, RES Phone No.

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• 90 OEC -4 UCLA SCHOOL OF MEDICINE HARBOR - UCLA MEDICAL CENTER DEPARTMENT OF RADIOLOGY 1000 CARSON STREET TORRANCE, CALIFORNIA 90509 Samuel Chilk Secretary of the Commission Nov. 27, 1990 U.S. Nuclear Regulatory Commission Washington, D.C. 20555

Dear Sir:

Please consider the enclosed document as my comments on the Immediately Effective Interim Final Rule of 23 Aug. 90.

Sincerely,

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Carol S. Marcus, Ph.D., M.D.

Director, Nuclear Medicine Outpt. Clinic Bldg. A-13 and Assoc. Prof. of Radiological Sciences, UCLA CSM:dt encl:

AN 2 8 1991 Acknowledged by card ..'""""""'mmt1rrmmm -

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• SANTA CRUZ UCLA SCHOOL OF MEDICINE HARBOR - UCLA MEDICAL CENTER DEPARTMENT OF RADIOLOGY 1000 CARSON STREET John E. Glen~, Ph.D. TOR_RANCE, CALIFORNIA 90509 U.S. Nuclear Regulatory Commission Nov. 27, 1990 11555 Rockville Pike Rockville, MD 20852

Dear John:

As we discussed, I have extensively considered _the Immediately Effective Interim Final Rule* (FR 55 (164):.: 23 Aug 90, pp. 34513-34518) and the exist-ing portions of Parts* 30 and* 35 to which *it refers. You requested that I consider interpretations that would be desirable and you also requested in-formation about types and fr!?-quency of package insert departures.

With my usual brevity* (!), I have endeavored to comply. (you certainly won't be able to say that I held back any information!)_

I have recommended and described numerous interpretations of Parts* 30, 32, and 35 as well as the Interim Rule in order to make the Interim Rul~ accom-plish that which I believe is necessary. Unfortunately, I do not think that this will r~ally be sufficient to solve the problem and I have added the concept of a substitution. I have included a "Surrogate Survey" to sub-stitute for the three-year recordkeeping requirement. I believe the Surrogate Survey to be more complete and more accurate than NRG could attain with the recordkeeping scheme described in the Interim Rule.

If NRG will accept the recommended interpretations and the Surrogate Survey, we can consider significantly shortening the duration of the Interim Rule*

and addressing the issue in the Petition,'which was to remove the package in-sert entirely as the "gold standard" by* which NRG is trying to make us practice medicine and pharmacy.* I think that this report should convince you that this has been an unsuccessful NRG effort for good reason, and that the Interim Rule will probably create more problems than it solves.

Gold standards are created by expert consensus, not by regulation or legis-lation . . You probably remember the story about the State Legislature that set the value of n at exactly 3.14. Scientists and mathematicians could not accept it, of course,._and it was repealed. Well, the experts in nuclear medicine and nuclear pharmacy are telling you that they reject NRC's false "gold standard" of medical and pharmacy practic_e, and it is time you repealed Package Inserts.

The nicest thing I can say about the Interim Rule is that it completely misses the point. * (I say less .nice things about .it as _this report goes on, but I want to lead you into this gently.)

The appended manuscript is -divided into several sections which I believe will be of use to you.Section I deals with background information essential to

the understanding of this issue in general and with the wording and back-ground of the Interim Rule in particular.Section II. covers my actual recommendations.Section III, The Surrogate Survey, covers virtually all

.the package insert departures or classes of departures that are used each year in the entire United States, and the approximate numbers of each departure. These totals are for the entire country, and do not distinguish between NRC and Agreement State licensees. There is also a section written by Dennis Hoogland, Ph.D., describing common nuclear pharmacy package in-sert departures. This was compiled for FDA and was received by Dr. Temple (and by Mr. Cunningham) in April, 1990. No one at FDA or NRC has. conveyed .

a single negative comment about any of these departures in the seven months since the report was received. Most of the other departures discussed in Section III. have been discussed in the ACNP-SNM Petition or have been dis-cussed separately in letters sent by members to Mr. Cunningham or Mr. McElroy,and to Dr. Temple at FDA. No negative comment concerning any of these departures has been conveyed to us, and 7.mos. to 21/2 years have elapsed since description of these departures were received by both agencies.

I sincerely hope you will give my recommendations careful consideration, as we would all like this Interim Rule to do as little damage as possible. We are also anxious to settle this.issue so that we may get on with the major issues of the Petition which have not been addressed as yet despite the fact that the. Petition has been at NRC for over 17 months.

Sincerely, Caro1 S. Marcus, Ph.D., M.D.

Director, Nuclear Medical Outpt. Clinic Bldg. A:...13 . .

and Assoc. Prof. of Radiological Sciences, UCLA CSM:dt encl:

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,RECOMMENDATIONS CONCERNING THE INTERPRETATION OF THE INTERIM RULE AND THE EXISTING PORTIONS OF PARTS.30 AND 35 TO WHICH IT REFERS Prepared by Carol S.

• Marcus, Ph.D. , M. D.

Director, Nuclear Medicine Outpt. Clinic Building A-13 and Assoc. Prof. of Radiological Sciences, UCLA November, 1990

SECTION I.

BACKGROUND AND INFORMATION

\ -,

I

The *Congress of _the United States relegated.the practices of medicine and pharma*cy to the States to govern. This has never changed throughout the history of this country. Each State has laws* and regulations pertaining to the practice of medicine and to the practice of pharmacy. Each State has a Board of Medicine* and a Board of Pharmacy to decide issues and review professional conduct. Licensure in a State is determined by the Board. Peer review is the es-sence of all professional decisions made by the Boards.

Guidance. for the State Boards comes from National Boards in every _medical and pharmacy specialty. Professional consensus is the very *backbone of medicine and pharmacy because these professions do not and by their natute cannot have detailed, prescriptive rules. Patient problems are exceedingly com-plex, with confounding. variables that are often unidentifi-able and at best, changing and only occa~ionally quanti-fiable. ~he standard of medical and pharmaceutical practice is* an elu~ive moving target, judged by qualified professionals on a case by case basis. There are no prescriptive regula-tions in any State for pediatrics, orthopedics, obstetric~/

gynecology, general surgery, urology, internal medicine, or psychiatry;: there.are none for hospital pharmacy, clinical pharmacy ,.or retail' pharmacy. It does not make any sense to attempt to make*any for Co,-60 therapy, brachytherapy, nuclear medicine, or nuclear pharmacy, either.

I. believe that NRC has made two erroneous decisions that are the basis of our current problems. The fir.st mistake was for NRC to distort Section 104 (Appendix I)' of the Atomic Energy _Act and decide to regulate the actual practices of medicine: and pharmacy despite a warning in the law to avoid this action. I do not accept NRC' s attempt to preempt States.

rights or -to overturn State Law and do not believe that NRC has any legal authority to dictate the practices of medicine or pharmacy.. NRC' s mandate is radiation protection of the public and of workers. Radiation protection of the patient is the responsibilit~ of medical professionals, and the responsi-bilit~ .. for patient radiation safety guidelines was specific-ally given to DHHS in 1981 (see Appendix II) in 42USC10001-10008.

The. Federal Government has passed numerous laws that im-pact on the practices of medicine and pharmacy, but none that dictate it. For example, in 1938 the Food, Drug, and Cosmetic Act was passed, and the present form of the FDA was established.

The* FDA regulates new drug research and drug manufacturers.

It is: specifically. _fqrbidden to regulate the practices of medicine and* pharmacy.

• Moreover, i t is* the* States that

decide that which constitutes .the practices of _medicine and pharmacy _and not FDA*_-1 : The. USP promulgates drug stan-dards, but does not dictate the practice of pharmacy** . OHTA controls technology_assessment for reimbursement,* and HCFA sets the rates. EPA regulates toxic' effluents. However, none of these: agencies regulates. actual medical or pharmacy practice, although they influence it. JCAHO: can suspend or revoke ac~reditatioh of ~ospitals and healthcare organi-z~tions bec~use of generally bad practices~ or they can in-sist that specific: _failings. be improved before certification, but they cannot prevent certain practices of medicine and pharmacy. They *cari*only prevent reimbursement by government agencies. Arid, urilike*NRC,. all JCAHO inspectors are ex-perienced healthcare* professionals.

The second serious mistake NRC has made is its relentless quest for the perfect procedure manual and the perfect and all-encompassing set of prescriptive. rules. with which to regulate the practices of _medicine and pharmacy. NRC :m.'ay as well search for the Holy Grail, the Fountain of Youth, or Second Law.Violations. This elusive goal is theoretically impossible because of the nature of the process. It may be appropriate and possible to wr*ite all-encompassing procedure manuals for nuclear submarines and nuclear reactors, but it is in-appropriate and impossible to do so for the raising of children, establishing a positive lifetime relationship with your*spouse,* painting masterpieces, composing fine music~ or the practices of.medicine and pharmacy. NRC often gives the excuse that* prescriptive regulation is its "style", and that its staff. _is* not capable of evaluating medical and pharma-ceutical judgment and needs this prescriptive regulatory, 1 Although this function was temporarily given to AEC from 1963-1975 for byproduct drugs, the FDA lifted the exemption and the change is documented in the Federal Register (Appendix III). It is discussed in a chapter written in 1975 and published in 1976 by Earl Myers of FDA and Richard Cunningham of NRC (Appendix IV.). The regulations concern-ing nuclear pharmacy, promised in the 1975 Federal Register article,* were never. written. Instead FDA published its 1984 Guidelines for Nuclear Pharma*cy. (Appendix*. V;: also appended to the ACNP/SNM Petition). It is still. very _much in effect.

When FDA took. back the regulation of _radioactive drug re-search. from AEC :some new FDA *regulations were needed*to accomplish this*.

• These regulations,* 21 CFR. 36L l ,* are in Appendix. v~.

~+

approach. That may well be true but it is also irrelevent.

NRC should change its style and its medically unqualified staff should not be practicing medicine and pharmacy with-out a license in the first place. Seeking a convenient crutch for its staff to clutch, NRC chose a false god in.,;.:.

deed; the package insert. In a remarkable stroke of regu-latory arrogance, NRC imposed as the standard of medical and pharmacy practice an informational and non-binding document from an agency that cannot even regulate the prac-tices of medicine and pharmacy in the first place, FDA.

Package inserts'.are.oversimplified, limited in scope, occasionally internally inconsistent, virtually always out of date, and are not the "manufacturers instructions"~ ~hey are FDA's instructions to the manufacturer and there are often profound disagreements between FDA and manufacturers about package insert contents. If Congress in its wisdom has denied FDA the right to enforce the package insert, it is difficult indeed to imagine that it would grant the non-medical professionals* at NRC this privilege. If NRC felt consumed by the need to regulate the practices of medicine and pharmacy, it should have gone for clues to those who do so, the States. In doing so, NRC would have found that no cozy cookbook is available. By insisting on using a "gold standard" as wretched as the package insert, NRC has jeop-ardized.patient care in a variety of ways, some of which were covered in the ACNP/SNM Petition.

When NRC's behavior became even more inappropriate after the Petition was received than beforehand, several ACNP/SNM members spoke with NRC about a "Gentleman's Agreement" to remain in effect until the Petition was put into effect.

The initial agreement, which was not very satisfactory but which was at least usable, deteriorated almost beyond recognition into the Interim Rule. Thrust onto the Nuclear Medicine/Pharmacy community without a period of public com-ment or an explanation of its meaning, NRC's excuse has been to blame FDA for the Rule's obnoxious content and to thus far refrain from explaining its meaning, in part at least from. basic lack of comprehension of our field. Blaming FDA is not convincing. If FDA informed NRC that reactors were determined to be "devices" and would in the future be regulated by the Center for Devices and Radiologic Health, would NRC obediently comply? What is the real reason NRC chose to craft such an inappropriate rule?

Let us take a frank look at the regulatory morass NRC created,:with its Apr'il, 1987 rulemaking and the plethora of .interpretations of.35.200(b) that followed. Today we

prepare about 10,000,000 rad.iopharmaceutical doses a year.

At least 5,000,000 of them depart from a strict inter-pretation of the package insert an average of twice, for a total of 9-10 million departures per year. NRC's present interpretation of 35.200(b) and* 35~300 (last sen-tence) has become nothing more than Draconian nonsense.

The Petition had a simple cure for this problem, namely, the removal of 35.200(b) and the last sentence of 35~300.

Can the convoluted, insulting, and (I believe) illegal Interim Final Rule .give us the "regulatory relief" NRC had sincerely promised? It is marginally possible, but it will take a great deal of cooperation by NRC on the question of interpretation and substitution to accomplish this.

For example, it is obvious that NRC had no idea of the ex-tent to which package inserts have been necessarily ignored.

(It would be interesting to see NRC's estimate of paper-work burden to 0MB in this regard.) The data-keeping and tallying requirement would be enormously burdensome. In addition, it is amusing to imagine NRC's (or FDA's) "data analysis" of 1 x 10 7 x 3 years x 40% = 12,000,000 bits of non-uniform data by staff who have virtually no understand-in~ of radiopharmiceutical chemistry. I have therefore de-cided to use this document to relate a good approximation of the nationwide tally of the litany of departures listed in Section III. This has two advantages. First, it reflects the whole nation, not just NRC licensees. Second, as FDA is blamed for this unpopular record-keeping requirement to begin with, why not give them the information they appear to want in an accurate manner? Licensees will be saved time and expense, and NRC staff wil.l not have to waste tax-payer.' s. money performing an impossible analysis. This should make eve~y6ne happy. Therefore please consider Sec-tion III the culmination of a three year survey of departures and totals. Now, what does NRC plan to do with it? I suggest NRC have it reviewed by its ACMUI, if anything, and send a copy to FDA if it likes.

Another example of NRC's interpretation flexibility that will be absolutely essential is in the area of patient benefit.in the category of "cost effectiveness". Cost effectiveness must be an appropriate reason for a package insert departuie. The DHHS has made cost effectiveness the First Law of Medicine in the USA, and NRC needs to internalize this. DHHS wants the cheapest way of doing a satisfactory study. As "He who pays the piper calls the tune", we comply.

FDA requires cost effectiveness before they approve a new drug, OHTA requires* cost effectiveness. for.new healthcare technology,* and HCFA requires* cost effectiveness when they

set the reimbursemeht levels that dictate federal and most private payor reimbursements. If we cannot do a study for the reimbursement offered, the patient goes without the study. Why doesn't NRC try going to HCFA and ask them to pay the extra cost of new requirements that NRC thinks would be nice but cannot prove valuable or neces-sary and which we think are scientifically unsubstantiable?

The bottom line is that if we have a cheaper way to make a satisfactory drug we will do it, package insert not with-standing.

Still another example of advisable NRC flexibility lies in the licensing options available under 32.72(2) (ii). As discussed in the Petition, the NRC has never permitted a centralized nuclear pharmacy to exercise this option and restricts such licenses to always exclude* it. It is in-teresting that NRC made.a regulation permitting an activity and then denied it to every single applicant for approxi-mately 15 years. Why not use it? The stabilization of NaI-131 to prevent dangerous airborne contamination is an excellent example of how to use the license to benefit public health and safety. Nuclear pharmacies prepare about 90,000 of these doses/yr for diagnosis and therapy from NDA-approved material that nevertheless requires stabilization. It is silly to ask physi~ians or pharmacists to keep track of 90,000 x 3 x 0.4=108,000 departures/3 yrs when all NRC has to do is permit nuclear pharmacies to do this by license amendment.

The same is true of the stabilization of Tc-99m-MDP and Tc-99m~DTPA with approximately 1 mg of ascorbic acid (vitamin C) per dose. Nuclear pharmacies then would stabilize about 1,100,000 doses/yr in the United States, which would re-present 1,100,000 x:3 x 0.4=1~320,000 items of recordkeeping for NRC licensees over* 3 years, which is also silly. This could simply be done by a license amendment as well. Nuclear pharmacies, of course, would not be the only source of this departure. This methodology _has been in the literature for many years and is used by other as well. Such amendments would be "interim", until the package inserts were dropped altogether.

NRC may well decide to rescind the Interim Rule and avoid all these problems and give us instead what we asked for in the Petition, namely, the removal of 35.200(b) and the -last sentence of 35.300. No one paid any attention to package inserts before 1987 and not many did afterwards and no harm is evident. Although many physicians will deny knowingly deviating from package inserts, most iri fact have no idea what is in the package inserts, either. After 100 ,ooo*,000".""150 ,000*,000 administrations of radiopharma-ceuticals over the last 53 years without very much regard to package inserts at all, NRC had better find a lot of

radioactive corpses or stop uttering self~righteous threats of mysterious risks. to public heal.th: and safety which i t cannot document. Now that NRC has ..the: information. it wants (Section III), it* needs to* act appro~riately and as quickly as possible.

In the event that NRC needs: an "Interim Understanding" of the Interim Rule uritil a final decision is made, please find my. specific recommendations in* the following section.

SECTION II.

SPECIFIC RECOMMENDATIONS

RECOMMENDATIONS FOR INTERPRETATION. OF 10- CFR. 35.200(b):

A licensee shall elute generators and prepare. reagent kits in- accordance with the manufacturer '*s: instructions ..

1. "In accordance with""means "in agreement with", not "word. for word mindless obedience". The package in-sert directs the u~er to make a safe and effective product, and if one does that he is "in accordance with" ~he *package insert. This allows for some measure of variability and encompasses Good Pharmacy Practice. This* more liberal interpretation was actually stated by NRC to be the intent of the April, 1987 Rule in the first place, but was eroded over time into the unworkable situation we have facing us today. This semantic, artificial problem may easily be relegated to non-problem status by going back to the original NRC intent of interpretation.

2. Kit preparation does not include how many hours have elapsed from nuclear pharmacy to nuclear medicine de-partment and how many more hours elapse until the dose is actually administered. Kit preparation does not include anything about quality control - if it is done at all, how it is done, or whether it is done before or after dose administration. Therefore, time con-siderations, Q/C, and any other aspects of the pack-age insert that are not directly about preparation should not be considered under 35.200(b).

FDA has begun to add items under "Kit Preparation" instructions that have nothing to do with k i t ~ -

aration, just to get NRC to enforce FDA's will. NRC has seemed perfectly willing to be used by FDA in this manner. We hope that NRC will no longer allow itself to be abused this way and will no longer abuse nuclear medicine/pharmacy professionals with FDA's insidious little mischief either.

RECOMMENDATIONS FOR USE OF 10 CFR 32.72(2) (ii)

1. Consult with licensees who manufacture and distribute radiopharmaceuticals in order to add license conditions that obviously facilitate safety (patient, worker, or member of _the public) and efficacy. Examples are the stabilization of NaI-131 and the addition of ascorbic acid as an antioxidant to DTPA and MDP kits.

RECO~ENDATIONS FOR 'INTERPRETATION. OF 35. 200 (c) *(l) and 35 *. 300 (b) (1) :_ Pe:rmis*sible benef,i t categories.

1. The wording of the conditions under which. a physician may .decide to depart from package insert instructions is deviou~ and* contemptible. It can mean: anything or nothing, and is so poorly crafted that I will not waste time dwelling on it but will instead list appropriate reasons for departures which will be necessary for NRC to accept in order for this Rule to cover necessary departures and be of any value to us:

The nuclear physician should have an appropriate degree of expectation that the departure will yield a result that has a) lower morbidity or mortality than an available alter-native b) higher sensitivity or specificity than an. available alternative c) higher resolution than an available alternative d) the. advantage of timeliness in diagnosis or treatment compared to an available alternative e) lower radiation absorbed dose to the patient than an available alternative f) cost effectiveness superior to an available alternative g) a chance of helping the patient when equivalent or superior procedures are unavailable because of location, lack of appropriate personnel, or lack of necessary in-strumentation or resources h) minimized patient inconvenience, unpleasantness, pain or fear i) a rather low probability of benefit but may preclude the need for a dangerous procedure, use of a dangerous dru~, or use of a relatively expensive diagnostic alternative procedure j) a high probability of satisfying the primary care or re-questing physician who does not wish his patient to undergo an alternative procedure k) a higher degree of worker safety than an available alternative

1) a higher degree of public safety than an available alternative m) advantages representing a combination of the above reasons.

The licensed nuclear physician does not know what.the package insert says and orders that which he. believes. is appropriate; only to find out* later that it was* a departure.

Whether or not the preparation is a departure depends on the brand of _kit one uses. A physiciari may order an ordinary dose but the brand the pharmacist used necessitated a departure prescriptiori.

Other reasonable reasons.

RECOMMENDATIONS FOR DOCUMENTATION OF PRESCRIBED DEPARTURES AND NUMBERS OF DEPARTURES IN EACH CATEGORY The record-keeping requirement of the Interim Rules is fatally flawed because it is virtually impossible to comply with as written under present NRC interpretation of 35.200(b). In the original verbal negotiatioris with the NRC we agreed to pre-scriptions for departures, but not to tallying totals in each category. The agreement for prescriptions for depar-tures was silly. but we could comply with it. Nuclear physi-cians kriow how .to use their drugs, but they do not know or care to know or care about what FDA has forced the manufac-turer to put in a package insert. Therefore, SNM/ACNP and the nuclear pharmacies were going to put together a "megalist" of*departure "prescriptions" and distribute it to nuclear phys-icians who would sign them as fast as they could, send copies to their nuclear pharmacies, put a copy in their procedure manuals and forget about it. Business as usual until the NRC finally acted on the Petition. If this prescription require-ment had been* tested in court it would probably have been thrown out, but it was so simple in concept we felt that no one would bother and NRC would presumably have acted on the Petition in a relatively short time and it wouldn't matter.

(You may recall that NRC was working on the "fast track" por-tion of the Petition at the time we were negotiating this. The fact that the "fast track" rule was a complete failure that had to be trashed in late December, 1989, and that it apparently died completely at that point, was not known to us during the November and early December discussions.)

When the Interim Rule appeared, only certain convoluted categories of deviations were to be "permitted", and it was al-most impossible to figure out what they were by reading the Rule. In the original agreement, any physician decision was to be "allowed". The Interim Rule made the tacit ass*umption that no Orie was *committing package insert departures. The~=-

• truth is.*that package*insert departures have nevertheless been a *prominent *part of *the *standard *of *medical practice,

especia:lly.with.-the nit~pickirtg interpretive esca:la:tidrt that occurred. *a:t. 'NRC *in *1990. . Virtually all NRC licensees had become "paper criminals 11

• at some time or other, except some of the broad licensees who are- exempt; and the situation has become ridiculous. Many procedures ~epend on departures which may well be disallowed with the Interim Rule.

One reason, therefore, that we cannot comply with the record-keeping requirements is the simple fact that by today's NRC interpretations as we understand them, most of our departures are in 11 disallowed 11 *categories and we will have to continue to.perform them.without reporting the 11 unreportable 11

• We have been surviving on Mr. Cunningham's memo to the Regions of Dec., 1988. As NRC never resolved the difficulties mentioned in the memo, NRC would be wise not to rescind +/-ts policy as derived from that memo. If the Interim ~ule were interpreted along the* lines ~uggested in this report, at least all our departuies would be 11 allowed 11

• on* 3 May 90, I sent a letter to Harold Denton concerning departures from package in~erts in the reconstitution and preparation of non-ra:didaCtive drugs, to compare similar situations. This letter was sent to Mr. Cunningham and Mr. McElroy as well. It is included here as Appendix VII. Departures from package in-sert instructions in preparing non-radioactive drugs at Los An.geles Courity:-U. S. C. Medical Center in the Medical Intensive Care Unit occurred about 25% of the time. It is the standard of pharmacy practice and very important. It is also, of course, entirely "allowable. I sincerely believe that if this issue of "allowable" departures ever came to court, NRC would lose without question. Even FDA, which crowed for months about how they _were going to take over a portion of pharmacy prac-tice through an interesting court case in which a pharmacist caused several patient deaths, had to back down recently, presumably because the Justice Department would not take the case. I hardly think the courts would back NRC's non-existent drug "expertise" with no adverse reactions to point to when they rejected FDA's expertise with deaths to point to. As your consultant, I would recommend that you avoid court at all costs if at all possible.

Now let us get to the really serious problem with the record-keeping requirements, which is the tallying. With NRC's current interpretation of 35.200(b), we will have.about ten million departures a year to tally, or about twelve million to tally over three years by NRC licensees, assuming no dupli-cation of tallying by physicians and pharmacists. (This is uriclear -in _the Interim R_ule ,- which reads. as though both physicians: and centralized**pharmacie~ have to tally duplica-tively. If this: is the* case, add another si~ million~) There are

millions of _instances in. which either the physician or_the pharmacist or. be.th will *n:o. t. 'kpow ,that a tal1yable depar- .

ture has occurred'. .(See* Section I.r*r, Note * (2) at end.) It is clear that NRC had no idea of _the maghitude of. this* cleri-cal nightmare, but neither physicians nor pharmacists can do it. The physicians are gambling at present that NRC will alter it~ interpretations so that millions of these "departures" will. be excluded. The truth is that most phy-sicians have no idea how often th~y hav~ "departed" and are unaware of the magnitude of this potential mess. The nuclear pharmacists have good reason not to expect reason-ableness from NRC, and are hedging their bets with an appeal of the Interim Rule.

If NRC subscribes -to the interpretations recommended in this report, the tal1yin~ requirements would go down considerably but would still be repugljant::to' licensees. There will, of necessity,. be gross underreporting and the value of the en-tire ~urvey will be exceedingly questionable. We are not getting anywhere.

I highly recommend that NRC use Section III as a more accurate survey arid tally for the projected three years than NRC would obtain through its Interim Rule, and abandon the tallying requirement entirely as a bare minimum and the pre-scription record-keeping as well as it would not serve any useful function. We would.then expect NRC to present this document to its ACMUI at the Jan 14-15, 1991 meeting, amputate the Interim Rule at 5 months (late January, 1991) as long as the ACMUI approves and substitute the deletion of 35.200(b) and the last sentence of* 35~300. Give it a reasonable public comment period and let the FDA make their comments public.

Or, just withdraw the- Interim Rule immediately and publish the substitution immediately after nuclear medicine and phar-macy*lea:dership*arid industry representatives *have seeri it, so that there is no more opportunity for mischief. I would hope that NRC has learned its lesson by now.

As an.aside, I cannot understand why NRC made a 3 year In-terim Rule when the Petition should be decided in its entirety long before then.

SUMMARY

OF SPECIFIC RECOMMENDATIONS The NRC has attempted to inflict an inappropriate "gold stan-dard" on nuclear medicine. and pharma~y practice. The ensuing discontent caused Mr. Curinin:gham to request a. Petition to correct the problems. The Petition was received in June, 1989. An Immediately_Effective Interim Final Rule to address a minor portion of the Petition was published o~ Aug. 23, 1990.

The Interim Rule is seen to be illegal, insulting, naive, and unworkable. It is recommended that. NRC adopt the

• interpretations described herein, accept* Section: III. of this report as* a suirogate recoidkeepin~ entity, then dis~

continue the Interim Rule and *immediately substitute uri-chariged the portions of.the Petition that relate to this issue (for physicians*and nuclear pharmacies).

SECTION -III.

THE SURROGATE SURVEY (Departu~es ~3 year freguenby estimates)

RADIOPHARMACEUTICAL DEPARTURES

1. CIS NaI-131 stablized with sodium thiosulfate-EDTA.

Sixty per cent of our 150,000 NaI-131 doses per year use this NaI-131 product. There is a very high vola-tility rate otherwise which jeopardizes workers and the public. Patients get less than the dose calibrator reading. One reputable laboratory reported sixteen (16) per cent volatility with unstabilized material which re-sulted in an action level worker thyroid burden and a therapeutic "misadministration" (underdosed by sixteen percent). Three year nationwide tally based on 1989 data= 270,000 departures.

2. Amersham medronate package insert directs that 2-8 ml NaTc04 generator eluant be added to the kit. Centralized nuclear pharmacies, which use 10 and 16 Ci Mo-99/Tc-99m generators, would fry the kit contents if they used so much activity (the package insert for the.generator calls for a 5cc elution volume). In order to avoid a useless product destroyed by radiolysis it is necessary to dilute the generator eluant with normal saline. The amount of dilution depends on the activity, age, elution efficiency, and time since previous elution. The nuclear pharmacist must use his own judgement here. The physician cannot write a prescription for this. It would be malpractice for a nuclear pharmacist to reconstitute the kit according to the package insert. The three year nationwide tally estimate, assuming that this brand of kit represents about 60% of the market, is 1,800,000.

3. Addition of ascorbic acid (approximately 1 mg per dose) to DTPA and MDP kits. This addition of antioxidant retards the inevitable tendency of Tc-99m to undergo oxidation to Tc04 and assures optimal radioph~rmaceutical performance for highest quality diagnostic accuracy. From 1974-1987, this was common practice (about 40-50% of doses). In 1987 NRC insisted that nuclear pharmacies stop, and they did.

One nuclear pharmacy requested a license amendment at the time but information requested by the agency (NRC), in reality, required the filing of a paper IND. The nuclear pharmacy asked the agency who would review the amendment.

NRC stated no one within the agency was qualified. The nuclear pharmacy then refused to submit the data and dropped the request for an amendment. NRC therefore degraded radio-pharmaceutical drug quality. The practice continues to some extent by other nuclear pharmacies and some nuclear medicine departments, although it is not very widespread.

Once this departure is "permitted", one nuclear pharmacy chain's three year tally would be about 3,3000,000, be-cause it makes about 40% of the nation's patient doses.

Other centralized nuclear pharmacies, which make about 14%,

would probably use ascorbic acid as well. I cannot estimate how many individual departments,which make up 46% of doses,

would- use~scorbic acid. Probably many of_the better ones wbuld do so.

4. Na3PO4-P-32 for treatment of idiopathic hemorrhagic thrombocytosis. This has been the drug of choice for this bone marrow disorder for about 50 years. Three year nationwide tally estimate= 25.

5. Preparation of NaI-131 (an oral drug) into a parenteral preparation by buffering and administration through a millipore filter. This is necessary in patients who cannot swallow dependably or effectively or who are vomiting. Three year nationwide tally estimate= 25.

6. Use of P-32 chromic phosphate for intrapericardial metastases. This route of administration does not appear on the package insert, which includes intra-pleural and intraperitoneal administration. Three year nationwide tally estimate= 25.

7. Adding more Tc-99m activity than stated on package insert.

The activity maximum listed on a package insert for re-constitution purposes must be applicable in the most extreme case, which is Tc-99m obtained from a two week old generator that was never eluted until just before expiration. The nannomolar concentration of Tc-99 is far greater than that of Tc-99m, ties up most of the kit ligand and limits Tc-99m activity that may be added.

Centralized nuclear pharmacies elute generators daily and often two to six times a day; the relative quantity of Tc-99 accompanying the Tc-99m is much lower. There is plenty of ligand available for increased Tc-99m activity. In order to maintain medical costs ALARA, while still maintaining safe and effective drugs that meet USP standards,itisappropriate to add increased Tc-99m activity.

The Tc-99/Tc-99m ratio in a generator eluted for the first time just before expiration is about 400. A generator eluted 1 hr. after the previous elution has a Tc-99/Tc-99m ratio of about 0.43. There are probably about four million deviations per year in this category in the U.S., or about 12 million over three years.

8. Deviations from the "six hour rule" for any applicable radiopharmaceutical due to emergent or urgent time con-traints in patient care.

The physician is obligated to do the best he can with what he has available within the time constraints appropriate to the patient. The same is true of a pharmacist pro-viding a drug to a physician for patient use. In the

event that the drug can be expected to meet USP stan-dards, there is absolutely no problem in using it after six hours. In the event that the drug is not expected to meet USP standards, the Food, Drug and Cosmetic Act is very clear. It is perfectly acceptable to provide and use the drug so long as "USP" is not used in the label. Professionalism requires that a physician be informed that the drug is possibly or probably not up to USP standards. In radiopharmaceu-ticals, this nearly always means more Tc-99m oxidation has occurred than one would usually expect. For example, let us assume that a recent renal transplant patient is suspected of having acute renal artery or renal vein thrombosis. The urologist wants a renal flow and function study now. The nuclear physician has enough Tc-99m-DTPA or Tc-99m-MAG~3 around to perform the study, but it was made fourteen(l4) hours before and might have fifteen(l5) or twenty(20) per cent free technetium (pertechnetate). Would the physician use it?

Of course. I would use it with the possibility of one-hundred per cent free pertechnetate. I could still get an answer that would help the surgeon decide if he needed to perform emergency surgery.

It is instructive to review the basis for the "six hour rule", in order to understand why so few professionals consider it particularly critical. The "six hour rule" is not based on product stability. It was based on a fear of an FDA chemist many years ago that as the kits contained no bacteriostatic agent, bacterial contami-nation at the time of kit preparation could cause con-tamination problems that got worse with time and so a recommended six hour maximum from reconstitution to ad-ministratioh was arbitrarily devised as a practical limit. This occurred before the development of centra-lized nuclear pharmacies, for which it was impractical.

For the centralized nuclear pharmacies, the essential question became radiopharmaceutical stability. This was ascertained for most products out to twelve(12) hours.

Bacterial contamination has never been a problem with radiopharmaceuticals, as documented previously in review articles sent to Mr. Cunningham in May, 1990.

Of .the ten million nuclear medicine procedures performed per year, about eight million involve Tc-99m. Four million of them are provided by centralized nuclear phar-macies. Of that four million, probably two and one half to three million ignore the "six hour rule". Of the four millioh made within the nuclear medicine department, probably about one million are used after six hours, especially, if one counts the departments that use "instant

tech" that was milked at 1 to 2 AM and has a "twelve hour rule" for the eluant. So, about four million patient doses per year do not conform to this package insert recommendation, which tallies to 12 million over three years. (This includes Departures no. 8 and 9.)

9. Departures from the "six hour rule" in nonemergent or non-urgent cases. If the physician has reason to be~

li~ve that the product stability is such that a per-fectly acceptable diagnostic study will ensure, it is acceptable to u~e the drug in order to maintain medical costs ALARA. The patient may have arrived late; the nuclear pharmacy may not be able to deliver another fresh dose for several hours. The patient may not be able to stay and may opt to skip the study rather that wait.

This is usually not to the patient's advantage and the referring physician may be appropriately annoyed that the study was not performed in the time frame he felt acceptable.

10. Lack of performance of quality control after kit recon-stitution. Only a few recent package inserts include Q/C under kit reconstitution instrudtions, and it is generally not necessary. In most cases, Q/C is performed to ascertain % Tc04*-. It is time consuming, adds cost to the procedure, and in many departments is performed only when there is a question of product stability (very seldom) or to validate a reconstitution procedure or stability measurement over time. Q/C procedures are often performed after the drug has been administered, as a random batch check, or to check a nuclear medicine technologist's or nudlear pharmacist's performance. In emergent or urgent situations it is generally ignored;and in routine situ~tions it is often difficult to justify the time and cost commitment. A physician needs to use his.limited resources in the most appropriate and productive manner possible. The centralized nuclear pharmacies routinely perform mudh more extensive Q/C than individual depart-ments.

11. Tc-9.9m-a.lbumin colloid for lymphoscintigraphy. No lympho-

• scintigraphy agent is approved by FDA. Albumin colloid, labeled with Tc-99m, is approved for liver-spleen imaging.

High specific activi.ty preparations, such as those used for phagocyticWBC labeling, are appropriate for lympo-scintigiaphy. If the final product is centrifuged before injection, the lighter particles on the top may be used and this: agent provides even more rapid information than the standard preparation. At present use rates, this would giv~ a three year tally of about 25. It could ris~ into th~ thousands.

12. Tc-99m-albu.min colloid for bone marrow imaging. High specific activity albumin colloid is a better bone marrow imaging agent than Tc~99m-sulfur colloid. About 30-40% of high specific activity Tc-99m-alburnin colloid goes to marrow; this% decreases as the number of particles increases and the marrow sites become saturated.

At present use rates, this would give a three year tally of about 15. This could rise to hundreds.

13. Extemporaneous compounding of cold kits.FDA law and policy and all state Boards of Pharmacy permit the extempor-aneous compoundtng of cold kits. Nuclear pharmacists whooeNRC license precludes this may obtain IND's from FDA to make these kits. Such kits have no "manufacturer's instructions" from which to deviate.

14. Homologous Tc-99m~HMPAO, Tc-99m-albu.min colloid, or In~lll-labeled leukocyte scans. The patient may be too leukopenic for autologous labeling, so homologous WBC's are used instead. Three year tally would be about 150.

15. Reconstitution of cold kits with radionuclides other than Tc-99m. Some _kits, such as DTPA, can chelate a variety of metals. Quantitative radioaerosol clearances may be performed with In-113m-DTPA, for example, after the patient has received a Tc-99m labeled radiopharmaceutical and a higher energy radionuclide is preferable. Unusual at present; three year tally about 15.

16. Reconstitution of a cold kit that was never intended to be a radiopharmaceutical. Many parenteral cold drugs are lyophilized and meant for reconstitution with normal saline. One can take desferroxamine, for example, and radiolabel it with Ga-67 or Tc-9_9m (after reduction) and use it for quantitative aerosol measurements when a larger molecular size than DTPA is required. Unusual at present. three year tally about 75.

17. High activity Tc-99m-MAA particles. These. are useful in several situations:

a) Pulmonary.hypertension

~) Intrapulmonary or intracardiac shunt c) Morbidly obese patient in whom one.uses the standard particle number but twice the activity.

d) A dose purposely set aside for emergency use at night, perhaps 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> or more after reconstitution.

e) Everyone, in case ahy of the above applies. We per-form about 1 million perfu~ion lurig scans per year.

Tally of _three years of departure would be about 2 million.

18. In-111-oxine for platelet labeling (autologous or homo-logous). Package insert is for WBC labeling only.

Labeled platelets are useful for platelet halflife, splenic sequestration, clot demonstration; some have found them useful for renal rejection. Homologous (donor) platelets labeled with In-111 may be used to assess transfusion efficacy in patients with antibodies (who are hard to cross-match). Estimated three year tally=

10,000.

19. In-111-RBC's for RBC labeling. Autologous or homologous labeled RBC's are useful for RBC mass, halflife, splenic sequestration, and intermittent GI bleeding. Homologous RBC's may be used for in vivo crossmatching as well.

Estimated three year tally =.300.

20. Tc-99m-a.lbumin colloid, high activity per particle for phagocytic PMN and monocytic labeling. Useful for locat-ing and evaluating inflammations and infections. Label-ing takes half the time of In-111; cheaper materials; faster study (within 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> instead of 24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br />); lower radiation absorbed dose. This study may be performed in children or pregnant women, and autologous as well as homologous WBC's may be used. Estimated three year tally=

600.

2L. Use of intravenous SnPYP followed by in vitro RBC labeling with Tc04. Useful for gated cardiac studies, GI bleeds, pulmonary bleeds, hemangioma detection, renal artery anastomosis bleeds, deep vein thrombosis and other types of venous blockade, and vascular graft patency. The package insert includes instructions for in vivo RBC labeling only. Estimated three year tally= 2 million (uriless FDA approves the Cadema RBC kits) *~

22. Tc-99m-gelfoam. Gelfoarn has an NDA and Tc-99m pertech-netate has an NDA and gelfoam may be labeled.with reduced Tc-99m to trace. vascular occlusions performed angio-graphically. Estimated three y~ar tally= 75.

23. Tc-99m mother's milk. for aspiration studies in newborns.

Mother's milk is food, but it has never been approved

• by FDA. There is a large body of anecdotal evidence concerning its safety and efficacy, however. Unfortun-ately, the USP has not published standards. The containers have always aroused interest and careful study. Tc-99m (reduded) may be labeled to milk protein, fed to an in-fant, and imaged for evidence of aspiration. E~tirnated three year tally= 3.

24. Reconstitution of several identical kits with saline, transfer to. a single vessel, and single addition of NaTc04 eluant. This* is in keeping. wi.th ALARA. for workers and is' especially important for compliance with the decreased hand dose standards to be released in the new Part 20.

25. Extemporaneous compounding of radiopharmaceuticals be-ginning with radiochemicals. Examples include Xe-133 for inhalation or dissolved in saline for injection and NaI-131 for solution or capsules for diagnosis and therapy. This is part of the practice of nuclear pharmacy as covered by State Pharmacy Law in all 50 states.

The reason for this in the case of Xe-133 is mainly economic; the.difference between "radiochemical" Xe-133 and NOA-approved "radiopharmaceutical" Xe-133 is a Ge(Li) spectrum for radionuclide purity. Many nuclear pharmacists and nuclear physicians have access to a Ge(Li) spect;i;o-meter. The difference in cost per mCi 2 years ago was a factor of about* 700.

The reason in the case of NaI-131 is both economy and convenience. It may not be possible to obtain uptake capsules of a desired activity from a manufacturer with the speed required; the nuclear pharmacist may simply pre-

.pare the capsule from stock radiochemical NaI-131. At present, all of out NaI-131 comes from Nordion (Canada),

also CIS has an NDA with the USFDA. So, radiochemical NaI-131 goes to France, where it is "blessed", and radio-pharmaceutical NaI-131 comes back to the U.S. and makes:

up 60% of our patient doses. We.don't need the "French connection. Three year tally avoiding France= 270,000.

I-123-hippuran and I-123-MIBG are also examples. I-123-hippuran has been largely replaced by the recent Tc-99m-MAG.:..3 but I-123-MIBG is otherwise unobtainable. Estimated three year tally= 9000. (Before I-123-hippuran was re-placed, .it could

• be obtained commercially but the NDA-approved product was significantly contaminated with I-124 and I-125. If you wanted to decrease patient dose, you bought radiochemical I-123 from Nordion and chemical hippuiic acid and made your own radiopharmaceutical. At Harbor-UCLA, we did this routinely.)

NOTE: (1) Every :example and* classification of activity_

enumerated here had been perfectly legal in _this country uritil April, 1987.' Fifty years of experience showed that there were no problems. The April, 1987 changes in NRC regulations were incompatible with laws regulating pharmacy and medicine in all states and are not compatible with FDA law, regulations, guid~lines, and policies.

(2) The record keeping requirement of the Interim Rule will of necessity be incomplete for certain of these deviations, such as for deviations 1,2,3,7,8,9,10, 24, and 25. However, ample experience with these deviations exists to show no evidence of problems.

f syncor April 17, 1990 Robert Temple, M.D.

Director, Office of Drug Research and Review U.S. Food and Drug Administration 5600 Fishers Lane Parklawn Bldg., 8-45 Rockville, MD 20852

Dear Dr. Temple:

Syncor has been contacted by Carol S. Marcus, Ph.D., M.D. to provide

.information relating to departures from package inserts (labeling) which Nuclear Pharmacists employ, or would like to employ, to improve radiopharmaceutical products. Most departures would normally be considered the practice of pharmacy, or the filling of physicians' pres.criptions as part of their normal practice of medicine.

• Package inserts are understood to be reflections of known drug information only at the time of Food and Drug Administration (FDA) approval of an original New Drug Application (NOA) or later amendments.

A departure from package inserts is, therefore, typically ba:5ed on technical information gained following FDA approval of NDAs for pharmaceuticals or radiopharmaceuticals. By medical history, this has been acknowledged as the practice of pharmacy as long as the prescribing physician is either awate of the proposed departure or has prescribed the departure.

• Were the Nuclear Regulatory Commission (NRC) to regulate with the understanding that there should be no departures from package insert information for radiopharmaceuticals, then technical advancements in Nuclear Medicine would be severely curtailed. The NRC has seen fit to permit changes in clinical indications of radiopharmaceuticals (unapproved uses of approved products), but has severely limited the practice of pharmacy or physician prescribing to make improvements in the compounding and dispensing of radiopharmaceuticals.

The practice of Nuclear Medicine has, therefore, advanced at a far greater rate than the practice of Nuclear Pharmacy. This may also be related in part to the wisdom of the NRC and FDA in not permitting practicing Nuclear Pharmacists to participate as members of their advisory committees. There are Board Certified Nuclear Pharmacists who would be more than willing to serve on such advisory committees.

Regulation of the practice of Nuclear Pharmacy in this manner permits radiopharmaceutical manufacturers to increase sales by using the package insert to severely limit the comptiunding and dispensing capabilities of Nuclear Pharmacists. For example, manufactures can

===:..=.

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control the quantity of radiopharmaceuticals sold*by decreasing the mCi of Tc-99m which can be added during formulation, shortening the shelf life, not adding anti-oxidants to prolong the effective life of products for certain indications, and not including known steps in labeling procedures which decrease preparation time or improve quality control.

GENERAL NUCLEAR PHARMACY CONSIDERATIONS Clinical efficacy of radiopharmaceuticals is most often determined by the specific concentration and stability of the final product, the availability of quality control procedures for radiochemical and radionuclidic purity, and a knowledge of interactions which alter anticipated biodistribution.

Some examples where the experience of Nuclear Pharmacists could have been used to improve the clinical efficacy of radiopharmaceuticals are the following:

1. Protocol for testing product stability should include introduction of air following labeling which would mimic removal of doses prior to storage up to ti me of expiration. There is common agreement that Osteoscan-HDP for bone imaging is not stable for eight hours when the nitrogen atmosphere is compromised while removing doses.

2. Allowing solutions of technetium-99m to stand with heparin forms a complex which behaves like a kidney imaging agent. This should be a precaution when accomplishing In Vivo/In Vitro red blood cell labeling for myocardial perfusion or gastrointestinal bleeding studies.

3. Manufacturers are not re qui red to define the potential effects radionuclidic contamina.nts have on the half life of approved radiopharmaceuticals. This is a special concern in (p,2n) iodine-123 products used for thyroid uptake where the clinical protocol provides for the nuclear medicine technologist to assay a capsule, administer it to a patient, and calculate a 100% value for the capsµle when the patient thyroid is assayed using 13.2 hours2.314815e-5 days <br />5.555556e-4 hours <br />3.306878e-6 weeks <br />7.61e-7 months <br /> as the half-life of the iodine-123.

The iodine-124 radionuclidic contaminant has a longer half life than iodine-123, can reach a 15% concentration at time of expiration, and its high energies are assayed in the thyroid of a patient. This causes the calculated 100% value to be too low, and this results in a significant elevation of the true patient thyroid uptake value (false hyperthyroidism). This error is increased if the assay instrument is not corrected for potential lost counts when patient capsules are assayed.

4. Quality control procedures reflect stability of a radiopharmaceutical only at the time the tests begin, and not at later time intervals when the product is administered to a

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patient. The quicker quality control is completed and a patient is administered a radiopharmaceutical, the more confidence can be placed on the quality control results.

If a quality control procedure is included as part of the Preparation Procedures in a package insert, then the FDA must be responsive to developments which improve quality control whether or not the manufacturer wants to amend the approved NOA.

5. Both the NRC and the FDA were notified that the product labels for MPI-MDP and MPI-DTPA were contributing to misadministrations where DTPA was dispens~d for MOP because of unclear labels, and the MP!

prefix has two. of the three initials of MOP (Attachment 1). No reply was received from FDA, and the NRC suggested contacting the manufacturer (Attachment 2). This error most likely comprises the greatest single cause of patient misadministrations in the past two years, and having written prescriptions will not correct the problem.

6. As manufacturers are not required to submit data for unapproved uses which become routine procedures, nuclear pharmacists become the focal point of information regarding special product preparation requirements, methods which improve product stability, and precautio_ns which maintain clinical efficacy of a product.

Yet manufacturers are allowed to distribute references encouraging their use without amending the Approved NDA.-

• There are specific radiopharmaceutical products where knowledge gained from the. experience of nuclear pharmacists could be useful to the NRC and FDA in its continual review of IND and NOA applications for similar products. The experience of nuclear pharmacists could be used by FDA .

and NRC to ensure proper precautions are introduced into package inserts for unapproved uses of approved products which require departures from existing package inserts.

GENERATORS The preparatiqn of all Tc-99m labeled radiopharmaceuticals begins with eluates from a Mo-99m/Tc-99m Generator. In practice, there are several characteristics of generators which must be understood in order for nuclear pharmacists to compound and dispense consistently high quality radiopharmaceuticali.

Molybdenum-99 is placed on an alumina column, and it is not soluble in saline. It decays to Tc-99m which is soluble in saline, and has a half life of six hours. The Tc-99m decays to Tc-99 which has all of the same chemical properties but negligible radioactivity (carrier). When sterile saline is passed through the column, both radioactive and non-radioactive tech~etium are eluted from the generator.

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The more often a generator is eluted, the* less non-radioactive technetium is present on the column to be eluted, so the specific concentration of Tc-99m is maintained at higher levels. There is also less non-radioactive Tc-99 (carrier) to compete with radioactive Tc-99m when labeling radiopharmaceuticals. Typically, carrier Tc-99 reaches its highest concentrations during shipment from a manufacturer to the end user because of the long interval between manufacturing and the first elution by the user. This is also the time when Mo-99 has the highest specific concentration for producing Tc-99m and Tc-99.

A nuclear medicine department which has a very low patient volume will have more Tc-99 carrier in its elutions than a high volume depart~ent which will elute each generator at least once a day. Nuclear pharmacies have minimal concentrations of carrier Tc-99 because generators are typically eluted more than once a day. With less carrier Tc-99, nuclear pharmacies are able to label radiopharmaceuticals with more Tc-99m than typical hospitals and clinics which must follow package insert guid~lines more closely.

The first elution of a generator received from a manufacturer is either discarded, or used to compound prescriptions or calibration sources for which competition of carrier Tc-99 will not be a factor. This precaution does not appear in product labeling.

Generators eluates contain Tc-99m in a 7+ valence state which must be reduced and maintained in a 4+ valence state while compounding most*

radiopharmaceuticals. The reducing agent commonly used in kits is either stannous chloride or stannous fluoride. This is why kits are manufactured with a nitrogen atmosphere, and stabilized by the presence of an anti-oxidant such a ascorbic acid (Vitamin C). Even though the FDA would permit nuclear pharmacists to stabilize products with ascorbic acid, all attempts to gain NRC approval have failed to date.

As the specific concentration of Tc-99 activity decreases with the age of a generator, the volume of Tc-99m eluate required to compound a kit and radiopharmaceutical doses both increase. This is a time when pharmacists must be very careful not to exceed recommended patient doses (especially pediatric doses) such as MAA particles for lung imaging.**

Generator eluates do not have a preservative, and the recommended time of use has decreased from 24 to 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br />. Most radi opharmaceut i cal s have a recommended six hour time of use regardless of the expiration time of the generator eluate used to compound the product. Why has an arbitrary six hour use time been selected for radiopharmaceuticals when generator eluates used to make them go 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br />, and there has never been pyrogenic responses to kits when they have had longer expiration times? Manufacturer.s would support short times of use in an effort to sell more product, but this also prevents servicing distant customers throughout the entire work day.

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TECHNETIUM-99m DTPA Technetium~99m DTPA kits are one of the products which are sensitive to the presence- of Tc-99 in generator eluates. No commercial product contains ascorbic acid to increase stability, nor are nuclear pharmacists permitted to stabilize kits by the addition of ascorbic acid (Vitamin C).

The preferred MPI-DTPA product is associated with a high percentage of patient misadministrations which could most likely be overcome with a simple change in the design of the vial label.

Unapproved use of Tc-99m DTPA to assess kidney gl omerul ar filtration rate (GFR) values is a common enough use that FDA has required a caution statement for this product to be used within one hour of preparation. Potent i a1 errors in GFR va 1ues are due to both protein binding, and free Tc-99m which is excreted at a different rate.

Stabilizing DTPA products with ascor.bi c acid could prolong the time period for use of DTPA to determine GFR values.

TECHNETIUM-99m MM for LUNG IMAGING Technetium-99m MAA is approved for lung imaging, and several products are available on .the market. This product is. also sensitive to increases in non-radioactive Tc-99 concentrations in generator eluates, but there are no precautions to this in the package labeling. The recommended Tc-99m activity for preparing this product does not permit the administration of sufficiently small enough numbers of particles to meet the recommended pediatric doses (Table 1). The choice is to overdose children, or not follow package insert recommendations which violates current NRC policies.

This may also be a case where manufacturers attempted to decrease Tc-99m activity which can be used in a kit in order to limit the number of doses and increase sales. The FDA has approved adding 100 mCi to a MAA kit with 4-8 million particles, but only 50 mCi to a kit with 3.6-6.5 million particles.

Not all MAA kits have been required to add a suspending agent such as human serum albumin, and these products have a tendency to leave a significant percent of a dose in the syringe even if it is rinsed with patient blood. This warning is not required in the package labeling even though it may lead to false positive patchy lung images due to the administration of too few particles. Administering Tc-99m MAA through a catheter c~n result in the same problem in addition to clumping which results in hot spots in lung images.

If one compares th*e data in package labeling for all Tc-99m MAA products, there are many discrepancies which appear as though there was an attempt to make representations consistent for all products without recognizing actual differences between products (Table 1).

TABL.E I.

Tc-99m MM LUNG IMAGING PRODUCT COMPARISON TOPIC MAL SQUIBB MEDI-PHYSICS NEN CIS l dose X dose ALBUMIN CONTENT MAA (mg) 2.0 1.5 0.11 2.5 1.0 2.0 Human Serum (mg) 0.5 10 5.0 10 TOTAL TIN (mg) 0 .12 0.19 0.09 0.11 0. 12 0.21 AGGREGATES Total x 10 6 4-12 2-7 0.5-1 4-8 3.6-6.5. 12-15 Ave Size (u) 10--40 20,-40 15-90 20-40 15-30 15-90

% Trapped 90 80+ 80+ 80+ 80+ 80+

EXCRETION 24 Hr% 75 No Data 40 20 20 20 LUNG HALF LI FE (Hr) 3.8 2-3 1.0 2-3 5.0 5.0 Indications Lung Yes Yes Yes Yes Yes Yes Venography No Yes No No No No LeVeen Shunt No No No Yes No Yes KIT LABELING Volume Saline (ml) 5-10 1-3 1.3 2-8 2-8 3-5 M~ximum mCi 60 50 3.9-7.8 100 20-50 20-100 Use Time (Hr) 8 6 3 6 6 6 DOSES (I* - 4 mcia Particles x IO Adult .2-1.2 . 2- .7 .2-.7 .2-.7 .2-.7 .2-.7

- Newborn= o.5 mCi per 10-50,000 particles Pediatric 15 year= 2.8 mCi per 200-700,000 particles DOSIMETRY (rad/4mCi)

Lungs 0.88 0.88 0.88 0.88 0.88 0.80 Liver .072 .072 .072 .072 .072 .13 Bladder 2 Hr Void 0.12 0.12 0.12 0 .12 0.12 No Data 4.8 Hr Void 0.22 0.22 0.22 0.22 0.22 0.48 Product Package Inserts Used as Source of Data Mallinckrodt= August 1983 Squibb = March 1987 Medi-Physics Unit Dose = October 1984 Mult Dose = February 1989 NEN DuPont = March 1987 CIS = January 1988

-,j

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I. Mallinckrodt MAA has 75% Tc-99m excretion* in 24 hours2.777778e-4 days <br />0.00667 hours <br />3.968254e-5 weeks <br />9.132e-6 months <br /> which is about 2 to 4 times greater than other products, but radiation dosimetry to the bladder wall is the same for all products.

2. Lung half-lives for MAA products vary from 1 to 5 hours5.787037e-5 days <br />0.00139 hours <br />8.267196e-6 weeks <br />1.9025e-6 months <br />, but the liver radiation dosimetry is the same for all products.

3. CIS radiation dosimetry is different from other products because a method for calculating dosimetry other than using MIRO values was permitted.

4. A pediatric dose of 0.5 mCi per 10,000 particles requires 250 mCi at time of labeling a MAA kit with 5 million particles. This means that soo* mCi are needed for compliance throughout the entire recommended 6 hour6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> time of use (excluding Mallinckrodt which has an 8 hour9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br /> time of use and requires even more Tc-99m).

5. If Mal Ti nckrodt has had a recommended 8 hour9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br /> time of use on its MAA kit for approximately 20 years with no adverse reactions, why should other formulations not have the same time of use unless manufacturers sell more kits with a shorter time? Based on Mallinckrodt's experience, is it improper for nuclear pharmacists to assume identical kits should have identical times of use?

TECHNETIUM-99m MOP for BONE IMAGING Technetium-99m MOP is a bone imaging radiopharmaceutical that is sensitive to carrier Tc-99. Performance of an MOP product is maximized when an anti -*oxidant is present to maintain Tc-99m in the 4+ valence state during initial labeling and throughout the recommended time of use. If Tc-99m becomes disassociated from MOP, it must be maintained at a 4+ valence state to recombine with a MOP molecule.

Manufacturers also maintain i nitrogen atmosphere in MOP vials to help prevent oxidation of Tc-99m. Withdrawal of patient doses immediately after labeling a MOP product introduces air, and compromises the effe~t of nitrogen. Under these conditions, most MOP products wi 11 not be stable through their useful time without the presence of ascorbic acid as an anti-oxidant. Adding ascorbic acid (Vitamin C} after a MOP product is labeled with Tc-99m is optimal to prevent any labeling of the ascorbic acid during the labeling procedures.

The addition of ascorbic acid (2mg/0.1 ml} has not been permitted by the NRC although it is al ready used in MOP products, and the FDA recognizes stabilization of a radiopharmaceutical as the practice of pharmacy. Product stability is recognized in the quality of bone images with higher target to background ratios.

Manufacturers have apparently attempted to increase sales by limiting Tc-99m activity to label MOP, and to maintain recommended time of use to 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br />. The Ma 11 i nckrodt Osteoscan-HOP product has been marketed for over 20 years with an 8 hour9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br /> time of use with no evidence that the

TABLE 2.

Tc-99m BONE IMAGING PRODUCT COMPARISON TOPIC MALLINCKRODT SQUIBB MEDI NEN CIS HDP ..11!1!:_ MOP MOP MOP MOP Quantity Drug (mg) 2.0 IO 20 IO IO IO Anti-Oxidant (mg)

Ascorbic Acid 1.0 2.0 Gentisic Acid 0.56 Stannous/Tin (mg) ci .16 I. 21 0.33 0 .17 0.5 I.I Blood Cone. (% dose) 2 Hours 6.0 5.0 <5.0 No Data

• No Data 4-10 3 Hours 4.0 No Data No Data No Data 3-5 3 4 Hours 3.0 No Data <2.0 No Data No Data No Da Urinary Excretion

(% Dose 24 Hr.) 50 50 50 50 50 50 Preparation Volume Tc 99m (ml) 3-6 2-10 0.5-5 2-8 2-8 1-8

\ T~tal Tc-99m (mCi) 200 200 150 Any* Any* 300 Sp. Cone. (mCi/mg) 100 20 7.5 30 Time of Use (Hr) 8 6 6 6 6 6 Any*= Activity to be determined by labeling experience with generator eluates and quality of clinical studies.

Product Packag~ Inserts Used as Source of Data Mallinckrodt HOP = November 1987 MOP = May 1984 Squibb = November 1982 Medi-Physics= August 1988 NEN Dupont = March 1987 CIS = October 1985

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time should be shortened. There appears to be little reason why all MOP kits could not have their time of use extended to 8 hours9.259259e-5 days <br />0.00222 hours <br />1.322751e-5 weeks <br />3.044e-6 months <br />, or to 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> which is the same as Tc-99m generator eluate used in the labeling procedure.

Tc-99m CERETEC The package labeling for Tc-99m CERETEC is the first time FDA included a quality control procedure as part of the labeling instructions. The procedure requires at least 15 minutes of a 30 minute use time.

Because the quality control results indicate the state of the product only at the time th~ chromatography strips are spotted, the end results do not account for product degradation during the 15 mi nut es of the procedure.

At least two better quality control procedures have been published, but there is* no apparent way for the instructions to be changed by FDA unless the manufacturer wants to amend the NOA on its own accord. The practice of pharmacy should dictate using the best technical data and procedures to accomplish quality control on radiopharmaceuticals that have a procedure described in the package labeling.

Technetium-99m Ceretec is also a radiopharmaceutical that has an unapproved use for an approved drug. The drug can be used to reliably provide Tc-99m white blood cells which enable earlier diagnosis and reduced radiation dosimetry to spleen, liver, and bone marrow than In-

.Ill WBCs. With this increase in safety and efficacy, one w-0uld expect that the NRC would have little problem approving its use by nuclear medicine physicians.

SODIUM IODIDE I-131 THERAPY SOLUTIONS The FDA has not required all Sodium Iodide I-131 Therapy Solutions to have stabilizers, reducing agents, and proper pH although several reports on I-131 volatility were published. Volatility of I-131 from these products endangers pharmacists compounding doses, increases I-131 concentrations released into the atmosphere, and increases exposure to hospital staff who administer therapy doses to patients.

The simple addition of 2 mg EDTA to CIS I-131 therapy solution has decreased volatility of this product by making it the same as the Mallinckrodt product. Air monitoring results in* nuclear. pharmacies indicate decreases in I-131 release into the atmosphere, and the decreased volatility provides increased safety for nuclear pharmacists and hospital staff. The addition of EDTA to the CIS product makes in nearly identical to that of Mallinckrodt Sodium Iodide I-131 for Therapy.

( 8.)

SODIUM IODIDE I-131 THERAPY SOLUTIONS The FDA has not required all Sodium Iodide I-131 Therapy Solutions to have stabilizers, reducing agents, and proper pH although several reports on I-131 volatility were published. Volatility of I-131 from these products endangers pharmacists compounding doses, increases I-131 concentrations released into the atmosphere, and increases exposure to hospital staff who administer therapy doses to patients.

The simple addition of 2 mg EDTA to CIS I-131 therapy solution has decreased volatility of this product by making it the same as the Mallinckrodt product. Air monitoring results in nuclear pharmacies indicate decreases in I-131 release into the atmosphere, and the decreased volatility provides increased safety for nuclear pharmacists and hospital staff. The addition of EDTA to the CIS product makes it nearly identical to that of Mallinckrodt Sodium Iodide I-131 for Therapy.

The package labeling for I-131 therapy solutions contains no warnings about potential exposure to nuclear medicine staff from patients exhaling I-131 following administration of these solutions. This is a case where nuclear pharmacists and or NRC staff could offer advice to the FDA which will increase safety to the health professional~ who have to handle I-131 therapy solutions.

The package labeling for Sodium Iodide I-131 solutions does not contain instructions for determining and using K factors necessary to ensure

• patient doses are within 10% of prescribed quantities. This is area where FDA could benefit from outside expertise.

WHITE BLOOD CELL LABELING PROCEDURES The two major problems with white blood cell labeling procedures is the slow gravity settling rate of red blood cells, and the ability to separate red blood cells (RBCs) from white blood cells (WBCs) because they preferentially label with In-111 Oxine, or convert Tc-99m Ceretec to the hydrophilic form which decreases labeling efficiency.

The use of hetastarch (Hespan) to increase the settling rate of RBCs by at least 30 minutes was used in the WBC labeling procedures since its origin in 1978. Th.is step was not included as an option when In-111 Oxi ne was approved by the FDA even though its use helps maintain viability of WBCs by increasing the time for reinjection of In-11 WBCs, and permits labeling of WBCs for customers 15 to 30 minutes away from a centralized hospital or pharmacy site.

Syncor has developed proprietary procedures for separating RBCs from WBCs, and increasing the Tc-99m labeling of WBCs by at least twice the current published capabilities. Patient care will be the primary benefactor of these improvements in WBC 1abel i ng procedures through Syncor efforts.

(9.)

SYNCOR GUIDELINE FOR COMPOUNDING Tc-99m RADIOPHARMACEUTICALS Based on over 15 years of experience compounding and dispensing Tc-99m radiopharmac*~uticals, Syncor has established corporate guidelines for compounding, dispensing, and specific expiration times (Attachment 3).

These guidelines are designed to emphasize the positive aspects of compounding and dispensing Tc-99m radiopharmaceuticals, and guarding against any negative experiences which have occurred over the years.

These guidelines are specific to Syncor nuclear pharmacies because they are based prim~rily on Syncor experience and not that of the nuclear pharmacy industry.

SUMMARY

The practice of Nuclear Pharmacy is a recognized specialty, and the expertise gained by compounding and dispensing radiopharmaceuticals has not been tapped by either the FDA or NRC. Although nuclear pharmacists have been accused of making changes in package labeling only to increase profits, this is far from the real Nuclear Pharmacy practice.

Some radiopharmaceutical changes a nuclear pharmacist makes is measured almost immediately in patient images. Communications between nuclear physicians and nuclear pharmacists are immediate when it comes to patient care. ~hftnges which increase* radiation safety, product viability, produtt stability, quality control, and more efficient*

utilization of products are not always measured jmmediately .

. Just as nuclear physicians consult with nuclear pharmacists, the FDA and NRC could also benefit from better utilization* of the knowledg*e base which practicing nuclear pharmacists can provide. The FDA and NRC may have to first recognize that nuclear pharmacists, nuclear technologists, and nuclear physicians operate as a professional team on a daily basis to provide the best patient care possible. As long as each member of the team is *:successful in practicing their specialty, medical care is maximized.

Whenever the FDA or NRC decides to take advantage of the expertise available from any specialty of the nuclear medicine team, .they would find a ready source of information and experience to help them. It is not obvious why the FDA or NRC in their wisdom have not used. a broader base of advisors in matters relating to radiopharmaceuticals and Nuclear Medicine.

• Sincerely, of)-/7~

Dennis R. Hoogland, Ph.D., BCNP Manager Technical Development and Training cc: Richard E. Cunningham, USNRC Carol S. Marcus, Ph.D., M.D., UCLA

ATTACHMENT 3.

SYNCOR GUIDELINES FOR COMPOUNDING Tc-99m RADIOPHARMACEUTICALS

• I I l S YNCOR r

Guidelines for Compounding Tc-99m Radiopharmaceuticals September 1, 1989

9/89 SYNCOR GUIDELINES FOR RADIOPHARMACEUTICAL KIT PREPARATION TABLE 1. TECHNETIUM-99M MACROAGGREGATED ALBUMIN (MAA)

Tc-99m Manufacturer Activity(mCi) (ll Volume(ml} Expiration(2)

DuPont 125 mCi 2-8 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> (3.6-6.5M particles)

CIS 340 mCi 3-5 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> 12-15M particles Squibb 115 mCi 1-3 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> 2-7M particles Medi+Physics 50 mCi up to 3 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> 1.5-2.5M particles Mallinckrodt 200 mCi 5-10 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> 4-12M particles I. Amounts used for MAA based on 200,000 particles and 5 mCi per dose, average number of particles per vial at time of preparation. These values may be increased to account for decay up to the time of calibration of the dispensed doses. For example, Dupont MAA which is to be used 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> after preparation could be compounded with 200 mCi of Tc-99m.

2. Not to exceed the 12 hour1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> expiration of the Tc-99m elution.

Page 1

9/89 SYNCOR GUIDELINES FOR RADIOPHARMACEUTICAL KIT PREPARATION TABLE 2. TECHNETIUM-99M BONE* IMAGING AGENTS Maximuml Tc-99m Product Manufacturer Activity(mCi) Volume{ml) Expiration MOP Squibb 400 mCi 0.5 - 5 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> MOP Medi+Physics 400 mCi 2 - 8 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> MOP DuPont 200 mCi 2 - 8 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> MOP CIS 200 mCi l - 8 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> MOP Amersham 100 mCi 1 8 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> HOP Mallinckrodt 150 mCi 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> PYP DuPont 200 mCi 3 - 7 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> PYP Squibb 75 mCi 2 - 4 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> pyp Mallinckrodt 100 mCi 1 - 10*m1 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br />

1. These activities are maximums and lesser amounts should be used where experience dictates.

Page 2

9/89 SYNCOR GUIDELINES FOR RADIOPHARMACEUTICAL KIT PREPARATION TABLE 3. TECHNETIUM-99M DTPA Tc-99m Procedure Manufacturer Activity(mCi) Volume(ml) Expiration Brain Scan Squibb 300 mCi up to 5 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> Renal Scan Squibb 300 mCi up to 5 ml 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> Aerosol Squibb 300 mCi up to 5 ml 6 hours Assess GFR Squibb (See Note I)

Brain Scan Medi+Physics 300 mCi 2 - 8 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> Renal Scan Medi+Physics 300 mCi 2 - 8 ml 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> Aerosol Medi+Physics 300 mCi 2 - 8 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> Assess GFR Medi+Physics 50 mCi 2 - 8 ml 1 hour1.157407e-5 days <br />2.777778e-4 hours <br />1.653439e-6 weeks <br />3.805e-7 months <br /> CIS DO NOT USE THIS PRODUCT!!

1. Squibb DTPA (Ca-DTPA) is not recommended to assess GFR even though it is listed in the package insert. Syncor experience shows Medi+Physics DTPA (Na-DTPA) is the drug of choice for GFR.

TABLE 4. TECHNETIUM-99M GLUCOHEPTONATE Tc-99m Procedure Manufacturer Activity(mCi) Volume(ml) Expiration Brain Scan DuPont 150 mCi 3 - 7 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> Renal Scan Dupont 150 mCi 3 - 7 ml 4 hours4.62963e-5 days <br />0.00111 hours <br />6.613757e-6 weeks <br />1.522e-6 months <br /> Page 3

9/89 SYNCOR GUIDELINES FOR RADIOPHARMACEUTICAL KIT PREPARATION TABLE 5. TECHNETIUM-99M HEPATOBILIARY IMAGING AGENTS Tc-99m Product Manufacturer Activity(mCi) Volume(ml) Expiration Choletec Squibb 200 rnCi 2 - 5 ml 18 hours2.083333e-4 days <br />0.005 hours <br />2.97619e-5 weeks <br />6.849e-6 months <br /> (Note 1)

Hepatolite Dupont 150 rnCi 2 - 5 ml 8 hours I. Preservative in forrnul at ion a11 ows 18 hour2.083333e-4 days <br />0.005 hours <br />2.97619e-5 weeks <br />6.849e-6 months <br /> expiration. Tc-99m must have Mo-99 concentration within limits at time of.expiration.

TABLE 6. TECHNETIUM-99M LIVER IMAGING AGENTS Tc-99m Product Manufacturer Activity(mCi) Volume(ml} Expiration Sul fur CIS 500 rnCi l - 3 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> Colloid Sul fur Ma 11 i nckrodt 400 rnCi O. l - 5 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> Coll aid Sul fur Squibb 500 rnCi 0.1 - 5 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> Colloid Sul fur Medi+Physics 400 mCi 0.5 - 5 ml 12 hours1.388889e-4 days <br />0.00333 hours <br />1.984127e-5 weeks <br />4.566e-6 months <br /> Colloid

- Microl ite DuPont 75 mCi 2 - 8 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> Page 4

9/89 SYNCOR GUIDELINES FOR RADIOPHARMACEUTICAL KIT PREPARATION TABLE 7. TECHNETIUM-99M HUMAN SERUM ALBUMIN (HSA)

Tc-99m Product Manufacturer Activity(rnCi) Volurne(ml) Expiration Multi dose Medi+Physics 200 rnCi 3 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> Unitdose Medi+Physics 70 rnCi 1.3 ml 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> TABLE 8. TECHNETIUM-99M ,.OMSA Tc-99m Product Manufacturer Activity(mCi) Volume(ml) Expiration DMSA Medi+Physics 44 - 88 rnCi 2.2 ml reagent 30 minutes 2.2 -4.4 ml Tc-99m TABLE 9. TECHNETIUM-99M HMPAO (Ceretec)

Tc-99m Product Manufacturer Activity(mCi) Volurne(ml) Expiration HMPAO Arnersham 30.mCi up to 5 ml. 30 minutes Page 5

!It LIST. OF APPENDICES I. Section 104, Atomic Energy Act II. 42USC 10001 - 10008 III. FR Article lifting AEC exemption, 1975 IV. Chapter explaining transfer of responsibility

v. FDA Nuclear Pharmacy Guideline VI. 21 CFR 361.1; Metabolic research regulations VII. Package insert departures for non-r.adioactive drugs

APPENDIX I.

Section 104, Atomic Energy Act

APPENDIX II.

42 USC 10001-10008

§ 10001 TITLE 42-THE PUBLIC HEALTH AND WELFARE as the Omnibus Budget Reconciliation Act of 1981. (Pub. L. 97-35, title IX, § 977, Aug, 13, 1981, 95 For complete classification of this Act to the Code, see Stat. 599.) ** '

Tables.

SECTION REFERRED TO IN OTHER SECTIONS § 10003. Definitions

.This section ls referred to in section 9911 of this Unless otherw~se expressly provided, for pur*

title. poses of this chapter, the term- **

CHAPTER 107,-CONSUMim-PATIENT (1) "radiation" means ionizing and nonlonlz.

ing radiation in amounts beyond nonnaf RADIATION HEALTH AND SAFETY background levels from sources such as med!,*

Sec. cal and dental radiologic procedures; .

10001. Statement of findings. (2) "radiologic procedure" means any proce--'

10002. Statement of purpose. dure or article intended for use in-10003. Definitions.

10004. Promulgation of standards. <A> the diagnosis of disease or other medi-10005. Model statute. cal or dental conditions in humans Clnclud, '.

10006. Compliance. ing diagnostic X-rays or nuclear medicine :'

Ca) Implementation by Secretary. procedures); or (b) Accreditation or certification pro- CB) the cure, mitigation, treatment, or.:

gram.

(cl Noncompliance; proposed legislative prevention of disease in humans; changes. that achieves its intended purpose through

• Cd) Monitoring; report to Congress. the emission of radiation; (el Existing standards and guidelines.

10007. Federal radiation guidelines. (3) "radiologic equipment" means any radk'

• 10008. Applicability to Federal agencies. ation electronic product which emits or de- 1 tects radiation and which is used or Intended;

§ 10001. Statement of findings for use to-

• The Congress finds that- CA) diagnose disease or other medical or' (1) it isin the interest of public health and dental conditions (including diagnostic X*:

safety to minimize unnecessary exposure to ray equipment); or potentially hazardous radiation due to medi- (B) cure, mitigate, treat, or prevent dis,.

cal and dental radiologic procedures; ease in humans; (2) it Is In the interest of public health and that achieves its intended purpose through safety to have a continuing supply of ade- the emission or detection of radiation; quately educated persons and appropriate ac- (4) "practitioner" means any licensed*

creditation and certification programs admin- doctor of medicine, osteopathy, dentistry, po-_

istered by State governments; diatry, or chiropractic, who prescribes radio-:

(3) the protection of the public health and safety from unnecessary exposure to poten- logic procedures for other persons; tially hazardous radiation due to medical and (5) "persons who administer radiologic pro-dental radiologic procedures and the assur- cedures" means any person, other than a ance of efficacious procedures are the respon- practitioner, who intentionally 'administers*

sibility of State and Federal governments; radiation to other persons for medical pur-'

(4) persons who administer radiologic proce- poses, and includes medical radiologic tech*:

dures, Including procedures at Federal facili- nologists (including dental hygienists and as, ties, should be required to demonstrate com- sistants), radiation therapy technologists, and

• petence by reason of education, training, and nuclear medicine technologists; experience; and (6) "Secretary" means the Secretary of (5) the administration of radiologic proce- Health and Human Services; and . .

dures and the effect on individuals of such (7) "State" means the several States, the.

procedures have a substantial and direct District of Columbia, the Commonwealth of,*

effect upon United States Interstate com- Puerto Rico, the Commonwealth of the

• merce. Northern Mariana Islands, the Virgin Islands, (Pub. L. 97-35, title IX, § 976, Aug. 13, 1981, 95 Guam, American Samoa, and the Trust Terri* ,

Stat. 598.) tory of the Pacific Islands.

SHORT TITLE (Pub. L. 97-35, title IX, § 978, Aug. 13, 1981, 95

• Stat. 599.)

Section 975 of subtitle I(§§ 975 to 983) of title IX of Pub. L. 97-35, provided that: "This subtitle [enacting § 10004. Promulgation of standards this chapter] may be cited as the 'Consumer-Patient Radiation Health and Safety Act of 1981'." (a) Within twelve months after August 13, ::

1981, the Secretary, in consultation with the:,:

§ 10002, Statement of purpose Radiation Policy Council, the Administrator of '.

It Is the purpose of this chapter to- Veterans' Affairs, the Administrator of the En* **

( l) provide for the establishment of mini- vironmental Protection Agency, appropriate*,

mum standards by the Federal Government agencies of the States, and appropriate profes* .

for the accreditation of education programs sional organizations, shall by regulation pro*

• for persons who administer radiologic proce- mulgate minimum standards for the accredita* ..

dures and for the certification of such per- tion of educational programs to train indivld* :*

sons; and uals to perform radiologic procedures. Such .

(2) insure that medical and dental radiolo- standards shall distinguish between programs ,

gic procedures are consistent with rigorous for the education of <1) medical radiologic tech**

safety precautions and standards. nologists (including radiographers>, (2) dental

Page 1481 TITLE 42-THE PUBLIC HEALTH AND WELFARE § 10007 auxiliaries (Including dental hygienists and as- (3) such program is consistent with the sistants), (3) radiation therapy technologists, mm1mum Federal standards promulgated (4) nuclear medicine technologists, and (5) such under this chapter for such program.

other kinds of health auxlliaries who adminis-ter radiologic procedures as the Secretary de- (c) Noncompliance; proposed legislative changes termines appropriate. Such standards shall not Absent compliance by the States with the be applicable to educational programs for prac- provisions of this chapter within three years titioners. after August 13, 1981, the Secretary shall (b) Within twelve months after August 13, report to the Congress recommendations for 1981, the Secretary, in consultation with the legislative changes considered necessary to Radiation Policy Council, the Administrator of assure the States' compliance with this chapter.

Veterans' Affairs, the Administrator of the En-vironmental Protection Agency, interested (d) Monitoring; report to Congress agencies of the States, and appropriate profes-sional organizations, shall by regulation pro- The Secretary shall be responsible for contin-mulgate minimum standards for the certifica- ued monitoring of compliance by the States tion of persons who administer radiologic pro- with the applicable provisions of this chapter cedures. Such standards shall distinguish be- and shall report to the Senate and the House .of tween certification of (1) medical radiologic Representatives by January 1, 1982, and Janu-technologists (including radiographers), (2) ary 1 of each succeeding year the status of the dental auxiliaries (including dental hygienists States' compliance with the purposes of this and assistants), (3) radiation therapy. technolo- chapter.

gists, (4) nuclear medicine technologists, and (e) Existing standards and guidelines (5) such other kinds of health auxiliaries who administer radiologic procedures as the Secre- Notwithstanding any other provision of this tary determines appropriate. Such standards section, in the case of a State which has, prior shall include minimum certification criteria for to the effective date of standards and guide-individuals with regard to accredited education, lines promulgated pursuant to this chapter, es-practical experience, successful passage of re- tablished standards for the accreditation of quired examinations, and such other criteria as educational programs and certification of radio-the Secretary shall deem necessary for the ade- logic technologists, such State shall be deemed quate qualification of individuals to administer to be in compliance with the conditions of this radiologic procedures. Such standards shall not section unless the Secretary determines, after apply to practitioners. notice and hearing, that such State standards (Pub. L. 97-35, title IX, § 979, Aug. 13, 1981, 95 do not meet the minimum standards prescribed Stat. 599.) by the Secretary or are inconsistent with the purposes of this chapter.

§ 10005. Model statute (Pub'. L. 97-35, title IX, § 981, Aug. 13, 1981, 95 In order to encourage the administration of Stat. 600.)

accreditation and certification programs by the States, the Secretary shall prepare and trans- § 10007. Federal radiation guidelines mit to the States a model statute for radiologic procedure safety. Such model statute shall pro- The Secretary shall, in conjunction with the vide that- Radiation Policy Council, the Administrator of (1) it shall be unlawful in a State for indi- Veterans' Affairs, the Administrator of the En-viduals to perform radiologic procedures vironmental Protection Agency, appropriate unless such individuals are certified by the agencies of the States, and appropriate profes-State to perform such procedures; and sional organizations, promulgate Federal radi-(2) any educational requirements for certifi- ation guidelines with respect to radiologic pro-cation of individuals to perform radiologic cedures. Such guidelines shall-procedures shall be limited to educational Cl) determine the level of radiation expo-programs accredited by the State. sure due to radiologic procedures which ls un-(Pub. L. 97-35, title IX, § 980, Aug. 13, 1981, 95 necessary and specify the techniques, proce-Stat. 600.) dures, and methods to minimize such unnec-essary exposure;

§ 10006. Compliance (2) provide for the elimination of the need (a) Implementation by Secretary for retakes of diagnostic radiologic proce-dures; The Secretary shall take all actions consist- (3) provide for the elimination of unproduc-ent with law to effectuate the purposes of this tive screening programs; chapter.

(4) provide for the optimum diagnostic in-(b) Accreditation or certification program formation with minimum radiologic exposure; A State may utilize an accreditation or certifi- and cation program administered by a private entity (5) include the therapeutic application of if- radiation to individuals in the treatment of (1) such State delegates the administration disease, including nuclear medicine applica-of the State accreditation or certification pro- tions.

gram to such private entity; (2) such program is approved by the State; (Pub. L. 97-35, title IX, § 982, Aug. 13, 1981, 95 and Stat. 601.)

ii:

§ 10008 TITLE 42-THE PUBLIC HEALTH AND WELFARE Page 148~

§ 10008. Applicability to Federal agencies SUBCHAPTER I-DISPOSAL AND STORAGE 0 Sec.

HIGH-LEVEL RADIOACTIVE WASTE, SP Ca) Except as provided in subsection Cb) of NUCLEAR FUEL, AND LOW-LEVEL RADIOA this section, each department, agency, and 'in- TIVE WASTE .. :: 't strumentality of the executive branch of the Sec.

• dt..... 10142. D Federal Government shall comply with stand- 10121. State and affected Indian tribe particlpaUo 10143. 'I' ards promulgated pursuant to this chapter. In development of proposed repositories

• 10144. C Cb)Cl) The Administrator of Veterans' Affairs, defense waste. "'>.

through the Chief Medical Director of the Vet- (a) Notification to States and al! 10145, 'I erans' Administration, shall, to the maximum Indian tribes. *.-f

• extent feasible consistent with the responsibil- (bl Participation of States and a!!cc p Indian tribes.

• ities of such Administrator and Chief Medical 10151. F Director under title 38, prescribe regulations PAHT A-REPOSITORIES FOR DISPOSAL OF HIGH* 10152. .A RADIOACTIVE WASTE AND SPENT NUCLEAR Fuc.~

making the standards promulgated pursuant to this chapter applicable to the provision of ra- 10153. I:

diologic procedures in facilities over which the 10131. Findings and purposes. 10154. 1 Administrator has jurisdiction. In prescribing 10132. Recommendation characterization.

of candidate sites for and implementing regulations pursuant to this (a) Guidelines.

subsection, the Administrator shall consult Cb) Recommendation by Secretary Lo with the Secretary in order to. achieve the President. ' 10155. ~

maximum possible coordination of the regula- (cl Presidential review of recommen tions, standards, and guidelines, and the imple- candidate sites. i,~:

mentation thereof, which the Secretary and Cd> Continuation of candidate' r:

the Administrator prescribe under this chapter. screening.

C2) Not later than 180 days after standards (el Preliminary activities.

(f) Timely site characterization.

are promulgated by the Secretary pursuant to 10133. Site characterization.

this chapter, the Administrator of Veterans' Af- Cal In general.

fairs shall submit to the appropriate commit- Cb) Commission and States.

tees of Congress a full report with respect to (cl Restrictions.

the regulations (including guidelines, policies, Cd) Preliminary activities.

and procedures thereunder) prescribed pursu- 10134. Site approval and construction ant to paragraph Cl) of this subsection. Such tion. 10156.

report shall include- (a) Hearings and Presidential rccomm CA) an explanation of any inconsistency be- dation.

(b) Submission of application.

tween standards made applicable by such reg- (c) Status report on application.

ulations and the standards promulgated by (d) Commission action.

the Secretary pursuant to this chapter; (el Project decision schedule.

CB) an account of the extent, substance, and (fl Environmental impact statcmen results of consultations with the Secretary re- 10135. Review of repository site selection. .;< 10157.

specting the prescription and implementation (al "Resolution of repository slllnll of regulations by the Administrator; and proval" defined, *;- J PAR CC) such recommendations for legislation (bl State or Indian tribe petltlons;:~'.-

(c) Congressional review of petltlonL'.-. 10161.

and administrative action as the Administra- (d) Procedures applicable to the Sen&

tor determines are necessary and desirable. Ce) Procedures applicable to the Ho (3) The Administrator of Veterans' Affairs of Representatives.  : 1 ;,;

shall publish the report r.equlred by paragraph (fl Computation of days. *, '1 l':'

(2) in the Federal Register. (g) Information provided to Congr 10136. Participation of States. . ,::, :*;"

(Pub. L. 97-35, title IX, § 983, Aug. 13, 1981, 95 <al Notification of States and **a1r Stat. 601.) tribes. ****11 (bl State participation

• 1n rep CODIFICATION siting decisions. ,,,,:,

(cl Financial assistance. PA Title 38, referred to In subsec. (b)(l), in the original Cd) Additional notification and co read "subtitle 38", which for purposes of codification 10171.

tlon.

was translated as "title 38" as the probable Intent of 10137. Consultation with States and affected Congress. tribes.

(a) Provision of Information. .

CHAPTER 108-NUCLEAR WASTE POLICY (bl Consultation and cooperation.".

(cl Written agreement. ' SUBCH..A.

Sec. 10138. Participation of Indian tribes. _ AND r 10101. Definitions. (al Participation of Indian tribes"' AL o:

10102. Separability of provisions. *pository siting decisions. -:;;~;; AND~

10103. Territories and possessions. Cb) Financial assistance. '.'* :-,1:

10104. Ocean disposal. 10139. Judicial review of agency actions.  ; . .;  :. 10191.

10105. Limitation on spending authority. (a) Jurisdiction of United States co 10192.

10106. Protection of classified national security in- of appeals.

• 10193.

formation. Cc) Deadline for commencing actlo 10107. Appllcablllty to atomic energy defense activi- 10140. Expedited authorizations.

ties. (a) Issuance of authorizations, 10194.

Ca) Atomic energy defense activities. (b) Terms of authorizations.

Cb) Evaluation by President 10141. Certain standards and criteria, Cc) Applicability to certain repositories. (a) Environmental Protection 10108. Applicability to transportation. standards.

APPENDIX III.

FR Article lifting AEC exemption, 1975

- Adit TIIf??MfiES1&i: bHt; A J.....J*IIC.J .. ,&..IUI u1,1 Ai A 18-*

Title 21-Food nd Drug, CHAPTER I-FOOD AND DRUG ADMINIS-TRATION, DEPARTMENl. OF HEALTH, RULES AND k&GULATIONS order c.ttect.1ng a tra.ns!er or re&ponsl-bllity for radloa.ctive blol0trit:al products from the Bureau or Biologics t,o the i I I

d dimiJ..il\.t.,,, t.h possJbllit)* c! o.c-tra,t1ve c1e1AYs ln forv:arding U1e essa.n* Wormallon to the NRC or EDUCATION, AND WELFARE Bureau o! Drugs. eement Bt.a.t.es. Commcn~ 11.ho commenta on U1e P?'OPo!Sal v:ere re* pouited out that the pn,posed re'-rul:.-

l'POCkct Nu. '7SN-o00 7 J ceived from ~1 different. sources; nn.mel~*. ticln does not provide a pr~u:-e lo:*

RADIOACTIVE NEW DRUGS AND hospitals, un.tveri:lties, pro!easiomil onta* n~YlnB' 1.be NRC &nd AgTeement Sta.te RADIOACTIVE BIOLOGICS ni=tlons, tre.de usociatiom;, manufa(.* ai.t.horiUes the.t the FDA hB-~ sporo1*r*c.

Termtmaticr1 of Exemptio"s turen. Agreement States (i.e., Stat~ ~ NDA or issued ~ bioJov,ic.'\1 pru<rnc:

which, under tormll.l aireement "11,*ltll t.he U~e.

Ill :i notice of Propoi;ed rule mnkinc NRC, are authorized to llcen:ie, under frhb; proposed reirulat.1on "as net :1: -

publli;hcd in thr. I-'EDERAt. REGISTI:k o! Federal la.v:, peri;ons enga(,!ed 1n the Poi:* te~ded to preclude I.he sponsor !rorr. !o1 -

July 29. 1974 (39 FR 27538.*, the CommL5* lles.1;1on, W!e. or transfer or react.or-pro- w~ding t.he S1.11n.marr o! In!ormat101:

liioner o! Food and Drugs proposed to duced radionucl!des in t.heir resi:,ective ciltectJy to tbe NRC or Ag.cement State~

terminate t.he present exempU011 !or raclioa.ctive new drnas (illcludi.Dg racl1o-i;ta,Le$/, a.nct State health departments.

The major ILNIIJl o! concern a.-; ex-ne r,ropo.sa.l war;'merely o. service v;:i,1eh

.P't)A would pr0vide to IND sponsors nnt.i ncti\.. e biolo(rtcnl productsl for lnvesti1;ri1.* . pressed by the comments were the com- id the Fe~eral and St.ate lice?llmg a,ze1;-

tionul use from uew drUg reau1remen~ :posjt.ion of the Radioa.cti~ Drur. Re* ci~ I.Cl expedite the proce..ssin(? of b-and c1a.ss1rr. by w;e, rndioacuve drugi; . 5 ea.rch committee (proposed a,; the iir.ig a.ppllcauous. The summar;* o:

elt.ncr n.s "new drui;s" or as renernlly Ra.dlat1on Safety Committee>, tbe use 0 t nnatioo serves no regulatory pur-recognl7.ed o.s safe and efiectfvc !or their Stn.te l\.dVisory committees. radl:a.tlon tor the FDA. Fa.1.lure of the Th-P intended ui;e s.nd therefore not ..new dosimetry, procedures tor i,rovidmg the II ta0r t.o i;,ubmit the Swrunary or In-d:rugi; v.*hcn UE>ed under the conditions summary ot l.niormntion on radJoa.etive f=~n. or to authorize its telea.se tn specified, J:nterested ~rsons were in- c:'lMliS for 1nvestjgat1onal use a.nd the 11

• g agencies, would not alter tile vit.ed to submi~ eommento on the proposal "Rep0rt on Research use o! Radioa.ctive status of the :IND.

by September 27, 1974. Drug to the NRC and a.ppropriate !The Commissioner had Intended that The Comm1Ss1oner o! Food and Drug-s Agreement st.ates, mnlto.tion on Jlhar- t~e relea.&e o! the Summary o! Informe.-

i!; t<:rminating the present uemot.lon tor macologlc.al dooe !or reaea.rcll not under tibn to Federal n.nd State lice~ bod-ra.dioacUvc drug.~, Including rt.d!oactlvc an lND, and the o.ppltcabUity of the i'lS would not wa.ivc any confldent1.ality E

bJoJcifl,cnl products, from Ule inve$til!a- propQaed regula.t.ion to ra.cliopharma.cies. tq ,r.b.lJ:h the sI>ODBor of the mD would tional new drug requirements of the Fed* E1Q"ht comments l!\lpported the propesal ~ entH~ed unl3er tne FDA Publle l.n!or-er.al Food, Drug, and Cosmetic Act. The 1n i:,rinclple but. offered 1wniest1oru: for zziad.on regU.lattons <21 CFR .Pan 4; 21 Pood and Drug Admlnistratton CP'DA) ls modification, cla.r!.e.c!ltion. a,i:1d addition dP'R 312.*: and 21 CFR 314.14), Under establis.hinll res-ulatlon.~ to MBUJ"e that to &Ome areas. The principal comment.a n:gUJ.&tions, FDA records which a.ft.er August 25, 1975 all radioa.cUve received 11.Dd thill Comml.U.lon'a conclu- . normally exempt .from c11sclosure drugs, except those tor oertaln r~rch srons are a.s follows: exiltence and contenu of u.n INDJ uses, introduced into int.erst.ate commerce be diacloaed. wUhOut requiring clti;-

are subJcct to a "Notice of Claimed In- In:rxNinoN OT" RADioAC'l'lYE Diroc: osure to the publi'c at !Aree. to a. de-veatlgational Exemption for a. New Drug" 1. One comment pointed out tha.t ill ~ t or a.,ena-t.hat ha.! concurrent CIND 1

• an

• a.oprovad new drug applica* t 312.1 the add1t1oll21l 1n!ormat.1ori to be Jµr1sclict1on aver the matur 11.JJd separate tion <NDA 1 , or a blololfical product supplied 1n new lte~ 6.d, 10.a. ILrld 16 lU,al authonty t.o obt&ln the apecIBc ln-llcensc. lt1 add.iU011, the FDA is eatab- o! Form FP-1571 1B re<iulred o01y 11 the .f);lrma~on Involved, 21 <:FR 4..8~. The

!d llshing reR"Ulations i;etung f0rth &~cific inveattga.tional drwr ts a. "radioa.etive JJRC (11.lld through it. the Acreement cond1Uon.s ui).(!er which ridioactlve c1ru~s drui." but tha term "radio11,,Ct1ve drug" 1.1. 4tate.&l would satisfy tbeae criteno.. The for eert.nin ret1earch uaes, other than not deflned in the 1>roPo~d regulation. liecul&tioris require, however. t.bat IUCI\

cllnica.l trialS to detemune safety tmd et- The commias1oner hM determlned 4l,eclosure "be pursuant to an a.,reemen~

Zecttveness, arl' not aubJect. ro the new that a .. raclloa.ctive drwf' iii any ub- '1&t ~e rec.ore! sha.11 not be .turt.her du-drug requirements o! t.hc act. i;t.a.nce de.fined as a drug In ~ion 201 by the other department or agency Tha Commii;i;Joncr, for the purpose of <gl ci:, of the ll'ederal i;1ood, Drug. alld pt ,nt.b Ule writ.ten ~rmilJslon o!

l!lll orderly development of regulations Cosmetic Act which. exihlblts POnt.ane- Food and Drug Admini!ltration." Thi' rel.D.ting to Ulc establWUnent or proce- oui; disintegration or un1table nuclei h.u l.n!ormed the FDA that. \t would dures !or codlfylt11r old drug monographs wilh the emission o! nuclear pa.rtli;.les or an-ee to thl..l. restriction and would for prescription drugs which arc 111:en- photoni; a.nd includes o.ny nonradioact.1Ye ILISW't a.ny con.Qdentia.1 treatment erall,v recognlzed o.s sate and el:1ect1vc reagent klt or nuclide genera.tor wbicl'l the Summary or In.formation.

a.nd not misbranded, has redesiimated 1.~ intended to be used in t.he pn!parat.lon The COmm.iBBioner belin-es that, under propoi;ed nev; 21 Cl"R Part 370 e.s 21 cm o! a.n)' such i.ubstance. The tenn "radio- circwmt.e.nee11, nt.a1ning the Sum*

Part 361 and liml~d it to drugs used active* drug" tnr.ludes a "radioac:tive ot In.formt.Uon would not be justi-1n resenrch, All future old drug mono- b1oloQ"ical pr0duct" a,.,; defined iri 21 CFR becllUBe the admlnl.strative i:,roblcmr gni.ph,; * !or such drugs wlll be incct* 600.3 <ee J. 'I'hili definlUon. does not in* hk:h would a.rue are too numerou,.

porn.ted int(') Part 361. elude d~r; such as carl)on-conta1n1ng st, epa,rate ai;

.ecments would be rP-Thc U.S. Nm:Ico.r Regula.torr Commli-* compounds or potasstu.m-contaJning sa.1ta for ea.ch of Ulc 25 Agreement sion <NRC,, n new agent'y cree.t~d b~* which contain trace g\UU'ltities .or na- tes; besides the practicnl difiiculttc~

PUb, L. .93-438 and EXecutive Order tumll;- occurring rt,dJonuclldes. section volved, the lenllt-y of these agreement~

11834, assumed t.hc llcensin,: and related SI0,3 llu ~n amended to u1clude this uld be ill dOubt, since the Ag.-eement re!l'ulatory responslbll1tics of th!! lormer definition In paI'llt?'l'IIPh ll'l,, tes derive autncrity from the NRC:.

Atomic Ener~_,. Commission <AEC* on* oncU~*. each IND 1ubn1isslon ,,:ith :1 Jarman* 19, Hl75. To conform to thi:*: IND R£'1t'IM:"'-£NTS " 011 RADIOM'TI\'.C umman* of In!ormation "*ould havP. tu organi7..ut.ional chancr.. all re!eren,:cs to Nrw *onuc,; u.amined to determine in which stntr.:1 th~: AEC hl this reB"Ulation .11.nd in the  :.i. SevP.rnl comm,nt.~ augge.,ted Ulo.t e IND druc ~ht be used: thoi;c ,;1:it11 preamble h:we been changed lot.he NRC': the summary o! InJonna.tion e.s reQulrcd greemenu for confidentl11,lity would be Ill the quotntion from and discu!;Slon o! b:,- f 31:!.l be to~*1uded directl,v b~* the notiAed. but those w1t11out, and thoi,1*

c.ommenta received from members of the manufacturer to the NRC or Agreement under NRC jurl.Sdlction. 9,*ould not br public on thii; proposed resul&ttm1, refer- Stl:lW-l'> rntMr than by the Food and Drui;: iio~ed. ln .short, providing this eervii*~

enc.ei; t.o the AF.C ha.ve been chanri:cd to Admini!;t.ration. such 11. Pl'Ocedure v.-oul<l w0Uld becoi:nc very complicated. One :il-thr. NRC evl'n ~oup:11 the* comments enh;m~L* the mnnufllct.urens enort.!. w ten,.a.t.!ve. to provide th11t an expllcit from the public were tno.de prim* to u1e protect the con!idcntiallt~* of any pro- w11.fver or con!l.denUalltY be r;igncd b~*

orl%aniznt.ional chan11:e. pricto.r~* infoimaUon contained ln the the IND sponsor 11 he chose to submi!

EL~cwhere in U1is ISSuc ct the J"£D1:K1.L i;umm.C1r::. would frp.1: the FDA from the Summa.n* or Information. seemrc!

Rrcm,Ttr. the C:ommlssloner is tr.,rnln~ an f\11*th1:r ndminlstrntivr. '111,'0l'klmu:!. 11nd unlikeJ::,* to gl!nerate 11, liii;niticant nun,-

.I...J*~~

RULES AND REGULATIONS 31.29!1 ber or CIMI~ 1n wbtc:'h l"DA coUld C11aclote 'l:be Coauntaaioner eonclud<<s that tt 1., tSeals. The comment f\lrtht'r s~-

tne Bummary of ln!ormatum. lt. mi.ht noL uccf:a:5&17 Lo ame11d ILl1 ewLln1 IND that a Cle1\n1\ive atat.e1211l1lt. .,., .. ~

al.lsu cuu.Cwe- .svo1~,:,ri, am.I lcMI i.o 111'- tor

• non.r&dioactive l.nveaUgatl.onal new nacde tecosnizinl' 1.he dJfference bc,-

rc,ncow or untni.cndod wa.lvcra, drug 1t Lhe dl'Ug I& "L.a~u1a<l" ft'ILh a ra- ~wccu Uu,e two typea o! phal"maccut.i-

• TneretuN the conunu,.iuoner has de~ dlonuclido ln a.ccord.lulee with t.he li&.u* cua, well aa clear gulc1ellnes aetu11~:

it,atlo114 r.e, to1*t.h hi t ~81.1 <propoaed !ort.h. ~ wurk&lllt: !urmat troi:n wlll~:11 lt!~~I lLt:111 10 !r0111 I.In: µru1,vi,e4 Cllllil:il'1*

mcntR to IND l"orm l"D-15'71 and U.~m d.l uml iLcm1 4.1 fruu1 Y.11: µ1*ulX,llte(I amend*

I 370.100), and I.he D~inc rc:tU.l'Ch a.tuc:l;v 16 w1t.lun the purpDSC& aet forth b:r m1&n act.uren t.o

= fa.ahlon tnt1r nud1c*

co pl)' Wlt.11 II\VeclJ11"-W!;llJ1&l m:w llru,*,

mcni.,; to l"orms FD--1,12 a.cd l"0-1~'13,' Ula~ 111:etloll.. Tlu r~ult.1 o! the rcaearch a:i w~ au ni:,w dru1 applie&t.ion requ1rl'-

res1,ect1veJy. *.rne c.;ommU1s1oner ae1vises study wing the "tagged" compound men Theat ruldel1nea ih0Ule11:,e* 11pec~-

u111t he remll.ln.,; qwi.e wu11ng to aciopt a must, however, be ruhmitted to the ex- icaU:v tailored to re!lect reall.suca.ll:., t.h<:-

pl'oceaure tor proV1dlilK m.rormauon re- isting IND. If phannuological data a*rc uru§u* riroblel:n4 ln tti.e ~ Q\ tllll.11:1*

l(ll.rding IND'i; directly to Federal and not sufficient to permit compliance with pha aceutle&l.s.

State agencies 1! 11.nd when all 1uch agen- u,e l'e<,UU'tnltnu ot t ao1.1. it would of Th Comm.l.N-loner rn.Uiea that n-,..,-,

. t:ll!!i air~ rmL t.o Cllnclose an:, connde11thd co= be ncccasar., io submit a. new IND rt:Q 111e11LII fur n&di=t.ive u.ruir::; will information 110 provided without the or, preferably. to &mend the existinz IND dllier 11n var1ow way,; !rom thoee 1m*oJv.

written permas1O11 or the FDA. for the nonradJoactive lnn.s~g*t.lonal ing ~radioactive drugs, and thlS IS The Comm1BBloner advi!es tha, the new dru<< t.o conduct a. r;tudy on the dn.111: t:111&r1f atawd In U1e. preamble io tht' FD.A. llll.!i nuuncct Agreement Sl&t.e11 ana "tagged" w1U1 a radionuclide, even proJ)Ofed re irw.a ti orus. "IlWI 11tu.a uon 1s

. the NRC or all existing approved NDA's thougb the n.dioactlv1ty limlta set forth not !Que, however. lillce req\llrement.s and blologiclll product Ucemes tor radio- in § 31!1.l an met. To amend *ii nm 1n for o e conracHoacttve drug may differ active dn1g5 t.nd n,dioact1ve blologieal Uita way, the tnfortna.Uon required in &harp 1 !rem those tor a c11tlerent non-products. Procedures ban been estab- items 8.d and 10.a ot l"orm l"I)-1871 must rad1 ctive drug, The reQUirement.1 of mme'1 to conttnue to nou.t:r the Nl't.C lllld be aubmltwid. I 31%. an: reIJeral nrq~nis at1d are l\ll Agreement States of all new as,provals 6. One comment aunested tN.t. to u- re,ul rl7 adapted u appl'Ol)rtate for ot NDA's tor rad.1oactlve drup and radio- sist the l'ederal and State ngwatory IJP8cl11c druJs. The PDA 1s currently in active bioluglcal products. 'l"hue pro- aa-e~ea 1n 1u1m11nr t.helr rupcml.bWty the itoeea.s ot drafting l!'Uldellnes for cedures do not, however, preclude an for licensing the use of n.dloactJve ma.- ccnd*im. clin1cal trtah invol~ radlo-A applioan\ from notsf)'inB the NRC or an teri&ls, the Summary of Information re- activ~ drUrs.

W ~reement State of an NDA 11,pproval. quired in Form FD-1671 should be ex- NDA ~'C'IltD[EXTg l'Oa Ro\J)IOAC'f1\'E. Nicw

3. one comnient. eUBg-eewd that* 312.1 panded to include: information deacrtb- Davos ODDAtLT

~

should include conciBe illld complete de* lnl the plan of investiration 1n 111llfflei11nt tails tor &n acceptable protocol and detail to pen:ntt a critical evaluaUoa of II. e commen\ queet1oned ,r,hether or pointed out that such areu as dosimetry, the method5 and controla to be Ulled: an not* mechan!am had been *tabllabed expected or document.ea clearance rates, lnd1ca t10n u to whether &nY COUJfl1e- for ~

• abbreviated new drug a;,plica-and rationale of d1e.sDoa1a or then.py mentary druit or ra.d.lonucllde adminla- tson~. I for diqnmtJ.c radiopharm.Aceu-were noL conta1nee1 1n the new proposed. tra.t1on ia s>l&nned or coot.6mp1Ated Sn tlew rules, conJunctton with the 1tu~: an ind.lea. Th Commlulcmer advilea that *J'\O The CommJ.ssioner ii or the opimon tion of tbt! 11XPCCted fate of t.he nd.10- mech hu been ettabllahed yet for that. the PJ"C!!Jent. IND RIUlatlOPS Pha.rmA.oeutJeAl t4mlnlsur.d: i1 for IRlb tt1.ng an ablll'f:vt&ted new d.rUI 1.µ-

O 312.1> and Form l"D-1571 with the Lhen,peutic P\1fPOMll, an 1nc11eation of pllca on for a n.d.10t.et1Ye drug, .The a.dd1t1oru; *et tort.h 1n the proposal, are the eJC:pected 11ffecta: and calculat1ona of Co oner recOKill.zel, however. that adeQUate u requirements for the devel* Uie ra.dlAUon doeea delivered ta t.be the ount o! cltnical data neeeaaar:r t.o opinent of a protocol for producinlf well* whole bOdy and to the crttical onran<a>. appr~e t.n NDA Yanes amon& n.dio-controlled cllnie&l dat.a on radSoact.lve AA at.at.eel 1n i,arqraph 2 above, the actlv~ drup, depen~ on eevenJ fac-drugs. l!:ach protocol for an IND study Commmloner bt.s deleted St.em H <sum~ tors. APPllcantll are Invited to meet wtth for a tadle&et.1ve drug wil be evaluated mary of Information) frorn tba amend- repr~tativea ot the PDA. Bunsu or tndlv1dua.lll'. In I 312.1, item 10.a of Form ment.a to IND POrm P'0-10'71. ln1orm.a*

• otviaion of oncology and Radio--

FD-1671 requires that the prot.oeol In* tion needed by the NRC and Aareement Ph& eutJcal Drue Product.I, to dis-elude studies wbJch wW obtain aumctent Stat.ea for Ucenainr ~ mut be ob- e amount. ot data needed prtor \o data for doatmetry caleulatioDJ and that tained frcm the IND *J>Onaors. 0Dl~10D or an NDA.

tliese atudies should evaluate the excre- CS. One comment IIUffCt!!ted that, al- e comment surrested that* then*

A tion, *hOle bod:J retention. and orran thoUgb n.41oJ)barmM:eUtlcalA are rela- echanlsm whereby PR\'1ou. worlc

- distrtbut.1on or t.ne n.dloactive snaterta.l. tively simple Ol'Bl'JUC eotnl)(IU2lda wtt.h pmo ed under an nm or a.n NOA The FDA 1s currently s:,repartng guide- little or no tozioolocical/Phann&oeUUeal could[ be referenced for a radlophanna -

. lines ror reaearch protocols on radio- actMty t.nd zna:, not nqwn chronic ceutit for which II new uae 1a beinr active ~s: Lhe RadioacUve Pha.nna- tozicity atudiea, the re<<ulatioos _should devel pad, provided th* previous work 1.-<

ceutJcal.S Advlaory Committee 1' aasiatlne require aemic.brcnic toxicity atudles Sn ap:pli ble to the new wse.

tn this and, a.a drafts a.re developed, thtT anti.C:Spatlon th&t 1&dioi>h&rmaeeuticals Tb Commia111tmer lldviaes that pre\1 *

'till .he dacuased In open 1easions of that may, 1n the near future, be. conaiderably ous published studies rel.a~ co a adviaOry commit~. When adopted. more eompla. radio \.lve drug for which a new we ls these ,uldeliDes will be 11.vaUa.ble :from the Agene:r. nm for rad1ooctlve drUP 4.. One comment. questioned* *whether case11 require chronic or subacua, to:ideitY ma, The Comml.u.loner recognizes that* an in aome beln,developed may be 1J1eorpoT11.t.fd by refer nee rroin one IND or NDA rue lnt.o a.no er only 11 the apo:naor or the 'P~Yl*

• 1L wa.q necessary to amend or othenriae 11tud1es. The preaml;)le to the proposed ow or applleani er ~ prevtow NDA alter an ext.el.1ng IND for a nonradJoac- 2-eruia.uons only noted that chronic auth mes the new i;p0nsor or apphe11r.t Llve tnve.stiga\ional'cew drug 11 the drug toxicity 11,udlea tna:r not be teciuired for to WI theae data. ,

is "tagged" With a. radJoactive element in some radioactive druP. The reQ~ement& A RJ:Qtm\'CMZN':$ l'Ol Cc11T#J,.

11.c:cordanoe with tlie umit.a.tions aet forth for any IND w1ll depend on the specific. . R.lDIO&C'I'IVJ: NEW O.vcs in proposed 0370,100. Tbe comment alao nattire ot the drUi a.nd ita propci.aed uses.

expressed ttie opinion . that, 11 an in* 7, one cominent. ar,ued that the pro- 10.tne cotnmen, lndlea~d t.hJo.t. at llu, vesttiational dnlg la **~gged" and ad~ posed reR'Ulatiom failed to dlBtinguish out.ae ot Ult J)re&mble to the prop0a,a.. a mlru.stered nt or near a Pharmacologte between ..!lot** tradioactlvel a.nd "cold" 1tate en\ I.II made thAt "&nY nd.1O0h&r*

dose, the new litl'ormaUon required l.n <nonradioa.ctivel pbarma.eeut1cals &nd mace Ucal which l.! not a 'new d~: t.e 1tema 6.d a1:1d

• 10.a or :f'Orm F'D-1571 between dlagnoatlc and thera):leutic wheniuaed under the eonditloN 1oectned i;~ould be tubn:tltted as an amendment to arenta by applying the e:1dstin1r IND a.nci a new IND 11hould nu~ceutlee.ls the aame ele,.ra.nee proee.

'° nd.ioactive phar- wW ~uire nelther an IND nor ~n JlfDA

'but 11 requ!n cartaiD document.a tton LO not be n:Quinld. dureR appUcable t.o nonrad1oacUve phar- esta. that the ( 1 ~ 1S 1n t~ ~

Rl>HAL UGISTH, VOl, 40, NO. 14....._...IDAY, lUlY U, 1*r

DUPONT 0(14 RULES ANO REGULATIONS ui:;ed undt:dhe condiLioru; set. !oTth ln I.he the l"\'ldionuclicte." li&~d inf 310,S0:.H:!.J O' t totlill;v agree 'lll:lth thoi;e c!

re[!ulation." The i:,ro,x,i;ed rules then go time to 5ubm1t to the FDA WotmAtion the NRC. other commmt ProP<>Ged t.l1E-on t-0 i;el- dlltei; for the filinlt or an N'DA necessary f<ir continued mt.rutinr o! addition 0! Indxum*l13m to the lli;t 2::

1or Rll radtoacth*e pharmaceutien.ls ~iU1 i.l\ese Product.s. ThU deadline !JI no~ IP* f 310.503C!J 1,.

well-establlAht:d medical ui;cs. The com- plicable to drug r,?'IX1uct.s, tnclud1nsr bio* The Co stoner ha.z detemuncc!

ment TC(JUe~l.ed clarification as to how log-kill products, conta1%11ng a.n:v ot the that onJy. oee rad1oa.et.1ve drurs listed tho11e phannaceut.ica.ls ltHted in f 310.503 l'll,dionuclide.~ li.st.ed in ~ !l0.503<cl <tor.; under I 31 .503 &hllll be eoMidered b:,-

<1

• cl

• relate to t.hose retcrred to above. mcrh** f 130.491c) l. Manufacturers and the PDA have well-established uset-TIie Comrni11--.1oncr lld,*i,;es that distrlbutors "-'ere given until March 3, in medical praet.lce. In the preamble tr.i t .'H0,503 in <11 Jii;ts a group of new

• 197:1 to submit an NDA. IND, or i.ppUca- i.he PrOPO l. the Conunwtoner h~\it.e.:,

dru(!s. reacu,r-produced rndionuclides tiori for II biological product license to any Deno who believed t.hat 01.11t*:*

and their, chcm1r.o.11orms, which the FDA continue cilstribution of those products -radJos.ctjv d?\U!S a.re Wide]}* UM-cl 1:*.

,inu tbr. NRC nave deteTmined have well- for any ot the indications lated, medical Pttiee ..nd ahould be added to r.stabliShed medical use1;. In view o! U1e 12. One comment Pointed out Ula.t the this list submit comment.Ii and data extent of eXPe1'lence WiLh dn11ts con- November 19'11 regulations allowed the 1>rooo11in~ d justi!)'icg the 11-dd!t.ion or taining these ra.cuonuclides. the FDA &1,Jld submisi;1on o! a new drull' applica.tion for ,ucl1 druri. The request for adclit.lon o!

Lhe NRC have c:-.oncluacd Lha.t. thf.Y Bhould an existing product witbout re<iutnnit the aot¢ne Ind..lum-ll!m to t.he "ll"ell-nut be distributed under lnve&tigationa.l thc pnor r;ubmission ot e.1t.her cllnlcsl est.abUSh~ll.St wa.s eub~tud. The data use labeling when they are actually in* dat.a. or an 1nvest1a-at1ooal new dnll 1,p. 1ubznitted in supoort o! \he nquei;t t.endcd ror use in i;nedical pr~ticc. such i,llcatlon and tiuest1oned whether such <whleh on displ.ar in the Hearing drug product!! have not. ~n used to a ""'li till - t Clerk's o ) have been rrvinred, the ma.t.erial extent or for ,a matert~ time a .-v cy WU 8 in .,.. ec

• Rad!oacti e P.llannaeeat1ca.ls Advisory and are not yet. regarded ai; generally The Comm.1uioner r.dviae8 ~ t this COmm1 consulted. and the request recomized as r.&le nnd etrective tor their r,olicy is "-PPllcable to th011* r&dloactive appro'\led, Section 110.&03<n Cll has*

111.bel~ Sndications, However, it may rea- d.rURS listed ill I 310.603(!) (1). 'I'bete are been .m fled ~:Y-nablY ~ ex))eel.ed that e.dequate eVi~ product:s which the FOA anl1 th e NRC lb, A mmen; requested th11-t the Ter*

nee or u.£ety and etrect!vene.ss can be consider to have well.,..tabuahed snedl- ulattons or radioactive new d."'"'s iri*

bmltted by manu!a.cturers and dl.,trlb- cal uses. The CollltllWSO:c.er ha.s eon- *-

eluded that. ma.nutactu.rera ~d d1$tr1bu* elude p vl.sJons to-clarify the nqu1re-utors for use of lhei;c drugs 11.5 recom- tori; of tbe.se drugs mA:Y reuona.'blr be ment.1 r rt.rcUnll' ret-et.or-PTOduced bll*

mended ln appropriate labeling. In order expectetl to be tM:>le to .cu'bml.t adaquaU product ten.ala when such product&

• to conUnue &hipping in Interstate com-

" " ' ,. " -.. . . _... ,,,~r:w-,,,_ ,. . . .

evidence of wety and e.irecttvenS&.S !or are proqeued and shipped 1n bulk to merce d.rugs c:ontaJnJ.ng the6e ra.dionu- use as recommeJld.ed In *P?TOPmte other tti.a.nu!a.cturers for reproc~

cllde6, manufacturtrs and dl.Stributors labeling 1Vi~i conduc~ additional into ftniljhed dr\1J tonns.

mUAt submit e.n NDA, IND, or applica- cl.llucA! m.tdie6 to obta.l.D such d&ta. 'l'Jle The domrn1ss1oner &dvaes tha.t. bulk tion !or a blologtcRl product license. on or before Aurust 25, 1975. An IND wm ..,._ 3 ln t.b. e Novec:i...,.,. .,_,,~ essil:li, or uae ln the m&nulM:*

not, however, permit continued cottuner- , li'71 order for ............r ture of other drUr ah&ll be Jm)CellMd, clal marketing of these dr'U86. rad.l.oactive drtlu. shipped and labeled 1n compliance With On the otner hand, t 361.1 (proPoSed as 13. One (:OmJneM *tated t.hJ.t tb1a JltO-- 21 CFRJ01.12l -(fOrn2trb' 21 CFR 1.1OG pogal would ~ t e *& MW , ~ ~ . 011 ( 1) l

• t 3'10.l00> B])eel.ffes cond1t.iom under & t.empare.ry buit, t() NSW&te * !'f:X.* 'Do* ~* T**

which radioactive drwts are 1renerally t.1vely amall number of druJ*." The com- vCIJU.a., ............CT,.._t1:i reeo~d as 11a:!e and effective and inent furtbe-r 11t&t.ed th&t "Jt may be 16. e comment inzeat1oned wheth~r therefore are not new c1rwrs. Such drugs more etrective to require l.tn.tned1ate sub~ the P'D had jurisdiction crnr J'MliO&C*

do not require an NDA, biolOll'ical product mis.s.lon of &D INP acd to penntt ibe t.lve ~.s. tn the 1nvut:2pt10n&l 1 ~ or license, or IND. The r;tatemmt quoted Jn cl.rug's eonUnued me 1n tatenw.te com- . tor w-e,ti-e&t&bllahed medSc&l UNC, tbat the comment referred to the t~t that, merce for a &boner period \Ul.der t.be a,-r P~!"ed by tbe 1111~ s,bystctan and for these drugs, report,; will be required .same c.lrCUin&tanoe,; u 1t ha.d laeen qua.llflflfd &a&Oei&te ate.ff nthtt t2l&D in:o-

• <in the form ot annual ol' special rePort.s from the Radioactive Drug Reaear~1 the~to used." . cureltfma col?Ullerci&J. ,Pharm&(:eutJcal a *committee <see p&rl\grti.ph 29) ) to as11ure w, FDA t.hat use of the cl.rug remaln5 withln The Com.Jnl.aioner u.,umee that ihe cotnment ii in rarnence to I 31OJi03 conce . The comment further ataud that. e pronaion ot nuclear medicine whleh lists a CJ'OUP of ne,r drugs, aervi and tbe contulued develOJ)ment.

the conditions under which the dn.ti i5 reactor-produoed rsd10nucl.1des 11.Dd of qu~. met.hocla and J)roductl; generally recoimtzed a.s safe and etreettve. their chem..t.c.1 tonna, which the .1'DA &2)d WOUid .be 1eveft.ly Jnhibtted bY requiting

• 11. One comment questioned whet.her ihe NRC deternuned. have well-at&b- an ~ or NOA under au.ch drcum-the Pecemoer 31. l974 deadline for sub- liahed medJc:Al uaes. No new n.ructu:re sta:c.c~. J)t.rtic:ula.rly 1n the lAivet' cl.ln.lcal mu;sion ot N'DA's applies only to thoae 111 prop,oeed to deal wit.a these dru,s. In a.nd ~Kreh cen\ers where much oft.he radioact.lve drugs ~ted 1n .. I 130(c) of view of the extent of ~ 'With 'the mnov.tive and dev~entAl advance~

I.he November 13, 1971 F'ZDJUW. R1:ou:n:1t" rad.lonuc11des Uated 1n I 310.:103 m u >, evolve~ Allother comment quutied lllld 1n Uie table included in f 310,5031!) the FDA and NRC conclUded that they whetl:'!er the propooe-d ~a.tion was a.p-O > ot the July 29:ls'lt propc,ul. ahould not be d.tstrlbutfd Ulldef 1nvtati- JlliCA~t to tboce ao-C&lled "res'ionaJ rn-The Commissioner assume& that the eaUon.al use labellnir when they are diop . es" Which ltt&llu.!acture their comrnent. meant to re.fer to "I 130.4ihcl actual!~ Ultended 1or use l.n medical own ioactJve 11nxn ineludi!li I.he non*

Ul tl1e F1;1)J:JIAL RECJSftJt ot November 3. :pra.ctlce, and that. m&nuta.cturen and racl.1 tive coml)Onenu.

2971 in,;tead ot "§ 130(c) in the Jl"EDUAi. distributors may reasonabl1 be expected here in this wue ot the huut RzGI!ttR o! November 13. 11171.," The De* to submit adequate evi~ce of aa:tety Rl:ar 11, the Comml.&sioner ls issuing c.

ecmber 31. 1974 deadline aet. forth in the and er.rect1venesa for use M recozn- no~~ :reirardinir the Pood and Drug Ad-J1,1ly 29, 1974 PrOPOSlll !or $Ubn\l51tlon of m.ended in apx,rox,ri&te l&bellna'. To con- rn1n14tra.Uon's policy on the "nuclttar 11.n NDA. IND. or application for a biolog- t!nue r;llippin,: drugs contamJ.ng these ~ " Issue.

1r.n1 pror:!uc:t licerue appl!e:.i only to druR radtonuclldes in ~ter,t:.a~ conuneree 111.n n E Q ~ Poa R&si:AllCH Usu or products, including bioloiric"l product,.,;, NDA. IND. or applicabon for a bfolo~cal ij%0AC'1'~ Daucs OSKJ:.UU.Y :Fl..&CO\J*

-which cont.a.in any or the rll.dionucl1de& s,rod1,1ct l.ken.sc, mu.st 'be aubmitt.ed. An 'If 11:ii AS SU-a! AXD Erncnvt AND >:01*

listed 1u A310.503 t!l ll l 1n t11e "Chemical IND w1ll not, however, permit continued BRANJ)su

!onn" li6~d and Sor t.he indicatu>ni. r:ommeTciA! marketulg of t.b.cst d:n.l&'s.

listed. Th.is dud.line h~ now been ex- 14. One comment reque.s~ti cla.ritlca- A. ,;corr. or OETU¥IHAnoN t.cooed to August 25, 1975. The p\lrPQse o! Uon a.s to what eft'ect, 2! aDY, the re* 1,J0necommentst.atedt.b.~tinmedknl t.11.1., de.dilne la to allow ma.nu! aetureri. v1'ilon ot f 310.603 would hAYe on lists 1.n.st.itutions opert.t1zlg under a.n NRC and diBtrJbutors who &N currently mar- n! "v.*elJ-ci;tablished u.sei;" which snan:v B ~ Medica.l License new fadjopnar~

lr.eting drui: Producu; con~ainlns an;v o! AgreemenL Stat.cs h11ve developed but m / tlcllJ, ..re IOnletimee dev~lo~d ill-

_ _ _ _ _ _ _ _ _ _ _ _ _ _ _,_i_D_fl_A_L_ltf_G_*_sT_,_*_*_\/_O_L._*_C. NO 1<<-f~DA>, JU-, U, > r ,

1, Sec. 104 ATOMIC ENERGY ACT OF 1954 SEC. 104. MEDICAL THERAPY AND RESEARCH AND DEVELOPMENT.-

a. The Commission is authorized to issue licenses to persons ap-

• plying therefor for utilization facilities for use in medical therapy.,

In issuing such licenses the Commission is directed to _permit the

• widest amount of effective medical* thera ssibl

• with'* the amount o specia nuc ear matena avai a e for sue purposes *and*

to impose the minimum amount of reftflation consistent with its*

obligations under this Act to promote t e common defense an4 ~e-*:*

curity and to protect the health and safety of the public.* * . !-*- .'. *

b. As provided for in subsection 102 b. or 102 c., or where specifi.:*,

cally authorized by law, the Commission is authorized to issue li~-

censes under this subsection to persons applying therefor for utili~"'.

zation and production facilities for industrial and commercial pur>

poses. In issuing licenses under this subsection, the Commission*

shall impose the minimum amount of such regulations and* terms

---of.license as will permlt theCommissio-n to °rulfili its oblig~tions under this Act..

c. The Commission is authorized to issue licenses to persons ap-plying therefor for utilization and production facilities useful in the conduct of research and development activities of the types speci-fied in section 31 and which are not facilities of the type specified in subsection 104 b. he Commission is directed to im ose onl such minimum amount o regu at10n o t e 1censee as t e mmis-s10n fmds will permit the Commission to fulfill its obligations under this Act to promote the common defense and security and to protect the health and safety of the public and will permit the con-duct of widespread and diverse research and development.

, f

~n1allf and subjected to clinical trial&

15:05 DUPONT ltULfS ANO REGULATION~

dislribUtlOD, Mil local.U&Uotl o: U1111 Vti.n-005 to c.!;t.abli.~h dill.l!'nostic or Lhcrapeutic et- ous **tagged" compounds. Certain irtudie~

f1cacr: 'I'.nc comment questi0ntd 'P.'hether included in tl-Js cate.:-ory may be e.55e11-1~* .1J1 necessarr tor t.bese 1.n.stlt\ltJO?Ui to t.ial par~ o! the development o! 11. ne" 1ub1w. ari INV even t.nougb in the dt* di,.aguost.ic aaent C!or ex.n.mple, 1tudiei.

vel0µmcnt.al 1md test.int: p.haJ;e the drug conducted to dckrmine 11"hne the radio-i.., not 6!Upped in int.ersoote c:ormnercc. aet1V't drtli is Jocal.lzed or the e~tent to T11c comment further questioned '11!:hel.her *wtuch it Is eoncentni.t.ed 1n certa.in or-suc:!l cl.m.lcal u*ials relating to CU14rDostic gans or ~esJ. Such stud.ie& fall WlthU1 efficll.(*,, were c:overed br propoged U1e scope o! l 361.l U' otller requiremenu

~ !17O.JOO aud whether it would be neces- of that sectioc are me1.. 'l'bese ltudies*

sary to file rePQtL~ ou inve5t.igators c! must be dist1ngUi.Shed from 1tudie5 this t.;vpc al)proved by a. radioisotopes intended to eva.luat.e the wety and ef-commit~e under e. Broad License, either fectiveness of a ra.d.\Da.ctive drua a.s a an.nun.lly or imme(iJ.Atelr. U sucb clinic..l dlagDostic B.1ilnt. ID t.h.1.S case t.bc drug trial.-; a.re not covered bY proI>OSed 1a u.scd, not o.s a research tool, but tu a

~ 370.100. would the dose restr:tcuous new dia,gnostic 14tent for which 1a!ety specified under that. section apply? e.t1d effectiveness mUBt be proven: there-The comm.1ss1oner a.d\'ises tha~ t.be fore, t.here is no bua !or concluc:Ung tta.t.

FDA has jurisdiction over all drua's, in* it 1.s gener:all:v recognized a.a u.fe and ef-cluclilig rodloactivt.* drug-e, shipped 1n or fective a.s a dU4rnostlo agent. The rarlio-1ntroduc.ed 1.nto interstate commerce a.ct.lve. ~ostle ae-mt. t.heT"efon,, must whether prepared bY a medical in.stitu- be studied under an IND.

Uon, phy.cic1.an. or a comnierc.ia..J c1l"Ui JI. LUlITS ON PUAUU.COLCXlICAI. POSJ:

m1U1u!11cturer. "Sh.tpm.ent 1n lnterstat.e CL>mmen:e" ii determlned not only by ~e 19. Several cotnn1ents were r~lved r~

1.ni.e.n.ta.te shipment or Ule tln.aJ dQMie ir,r.rdmg the reqwrem.erits under the pro-A form of the d.rue; product, but also b;v the posed f 1170.100 t.bat the p.barm&eolocical

. , inter.Gt.ate srupmect. of the component& o! doee thall be knowu not to cause &lJ;v the drug prot1uct, u well a.s other Cac- c11nlrall;v deteet&ble pbarmacoloeiea.1 ef-

°T ion. Therefore, where a determlnAtJon ill fect ill human being&. One aommmt a*

ma.de that 1nt.erst&te com.mer~ 1s 121- J)resll!led tbe t.houaht that sUCh a Umit on

~- volved (&lao see PA-r&rr&Ph 11'1 o! this the pbarmaoolOgi.e&l dose WU' unnalJ.$t1e r: ~ e ) , &n IND lllU-Si be S U ~ and UDIWY'M&T7 and would s,l&oe lleYere t be!ore the ~ product may be uaed Jn and ~ rmtricUona uPOn n-

~ climcal tr1&28. aeareh m. mch .-ital ..... u human drug

.&a at.ated 1n tbe preamble to Uie in-o- met&Dcllsin. Tbi! fJOllllllll!llt f urtlltt noted t* Poaal; tJ>e Oo~ner hu eoncluded ibat. ldnce d09IN tnoWJl nm; to es.me 11.IlY f that the proY1siotl$ ot I 381.1 <proPoeed a11%1JcAllJ detllllct&ble pharmacoloeieal at-f.ect are oft.en ,u..bct.1mti&lty below the

• I 3'1D.100) are not applicable to c:l1n1cal tbefflpeutie dme. l"IM:UOacU'Pt studin 00n-I triaJe intended ti> determine the Afet.Y and/or etrectJ"leoa.5 o! a t'M!1oaettve .ducted wtth *uch minute doecs would not ctrua. Section 361',l cnll:, appllee to N- be lWJWEGt.U\'f Of ~ Phan:Da.oOkJ*

aearch "in.r.ended to obtain buic lnfor- :i:i.et1.cs of the dnlC st\lCUed at the t.hua*

r matlon NtrU<llng the D\etabo1ha:n. (tn- l)eUt.ie d..oA!! * .Pwtber, it .,... *tat.cf ~

" Cluc!JJl.e kl.net.tcs, diltnbution, and klc:al- auch .ltudJ.e& would ZKJt fm:n!&h eoourll t ization) 0: a ta.d10&Cti\'ely Ja.beled drug 1 ~ ~ta.bout.ea to conduct ~ l i t e j or ~ g human phJ'lliology, pa.tho- irtudlea. Another c,omm11nt wuested Uit.t

, Wu-1.IOloiY, or b l ~ t n but not m- the exemption El"Oal IND NQuin!malta l tmdelJ !or f.mmedla.te t.hll!r&peu.tic, dial'- 3b0u.lt1 include t.be taainir ot a C!ruc at

~ JlOltic, or aimilar pUrpc)oe8," CUnbl a doee lePel ha~ a pb&rmaocIOC1e e!*

Atrlala U&ing new rad1oacth*e drup are feet 1f that doae inel 19 we and dect.lve,

• 1ubjeet to the requ1remect11 ot an IND U ~ b1 an .appl'Dfll!d NDA.

• 9,.1 eet torth 1n I 212.1. Section JGl.1 o! In the ~ l e to tbfl ~ l"e8'U-Ulla r ~ c hU bMn cl&rl..ded to req 1Atio1:1, 1obe Cornmtv1n"3er made U. ,;:1.-r

tl.ect thi11. The dole rewioUopg Mt forth ~ t , tor rat1ioe.cUve drugs to be COD.-

1IJ f 36U do not apply to cllnieal ~ al.dcred not :ne-. ll1l'Ua:a far certa1n mee conducted under I .a~.l. it, WU neoeMllrT to ocmdude that. the)'

J.8. One eommen~ apJ"ei&ed confuaiOn were ganer&ll:, ~ u -.ro tor 1n uit.erpret1Dg the eoope of the exei:ru>* such U8e9, The OOrnmf.MlonM" INKiWted t1on Pl"Clvlded by prooo.!led f !70.100 u it t.hat. such

• CClllclumo:n CIC7Uld cert&llll:r be relat.e, w the development of new ra.dio- .re&c:hed, wit.a ~ to t.he pba;nn.&eo-aetlve ~OISl.ic: ~nt£. The comment lotriea.1 aa.!ety of the '1~. it t.b.e drue further stated that it was not ~lear whr wu known not to produce cljnically de-t.he J)UW::ular agent bel.n6 studied cannot tect.able paannacoloc;:!CAl effect.a on Ul.e be wed r;i,ecifically for ~ t 1 c pur- bai.ls or data. from studies in bum£n be-005es 1f the crtterla for exem.ptiOD UDder ~ - I! such d&t& are :u,t. available, evm or croposed I 370.100 ci.re met <1.e.* radJatlon t.be sma.llest amount t.bat drug muat be safet"y, pba.rmacoJog-k:al 1naet1Y1ty., -.nd IIIJl3UIDe<l to produce pba.nnacolotde&l ac-Radi<>&eUve Drut Resesrcb Commit~ tMtY. Once pbanuacoloigical actMt1 a a:pprovalJ. known or usumed to ocair, ph&zma.oo-SecUon 361.1 (prow1111:d I 370.100, r,ro- 1DQ1cal safety c.nnot be i,r"elJUmed and vides %or Uu use ot tracer amou:cts o! otl'>er evidence of iretiera.l reeognJtion 0!

radlonuclJdes, attacb6cl to nrlou.s com- wety 1s neoes.ss.ry, With.out tbl.s m-PCll.lnd.s. 1.n rese&rch studles &o obt.&in d.eru:e, t.lJ.e d.ruc Is con.aJde:red io be & new buic Wormatlon on drug m11taboUlm. dl'\a. !Llld 111:iy reeear~ with It lllllat meet

~ ~Oloric or iiaUioo~c the r,!(JUirementa of J ~12.1, including the J)roocwe, lil Jluman.&, IUld the t:tnetles. su"bmt&idon o! an IND.

flPa.AL lllEOISTU, VOL. 411, NO, l ~IIOAY, JULY 2S, lt1S

31302 RULES AND REGULATIONS t l.lter U1c- rl!Quircm~nL uu,t th,.

,;ion of 11 pharmacological n1:ellt when not. ncv; drulis ha,$ tbe efl:eet of n1Aklnl lt, unneces.so.ry to aubmlt 11.11 IND before on dose, even thouirh It L~ w:ithu:

t.lll.s pha.nnacoJogical 1Lgent 1s ad.min~ t, &hould be the unallest amoW11 u;t.ered to the patient. 1n pharma.cologica.l uslni;i: them.

2~. One comment questioned whether neede to c&rrY out t.he study. lt is onlr doi;es a.s pnrt o! a \.hera.peuuc treatment cc,nclt1ded that. 'lnthin the contexL of the nnr..1 to ~ess the eftecUveneu o! that It was necessary that there be a radiation pnrUcuJar Ulerapy. The comment sug- dui;c Hmlt l.llcluded among the cond..1tions benef!.~ to be obtain~ trom the re.,eucr.

gested adding the &tnt.ernent "lf e. drug under whlch the ui;e of radloa.cttve d.rugs atudY,:that .such rad1a.Uon doses are gen-i~ wed under protocol tor t.herapeuuc tor re&es.rch ii; comldered r.de and ef- erallvj reeogruz.ed 8.5 we. Rlldloacti\'<

purposes, then n. m1nimal dot;e o! the rn- fective. The comment stated that "I! 11. dn.ig~ which deliver lar~r doses are con-cilo-111.bcled isomer ol this drug cao be loci\) committee is deemed LO have the sider to rer:,reaent ne....- drug~ and t.t, added to nelp P.vahlBU' t.he rndiopharma- Judgment to a,;sess and e,pprove varied requ e an IND or &pproveO lmk.

cokinetJcs of thlS druit." Jei;ser dose procedures, need the1 be lim* 24. e cominent Quei;tioned whetht':*

Tlie commis3ioner 11.ch'ises that. t.hii; ited J.n regard to the tar less frequent it

• u,propri11,t.e to use the occup11

• regulation in no '\'ITBY restricts the use of i;ltuations of a particularly 1mport&nt t.iona penuwlblc exP05ure criteria. u 11

a. nonradion.ctive drUg. I.e., under an IND. rei.e11.rch i;tudy t.hnt miiht necessitate a limit pon the awroval 11.Uthor:lty of the NDA, or old dTUlC status, whether or not larger orgM dose?" The cornment. 11\li* pr d Racl1o.tlon Safety Commlt.t.ec tht! raa1011.ct.1vely J.D.beled version of this Kes~C! that It i:night be preferable to o!- <Und r proposed § 3'Z0.100Cb) <3> l stnce drug IS administered at. the same time .t:cr the option LO the local comm1tU!e o! l'UCh mJt~ were developed for a. specitit*

"to evaluate I.he phannacolUnetlcs of the rererrins to .a.n l"DA-~nsored "auper* i:, and ahould not be extended tc, drug. For such a study to be permitted committee" reseo.rch prol)C)Sal$ which, be*

• h we of radl&tion in numa.n vol*

under § 361.1, t,lle conditions of that sec- ca.use of larger dosage or ct.her unWJUa.l un r 1ubJect.l\.

tion must be met., except that In this ease ooiu;iderat1oos. the local coinmitt.ee would As stated m the preamble to the pro-the lim1tation on ph1.umacolog1cal d0&e prefer to have acted upan by a hl.iber

• the comrnisaioner fully agrees with wW be such that t.he a,glrregate a.mount ot 11,UthoritY. the ational Council on .Ra.d1ation Pro-the dnlg administered lnonradio~ctive Toe Commissioner disagrees wit.h the tect.1 n and Measurement.ii who, 1n clll,-

dn.1g and tagged compound> Bha.ll be GtUtgestJon of the comment. When a ews radiation dose t.o reaevch sub-known to remain an 11,ppropriate dose for PhlLl"macologlcall11na.cUve a.mount of 1, jec noted tha.t "ea.ch proJ)()&ed humt.n the use for which t.he nonrad1oa.cuve drug radio!LCtive d.rug is use<!, tht 1.Bsue of res ch 1.pi:,lice.tion mu,;t be Judged on is bel.ng Jinn. The regU.la.tlon ha& been i;a.fety !or we 1n human BUblec~ is en- it& ertt II.ft.er review by competent clartned to reflect tM.1;. The Comm181Jlon- tirelv related to the amonnt of radlation J3ee

• a.nd tha~ dose-1.J.mjt.ing recam-er also o.dvlJie.s that 1f the nonrad10&ct1ve admintstered. Beal.Use~ nparure to rnentlattons for radlatif>n workers or the

~ has an IND, the resulta of any re- radiation 1s preuumed to have IL%l attend* pubic do not apply to the lndJviduaJ to selL!'Ch litudie& usil\8' the radJ.011.ct.tvely ant risk (due to a la.ck of e'rldenee &how- be irradiated," The Comm!Mioner con-labeled venion of the drug and pertonned JDlil' any &bisolut.e.l.y sate level of n:sxi-ure l , cludes that I 381.l of th1S regul&tioo em-IUlder I 3Gl.1 must be included e.s part it. 1S obvious that. no n.di&tton ellpOSUN th.u recommendation and ntQuires or. the required IND reports, can be jwit!J\ed or coDBJdered ,ener..Ur tha. ea.ch *tudy be apprcrred by com-

21. One comment stated that the run- .recotmized u ia!e aa & rei,earch tool 1f pe t peera <the Radioactive Dr"ul' Re*

damental 1n.formatlon to determine what the atudy .ln which ft a 'l1led le of PQOr h Committee) and that tbe tad!&*

"tradlUonal phannacology baaed Juda'- quality or 1s not. llkely \o provide useful dose be kept a.a low aa practicable.

ment" rneam needed IJllPll11cat1on and ln!orma.Uon: The Comlniaaioner bu con* radl.&tion dose cr1teri& In I 361.l (b)-

the term "no resporuse" *u not clear. eluded that the Rad.la&etive Dru<< Re* a.re for the pur,:,o,se ot natu,s that NJRarcb ~dies a.re senerally re,c.

In J)S.ragnph 0.1 of the preamble to eearch Comm1~ . (lff pa.rqrapb 2SI) the propo,al, the COmm1se1oner 1tattd can a.aure the ciu,J!tr or studies and the acIJW~ a.a 8Afe &nd not to aet a apecWe tbat "when radioactive druga are admin- inin1Int.za.tJon of tbe radi&tion dole. Nev* llm1t. for research aubJecta.

istered ln amount.& wh1cll have been ertheless, despite thJs conclu~on. the Comm.l.ssioner referred. 1n the DN!*

demomitrated not to produce cliniceJI:v Conunl&sloner .baa no baa16 tcr conclud- le t.o the. prooosal. to -rartous lt'lldiet<

detectable pha.rma.colotric acti-rlti' 1n inz that all doses or a radio&ettve ~ ,

lluman bein,:s. l'Ueh drugs are and mmt. even 1f used for ~ ~ and be Kenerall:r recoimiJled as we from the monltored by a Pl"OPeriY tunct1on!ng

• lewpol.n\-.of tni.ditlonal ~mlMlOlotD'," committee, are generally recOlll,.lsed as In this contut "tr&dit1onal pllarmac:ol- safe for the Intended we. He ha.s t.here-ogy" waa intended onl7 to dist.iJl&'uWl fore eonclude'1 th.a.ta llln.lt m NldlaUan b.azards related to the toxic effects.of the do&e ts n ~ a r y to z:nalce 11. determina-

~ s <tmdlttonal pharmacology/to~- tion of senera.l rec:otmition o! s&feb' tor

= .

hed Uten.ture wtuc:h ffltiect 11, wh.lc.h p&rmitted the .Ub-of ~pocure Jetoels aeeept&ble f ~ the et&ndDoi.tlt or ndiatton 18.fe~.

~ NRC crhena, aet. forth tn 10 CP'R 20101 and 20.102, accord with th.I.& con*

lie IUI:

e NRC requirements t..ke Into &e*

00logy> :trom those rela.ted to huards of rese&rch U&eS. & diseumed below <in N.diation. The tenn "clln1call7 detecta- J t ~ P h 24 >* the .coininJgg1oaer bae ble pharmacolOKic a.etivity" 1n bu.ma.n concluded thM the ti..s.ic oc:cupa.tlonal belng15 he.s been dlscru.ssed a'bOve. Neither ra.cllp.tion protection cnterla. est.abtt&bed the ten:n "no response" nor -"tra.dit1ona.l by the NRC UJHkr 10 C'l"R 20.101 and tiE co t both the ria.lc to the t!Ublic health of 1Jarser da&es of radtauon for a i;iar*

,roup Of r,enon.s and t.he J'1s.lc to th 1ndiv1duaa 1nv0lftd. lnvestlptloD.kl l'\J Jeet.s. like radlaUon workers, r-rtm**

pn.a.rma.cology" are used 1n the regula* 20,102, even thOU&'h they were not in- Be.ta 11m.1ted ,e,ment. of the total p0pu-t.ion; therefore no change 1s Deeded. tended to be crturia rela.ted ln a.ny way la on; the public hnlth impltca.t.lons o:

C, LIMI'IS OJI' IUl)UTIOJf 1>0B to subjectA 1n clin.teal reeeareh, provide & d of radl&Uon to research 11.1bJect.~

reasonable bul.! for the determinatJon a no di.tferent from those .resultlns-

22. One comment indic11,ted that the in* tha.t a radloactlve d~. when &dmln4.* f 01 e,cposure of radiation workers a.nd knt o! proposed*J 3'10.lOOCbl <3> was; not tem 1n a.mount., such Utat lhe ph&nna- th 1'1.5ks an eQUall:V accept.&ble t.o so-clearly ,;tated in the J)rea.mble but Jltt* cologielLl and radlr.tJon dose from such c:i ty. Conaidera.Uons of risk to t.he 1.1:ldi*

11wned that the :racUa.uon lhntt.,; are cll"lll!' is within the limits of f 31U.l<bl, v1 UA1 also appear rea5onably stmllar ro:-

at.ated so that it will not. be neceflll*n* to and under the C-Ofllll&ll~ or 11.11 FDA- th groups, An informed potential re-ti.le an IND for research projects w!11ch a.pproved committee. 1li generally teeOA'* h IIUbJect ~ able to make .o. decision do not-lead to cHQi?lostlc ieau:. niU!d BS 11a.!e. It should be elllpha&lzed ~ g part.1clpatlon 1n a study be*

The Comm1!s1oner adrues t.hat the in* that thls llmlt for pUil)Olles of e&ta.bl1.sh- c~we he will, In eifect. be aecidJ.n~

tent or I 361.l <prop0sed I 370.lOOl 1s ln1r general rec~tion of .R&!ety In no "9i'fle'ther or not he is wi.lltnr to partlci-i.ci ldenU!y a cla.-.s of c1rue11 that 11,re not way repre,;ent..~ a* eonclw.1on that such J)f.l.e 1n Uie study n.nd &SSUme a. risk in new dru1ts becau,p;e they e.re Kenerally radiation dose~ do not re1>resent aome tije u.me sense a..,; does l\ radiauon recogn.Jud as aafe a.nd effective under wprker. Althouith the beneAu to the in*

irpec111e c1rcumi;tances. One of those c1r- element o! risk to the individual nor that ~vtdual are Quite different. in one ease CWJU1tances la U'lat the n.cliat.lon dose to l&rier d05es a.re neee.ua.rtiy un.sa.!e. It is Ue oppc,rtunlt>' to ea.m

• llv~llhoo<l. 1n eubJecUi doe11 not exceed certain* limits. further emp~iud tlla.t set.Uni & llmJt e other t.he opportunity to s:,&rticipa.te

'l'he idenWu:atlon of this Clrus clas& a.s on radlo.tlon dose for purPQSe& ot ~ 3Gl.1 a 11cientlt\c study. eacb .situation in-FIDHAL a101sn*. VOi.. 40, NO, 14"'-"4t1DAY, JU~Y !15, 97.S

lJUt-'UN! 00?

RULES AND REGULATIONS vol\'es ** decision kl t.alte a 11peclflcd risk for a. specified purpose. The Commis*

siontr concludes th11t these dooes repre-11cnt, ~ mlnilnl\l rii,k t.o the individual ~d l'lre 11.i,proprlatc criteria. for a. ieneral recogntUon of i,afety ~het-c there 11,re so-r.lct.nl beneftts from research studies.

21i. One c:omment expressed the opin-ion i.haL we of Lhc occupauonnl radt.a-loion exposure l1mttu1on {M an upper limit for cxpo.rnrc of research iubject.6 in 11tudies covered by proposed C 3'10.100> 115 too h1,:h in comparison ~1th the intended scope of the .11tudie11.

The ComntJ..1.Sioner notes th11.t it is prooabl& th;i.t rna.ny studies under I 361.1 1prol)Olled a.s t 370.1001 can be ca.rried out US1ni smaller doee. ; of radiation than would bo permitted under the 11mJt.s on r11-cUa.tion t:IOflc. A1!> nowd earlier, it 1.$ the resPOnslbllitY or the Radil)A.CIJve Drui ReselLl'ch Committee <.see paragraph 29.l to a&&ure that the smiillest dose that can be wed w1tho1.1~ ,leopardizln, the study is used. Thtt Commi.&litoner believes that

• E doses ui, t.o the llinit.s "et forth 1n I 361.1 used UDder conditions specified 1n t section CD.I1 be considered generaUy eco~ M we and etrective and con*

stltuLe a reiu,ona'ble limit !or re11ea.rch studies conducte4 under this section. The t Food and Dnia AdIJ'l11mtn.t1on wW con-tinut.llY evalull.t,e the U$9 of radLOaetive drugs under I 361.1 through th@ ff'View ot tbe re.Quired &n.Dual reoorts &Ubmltted by the Radioactive Drug Research Com*

rnittee. Ttle Dresent criteria tor est.ab*

I1sh1ng a radiation dose l1m1t will be re-conslde~ 1t jmtl.1'!.ed by th1a *valuation.

26. Beve.al comments auest1011ed the partJcul.o.r radiation doee llmlts aelected.

One comment suggested th.at lt wOUld be riru11ra.ble to state a,ny limitation as a ma.XUnum oJ"g!Ln dose 1.1l IUlY one :vear with the further quallncation that In the event ot

• very long effecttve hal!-ltfe situation. the total dose over the Ute ex-

-pecta.ney or the concttned 11ubJect would not exceed some considered value. An-other comment stated that it wa.is not clear how U'le :,el:\!'lv cumulative t.otal tor whole body ex-posure for adults and the yurly- total for critical organs ~re derived.

• Tlle commissioner has reeonsjdered the proposed ma.ximurn radiation dooM in light of the c::omment.s abQve and tur-

• ~ t.b.cr 1ntra*11.2ency dacus:ilon. & ot1g-1na.11:,, proposed. maxi.mum :vearlY dooe.s

... were s1Vcn. To provide adequate protec-tion for trubjects 1n special clrcum*

st.ancci; \ll'herc lon~ hal1'*11!e radionu-cl1des arc used. t.he wordJ.nir h:u been ch11.nl{ed &o that thP.rc will ~ bo.h an annual limit on dose received a.11d a. J.J.mlt on the total dose c:on1m!tment resultJ.ng from studie:< conducted in a ,;mgle year; Thus. the regulo.tlon has been mod!tled to mclude both thc "11-nnuo.l do!le" and "to!Jl.l dose commitment" from 11. study or studies conducted withln n single yeru-. In addition. mnximurn whole body dose and the close to ~rlt1co.l ori;ans <active blood*

!orminit org:im. lens of the e}*e, and l{O*

na.ru;) have .l)een made identical. The Proooaed nouce 5Pf!C1fied l1m1tat1oru; for "critical" organs 1.t1a.i should ha.ve ~en applied to other organ.-;. nits has been

~fCIEiAL aEGISTU, VOL .CO, NO, 1-U---l'AIDA'I', JULY 25, 197S

15:09 DUPONT 008 RULES AND REGULATIONS sent.at.Ion on n Ra.dioa.ctlve ?)rug Re* t.he Dew mcmber<11> o.nd the.eompOS1t1on .H.1'!,U,,,~lJ Committee 11bo.ll meet at leas:

t-earc'.h committee under the proJ;>Oaed of the Committee and be assured that the ~ quarter In which a re.earcb c 370.l00<c> <1*,. Other coin.men ts ex- Committee conunuu to tnclude au or the ac vity has been .,uthori:ed or con-prei;sed the feeling that a r;ihumacolo-- neeeasa.ry fl.el~ ot eX?>e~- sect1on du ted. No more t.b.a.n 90 daYI should i>a..u fist i;ho\l.ld be a reQUired member or guch 361.1 <cl (4) <riroposed I 370,l00<c> (f.l > be een 'the &tart of t.he research and the

,:iomm1ttee. Commen~ also differed as'C.O ha.o; been revised to prov1de tor this pro* tor1ns of t.he study'i; proirresi; by th<*

whether o. r~dlophartnaclst should be 1.D- cedUTe. The C~loner advises t.ha.t ttee. More frequent mee~s ma*.

eluded In the membersh.lp of the Radio* once a Radioactive D?'Ui' Ruearch Com* eld at the dlSCretion of the commn~

a.etive Drug Research Committee. Some mJttee 1t; approved, it continues l.n such commenl.6 indicated tha.t there may be status until t.be approval b w1thdn.WD e Commi!J6Joner haN also deurminec; some misunderstandln1t as to who the b:v the P'DA. lndlv1dU&l chQ.ni'es ln mem* t. to provide re!Wlnable a.i;.surance Ul::i:

required member& o! a Rad.io&etive Dn.18' benhil"' may t.bere!ore be Implemented th* exi,ertise 11.vailabh! within the corr,.

Rese11,Tch Committee o.re, wit.bout FDA approval; .FPA disapproval snittee will be utl.1..1!:ed 1n committee de-The commtsi;loner concludes that the of a. new member would take the form Qf ll'b;Tat.lon.,, it i.s nec~rr to lndica~ th( .1 composition of the Radioactive Dnlll' Re* withdrawal of appronl o! the Comm.IL* nwnber o! members netldl!<i to corv;unrn search Committee a,; ut forth In fi 361.l tee. a~ rum. He hM concluded that rnor ..

<el (1) is adequa.t.e. AI. eta.tee! In the pro- J2. One comment upreai.;ed concern :SO percent of thP. membership o!

poetd reg-u.Jation, 11.J:)P,roval of a Radio* oveT t.he prourera.tioo or dut>lkatlve com-

• th Commit~ must be present to con-active Drug Re,;earch Committee shall be mittees deriving their *utho.rity !rom , ute a.Jlllorum nnd I.hat there must bt based up0n an 1!,,61;essment of the QuRll.1\- var1ou.s .I-'ederal a.nd Stat.-e regulat.or.Y ., :pri*te repTestnta.tlon of I.he re--

cations of the members of the committee agencie.s. It recommended tha.t l"DA Q red tlelds of speclallz.at,ion. Bect.!01:

and the usurance that all of the neces- limit, at least ln.ltlally, those committees 315 .He.I (2l <proposed u J 370.1001 t" 111.rt fleldli of expertise are covered. Cer- which 1t approves punwmt to propo&ed (2 > bu been revised accordingly, tincatlon In a particular discipline is r,ot ~ 370.l00<c) <4> to those &l.read:, estab* .f., One comment exi:,re.-sed the opl.nio 11 neceBBal:'Y. For example, one Of the re- l~hed medical a.ovisory eommitt.ees of t more ettlclent use of the ooncept o!

quired inembeTli of the committee &hall .n.dioact1ve m&terial licens!ns agencies

• oa.ctive Druz Re6aJ"Ch Committee be a person quo.lined to formUJate radio~ and the ra.dla.tlon ea!etY committees of . a wa.tchdoB" body'* in C9BH of exi,en-actlve drugs, This peri;on need no~ nee* broad medical Ucensee111 of the NRC. An- in tal UII0 of radioactive druts &houlc:

e6B&rlly be a radlopha.rmacist.s; he ma:,.* other comment expressed e0ncem thAt to expa.nd lt& function to cover both be a physician or other quall.fied 1.ndi* t.he p;'DA might not approve a R&dloac- n w and not new ra.d.loactlve drugs, Yidual, The Commhsioner llltlo sees :no tive Drug Research Commit~ which has e C:ommlss1oner adY1.te1 that revie9,*

reMOn to 11~i!y addlt.1ona.l disciplines been appi,;,ved as 11- Broad l.Jcense Com* 1.nvestlgat10ns o! new radloa.euve drug:-i as required members because

• 391.1 m1tt.ee by an A.Bl'eement Bt.ate or the bmltted pUt'IIUAllt to I 312.1 1s clea.rlr (el ertise in e.ny

• ance o! 11. Radioactive Drug r~arch ted to a Radloa.ct.lve 0rug ~ h f.£:mm1ttee.

r:

needed area. can thua be obtained. The Committee. Ttie comment further ques- lnstitut1onel revin> Is al,io Comm1&&1oner advi&es that. the only three tioned whether the r~ation would al* d for 1nvesth:at1onal new drug~

required S'lelds of Sr>eel.&lizatJon of a low the Medical Committee of a Stat" an nm where the ellnka.l nud.lu.

Rad.loe.etive Drug Research Commit.tee ltad.iatio11 AdviAorY Board lo r11View and nducted on iDIIUtutlonal!Sed sub-are <1) a physician reeoirnlzed as a we* CLpprove reuearcb progra.nu for mna.11 user ar are conducte<S by t.n lndivtdual

. clalillt 1n nuclear medicine, (2) a person licens~. ated with an lnst1tut1on wh1eb ~

qua.l.lfied by tnuntng il.Ild e:xpertence t.o The Com.m.issloner hu determined usume rmponeibllity for the *~Y-fonnulate radioactive dru1t.s. and (3l a that, to conclude that a radloact.lve d,rug Ef.&dJoaet.lve Dnsl Research Com-person with &pecial competence In radia- is iienerally recocntud u -.fe and effee* ~ttee would not ful1Ul th1s reQU!rement tfon n.fety and ra.diat.ion dosimetry. The tive. when U5ed for certa.ln reeeArch bec:aw,e 1t.s compogtUon lacks lay mem-remal.nl.ng memben; shall be aelecte<l atudiea, It 1.5 neceN&l'Y to es~bl.1!.b criteria

• p. The FDA would, how"er, look from lnd1vidua.1s QualU'led 1n vaned dis* 1'or we of the drug which lnelude a mon1* 'V02'a..bly upon a R.11.d!oactlve ~ Re-clpUnea pertinent to the ~eld of nuclear toring o! that \1Se by" R&dioacUve Drug b- Committee servinit u a subeom-medic!ne <e.g., radiology, internal medl- ltesearch CommJttee. The st&ndardll for ttee of 11-Jl In5tJt.utlon&l ~View Cow*

dne, , clln.ical pathology, hematology, the compos.lt.k>n llolld fµnctlOllUtl of the ttee when the Invet;t.iirat1ontJ ne~

endocrinology, radiaUon therapy, radia- Radioactive DrUi' ReMarch Comm.lttee r 111 a r&dioactlve drug, The Comm.ls*

Uon phys1cs radiation biophysics health are a :unda.meni.1 elemmt In the Com- oner &d~ that this ~aUon does phygics, and radlopharmacy>. SecUon snissioner's detennmatlon. The Comm.ta* at in anr way prohibit an tnaUtuuon 361,1 Cc) <1> has been rewritten to 1ndi- sioner cannot. usume that the require* lnvolvinr it.a Rad1os.cUve t>rua ~-

eate more explicitly the required anent.& ror &dv1Bor,- or ~*"' committees ch Commlt,tff *1.n other i:>0Uc, mat-memben. or other Federal or State Nilll&torY n. including uee of radloactlv, nn

31. One comtnent i:>ointecl out that the ~enc1e 5 will usure 111. cam.mUtee t.h&t ru,s.1f it so cb.ooaes.

proposed § 370.l0O<c> gave no Ku!dance aneet.s FDA criteria for a Radibe.cUve ll5, one comment aunested that. ~-

regarding notification o! changes 1n the Drug Researc:-.h Comtn.ltt.ee. Theretore t.he *use o! t.he Inherent tlznP delay* In-

. membership of the Radioactive Drur Re- FDA cannot, without an indepe nd ent olved 1n obtAinln; protoccl ~VIIP"' anc, search Committee (e,g., becaUAe of re* deuirminatJon, approve

• Committee pproval from a Radioactive 0ru, RL*-

loca.tlon, retirement, or death of mem- that hu been approved by another earch Com.mi~ a.~ e,zn1s1oned b,* thf' bers) and the eff~t o! &Uch chane:es Uency, However, any utablished com- gulaUons. and ~caW1e at the relauvel:,

uoon P'DA approval ot t.he Cozrunlttee. mit.tee, such as the Medical Committee of QM, lhelf life or many of U'\e tarr,d The comment suggested that such 11. State Ra.dla.tion Adviaorr Board, mas. ¥5 utilized. the re((Ulation" include ;;

chapges be reported and documented In lf constituted In ncco rd 11t.nce with J 361,1 um timl' Umit wlthln *hlC"h u1r the e.nnual report and that approval or le) Cl l_, apply t.o t.he l"DA for a.pprov_e.l as oaunittee would tia.ve to 1pcro, ~ r.:

di.sQpproval of t.he revised Committee be a Rad1oa.ctive Drug Research Co~ttee. ject

• pror;lOlled protocol.

determined by the FDA followilli receipt 33. One comment qtJestloned t.he need The Commi11&1oner r:oncludp* rn~:

of the annual report. for ea.ch Radioactive Drue Reseuch ,ula.tlon ot the ti.me required (c:,r l!J*

The Comml.ssioner hu studied t.he Commit.tee to meet at leaisL Qua.rterly, as roval or reJec:tion b:v a ~dJoacu,*r comment Rnd concludes that all change,; provided in proposed ~ 370.lOO<c) <2l, be- rug Reaea.rcl:l committee of I prooo,ec in the memberi;hip or the Radioactive ca.use the Quantity of bui;lness to be con- prot.ocol mui;t be ldt to the uauc-.rnor.

Drug Research Committee e.nd. 19el!Ction sidered by the Committee may not Justify or state or Federal a1otency ,nu, .-ruch o! new memben. Rhall be communicated such rreQuent meetl.ngi;. the committee ls &SFJOCla~d Thr Com-to the FDA u ea.rh" as possible t.o that The cocnmifl1oner concurs ln part and znla$loner cannot pTedlct tti* 'lllorttloa.d the l"DA may review the Qual1fic:a.Uons 0 ! has concluded tha.t the Ra.d.1onct.1ve Drur, of each :R.ad!oactlve Drur ~,c&rch Com-

15: 10 DUPN*1 1*

RULES AND REGULATIONS

... ~ttec; t.hei*e!ote, s~ is no~ ieMible to,* al) Rad!oact1ve l:lrui.:- l'tele&rch Commil- One comment suaestecl t.hat item the FDA to est-'1.bll.sh a time fr&m.e for teei. a.ud will be daci1,15ed In accordJLnce the ".lupan of Re&ee.rch U.se of

,re\rie'III* and appruvul or reJect1on of a witll 1noceaure5 aet iort.n 1n 21 era oact1ve Drug" bO revised to read a.s propoaed prot.ocol. The FOA believes, Pa.rt t. Tbe comm1ss1oner ha& concluded s:

however, thd *1nce the Ra.dioaotivc l.ha.t 1; 1& impracucal, beca1.1,5e o! n:-

Dr1.11:t Research CC>mmlttoe 1r; composed 60urce 11.m1tatloru;. to provide thue re* l&t1on Ablorbad Dok:

i;! per.1;0iu !a.miliar with the wuque poru to Agreement SI.a.Lei; a,nd otber onucl.lde ldcntU1cat1on.

dmlnlatand -.CI.J.Tlt'f CiOH-chile1, a.au1; a,rubl1un., of rese11.reh with >*a<llo11.eLivc _llcens1ng agencle.s and to other 1"'1.JA -I* .

drug:;, cornn1lttcc r-evtew ...-m be ~pon- RadloacLlvc Drni; Rt::iean:ll Commltt.ees eh*e to U1e need" or individual r-eeee.i*cl.l* on II c:ontinuing bans. A spec1tlc reQue11t er~. The Contm.1.,;sfoner further o.uumei; v;11l be required under the public: i.n!or-

,,.u

e. i.&1.ww.. UW1Jb1::.r or &Ctl\"ll1 dOHS per d.

t.

tlm.&ted *btorbed dose, per ..in1n~

that. ordinarily approval o! a protocol ma.tlon regui.a.tlc,11-5 121 CYR Pan ,)

• p 11ur-e-whol1 boor. ronad Mid cr1t1ca.:

w!II be 11ouf(ht bc!ore the tagged drue; ~ arr 37, One commen; recommene1ec1 ~hat obtll.11'!.e.J: thff1*elurl", L.l1t' 11.hcll ille ol the the age o! all rese3rch aubJtcu., not. Just rle Commissioner ha..~ nv1ewea tne t~i.t~e'1 llrui,; will not be arem1ane. rnmors, be included m the "'Report on te~tnolol)' 1n 11.em ~ an<11S or tne opin-

in. &:vend cum.mi!I]l.8 11ugiested \.haL R.e:,scw-cl1 UDC ar J\-.Cl.luu.u~l'l'lt: Dr-UK" 11e, ion ~ t ~lw .n:c.,u.i.rcmenus ,nowct ~

Lhc "&cporL <>n Research Use of Rac1lo- !orth in i.,ro.lJ()Sed D 3'10.lUU(Cl (II). st.a cl in more &l.leCfflc terms. He h!i.!,

acUv i:i Drui;" wl11ch each Radloacuve /U10!.11er co111me11~ O\.Ul8~Cell Lll.uL I.he thcz--t:forc rerued \.heise lJl&r\.15 o! the "Re-Dru11 :Re1Searcn committee 1,; reQWre<1 to nwnbcr o! *du.11.:t i,.m.1 chlldren be 15pec:l- POrtl ot Retie*.n.:h Use at Radioactive submlt annually under proposed I 370. iled separa~ly en ew.ch rePon. " to read as tollows:

l00,c11:ii Sc,r each !Study cond.ucl.t:\l Wlillc ISLICll \J!l\a II.Tit: nuL Ua<:t:2111llr,V to &tile Of th* n.dlO!\uclld*I*) u.aad. 1Il-durin~ the Pr=edlns- :,ear be m.aoe lnOnit.CJr compliance, t.he Co~oner a.nr preMni 1111 ~ e & n t con\&m *

.;:** av&ilAble w A11n:t::wc11L !11.11.t.e& or other conclueles thU daw i,ucn as u:ie ~ anel ur Lmpurttt"G .

.;:;. lh;cll~UI! lf,Mlt:UCICII for future Uceml.ng 11ex ot all res.e&rch irubJecu woul!1 be w;e. flCJ> a.t>eOt"r:...1 cl.-. 01,., th* mstn*

• - &ctlous Wll.hout forfeiting the nondl:J- tul l.n evaluating the tot.a.! ruk t.o the T wbleh -Nodl.at10n aoae CIOOUl>Jtm.n:

cl011ure provisions v:h1ch a.pply t.o pro- Pu,.,>--Ji C h ealt.h an d to ..... 1 -d-vid a.I I

w-u tlm&Ced, *\lcb u bJ ~a.UQo. by 1n I.I s. YITO ~ ~ ~ u ; . , by 'UptAJl.e UCR\lon. or s,netary 1nforma.t1on. Another comment Funher, the Commissioner notes Uiat ~ t . h o d a . l"m Mell *ul)_!K~ proTKle!

11u,gested that FDA con&ider enabllsh* this data would be use!UI to the FDA in .

inl aome mec:han.i~ of advising ltl ap- 11tud1ea of. t.he radiation dose to the PUbUc i ot .-cb N41onucUde MlmWIA*

proved Radioactive Druir aeua.rch com- trom 11.ll radioactive dru,ts. Accol'dingJ.y, wJHc:ca u! UllY liLUdlea WhlctJ nave been I 3ol.11c><~l ot the i-eguJ11tton nas been u. ~l.1-.w(I ab1110rtled ooee per ~11* 14.

-approved uncrer proposed a 370.100 by m0<11nee1 to reQUlre the '"Jtepott on Re* ~tra,1011. a t ~ .... ~.~ u Kesea.rch Committt-e.

TJle Cemm1s111oner 11av111efi tnat. con* b:, *~e a.nd acx.

tenu ot the "Report on Resear~h tJse of. 38. One eomtlleni objected to the re*

Radioactive IJrug" are 11.vaUabJe *ior Quirement ot reportina 1mmediatel.Y publll: Cll:sclu:iun:: uulcu i:cnfidenUaUty . when mor11 than 30 reeeai'Ch *ubJecll>>

1a request.ell bY Ule mveat.1gator o.na lt is were involved in a research project. under adequately shown b:v the lnYe6tieatot i>roposed I 37D.100 alnce t.he lndlvid-J'*

611Y other approved :IU.dioactive Dru.i aeareh use ot &aa1oaet.1ve Drug" to in- ~If bod1, aci1u 1110,ocl-firming arg---,

cl-Ude the dose to eacb research aubJect lea. lot th * *~. 1011.141. uid OUlM Clf'i&ll

°T.*~ more ~ oua &ClmUI.Ltlra\lol::I of .,

e1rug per IIU.bJeC\. inmwa.u,-e OD cicme 11.Jld &at ootwnltmant, u-u whole bod,-, ~IH t.luud-.tun:nuiz

.i.ra.s tA lb* . ,** gu..aa, aud other OMS tn>m the ad.m.ln1atore4 ndloJlu-tba.t the report constitutes a trade secret ual risks to a human 1NbJect. rec1!11"1n<< oM *

. ~r confidential commercial l.ruormation ni.d.loactive material.I are independent s. onu:1. cowt1mon

, u <1e11.ned 1n '21 CFR i.61, A trade se* of the nusnber oJ. eubJeci.a. Another oom* C="nu'ft

. C1'et. as denned m ;.ii C.t'R 4.61, may con* meet telt that 11.llDU&l reportm.J b7 the oi, on t.tiat p r o ~ I 370.l00Cd) Cl>

comment.El expreue<:1 the 111.s~ of. any .ronni.ila, p1Ltt.em, device, or :Radioactive I>rur Jleae&reh Com:n!ttee aho NQUin Ule radi0&A&7 of the

,c,o111pUat.1u11 ur 1.n!urm~Llun wWch Ja ancl their f\mctlon aa a. peer re'riew pba 1naceuL.lc:al prior to Mrnlol@traU.0.11 med in one's bus1nei.s ancl which .8'1v* BTOUP were IIU.fflcient and thue!ore ob- *a.nd e comment. sun-ested th&t the use him an OPPortunity to obtain an advan- Ject.ed to ltti.a)ediate nJJOTtiDir u stated ot doee calibrator be rec;i\1.U'ed. ODe tage over compet1ton -w110 do not know above or wben the reAelll'Cl:!. subject 11 ent a.aumed that a doue ca.llbrator

<< 'LUii! It. t..'OmmerciRJ lntormatton that w:ulcr 18 .J'lt&Z1I ol a(le. be reQU-lnd.

• lit pr1v1111KCd ur cunfldent.lal m11111.r111 valu* Tbe OoPunlatoner w1slles to be certain ouch prol)OM:d I no.too 1mp11es able data ur inlormat1cr, which ii ueed thai tlle recilllJ'e!llanta or t 3151.1 cpro- that the radJoactJ.ve drwr w1ll be uaa1ee1 in Olle'o bU~h1e1t:11111d la u! ll type CWILom* pused. I :170.100) are being lnteTPret.ed,. J)riO to uae. this 1a DOI. 11111.&l.ed EXJ>l.lc:1tll'.

• rll:V hela 1n 111.rleL coni,dence or l'e* and followed ln a aatisractol"J' manner. 'nie Comm11111oner tllerelore concurs ma.Uen 15'Ubmltted or divulged to the- ca.t.eirory of 11tuc\7 In which lt ma::, be l"ood ana orug Admlnlstration wnicn part1cularly appropriate to uamlne br11 r itJ lu.ai:>l,m1PrlaLe, however. 111nce a

sa.r<1ed as prl Vllefl'e<i K..D.d nor. Cllacloseel. Relatively 1.&rg11 reMan::h stuc1ies, 11uch as w1thl \his s,a.rt o1 the comment. coticlud-1.o lilllY member of the public by the per- th011e rei,ultlng. in the eXT)Oflure of more hlt- ihat r-ad.11:iMay of aomc kind 1s nec-lK.lu Lo WilUUI IL 1.M:lunai1S. Dal.a and l.n!or* Llmu :SO rmtmrch aubJects, ntP"811Dt a eaa&t:,- Prior to lJ8e ot the radl~ve fall l'.'ithln the defln1Uons of ., tra.de 15e- whether the need tor the num~ of. othe UNJ' methods would be accent.a.ble.

cret or connt1ent.1a1 commercial 1nrer* ISUbJec~ c:hoaen ill documented, the Bee en 91!li.l <d) <1) <Pro.Polled I ;570,100

!!peel.de deaJ.gnatton of a dose C&ll*

.matlon nrc 11ot e.vlUlablc for public d111- rad1at1on dORe III well Justllled., and. tne- Cd) c >) ta therefore amendecl to re<1U1re cl01:1ure. dl:sLl11cWun uc~wKn ~earch prot.ocolJI rad.I "1' ot tlle n,.d.lun.cLlve drug prtor The note under **Report on Reuarch B.Ud clinfo&l l.rl11.lli I.I ob&vrved, 81inllarly, to i \lee.

U11P. ot Rarlinar.t!vP. Dnl8'" set forth Sn any sti.id:v 1nvolvinll' nd1atlon exJ)05Ure e Commias.ioner advise! tbo.t I 361.l proposed f 370.l00<cl (31. stated that to research subject.a 18" than 18 Jll!!e..rs o! (d) ( > ha.a alao been amend~ t.o st.at.e Lhe name or Lha lnvest.la:ator would not a~e may need s~lal .. ttention to ex- m.or=tfica.l.ly the reqUirement.s whicb be duclosed publicly. Under the nn* amine the b1L81s for carrY1nr out the the oa.etive Drug Research Comm.lt-teguJation Prnmulnated under t.he Free* st.udy 1n that &a'I!: RTOUD and B,11.!;\lre that tee t com.Ider to usure t.l'la.t the rll-dom of Inform11-tion Act. suct1 inform11- the protoc-.ol 111 adequate foi- the saf.et:v dla~n dose to research i,ubject6 is u llon m11:,, be publicly dise101;cd. section of such subjecb. The Commissioner low ?ra.etJc,.ble to perform the atudy 361.l<c) <3) <proposed § 370.lO0(c) <3) l empha!llu.& t.he.t the early notification o! and to meet the criteria. aet rort.h in has been nwlsed 1Lcc:ordl.ntly. FDA under these circumstances 1n no t 88 .1 <3>. To hel'P achieve tbf.l as-way 1mnllu that such atudlcs are unac- aura ce, two &dd1t1on&l rtlClul.rementa Therefo1*c. 1n!ormnt1on from this re- ceptable or 1nappropt11.te or that t.hl!S8 ha~been added to l.b-1$ s:,aragraph;

. ~rL ,*hlch Is nva1Jablc for public 41£* studies reQuire preclearaiiee b7 tl:le l"DA. 11, t.bat the r-ac:Uoactin dru&' cho.&an c:loeure ill 111,ll;o available to A~U1ent Not1ncatlon 1s entirely for PDA'11 biter* fw e study hu tbar eamblnauon or 2:IL&Les nr other lJcc=!lig ~t:'miles aml 11"l 111unlt.u1*lu11 uf 1J11h 11ew reSQlatlon. ll&lt We, tyl,lt::ll ur n&dlat.ion. r&d1&ilon PEDHAL UOIITH, VOL 40, NO. 144--fflOAY, '11LY 2,, 197

vt-1rt-1111

.31306 RULES AND REGULATIONS energy, metabolism, chemical properties, The Cormnw.toner ad~s that the 1e.~r.ltcm.at1ve. The requirement.ab:,'

etc .. ._hlch ruult.5 1n the lowest d~ to definitlon o! "active .tng-redlent" 1n 21 the A for l&bellnc MAY be an addition the whole body or 11peel.nc orgaJU wlt,h which it 16 possible to o'ct&ln the neces-i;(j,ry 1nformaUon and tha.t t.he investi-CFR 210.3<d> <&> <formerly 21 C1'R 133.l<d> <6.1 prior to recod1~cation J>Ub*

11.s.hed tn the Fi:111uw, RaCU.ST'lft of Ped' to t requirements o! the NRC, other autboritiei;, or St.ate az1d local radio ol[ical health authortt1es. P&n-gator utlJiZe adequate and e:ppropria.te March 27, 1975 <40 P'R 131196 > > i8 &J>Pl1- P'I.P (! 1 ot Dl'OPQM:d 370.100 WM ther~

lllStrurnentaUou for Lhe detection and cable t.o l 361.1 (!) <4> of these regU.la- fore ~tten to allow the NRC or t.hc mensurement of l,hc speel.nc radionuclide. tions. Active 1.Ilirredient I.I detuied e.s "any Sta &nd local health f.Uth0r1t.tes to dt-4 I. One comment i;tated that proposed comPonent which 1t, intended t.o furnish clde hether they wLDt.ed a disUnct ra.

li 370.lOOCd> <5> 11,ppearec.'. to prohibit re* pha.nnacologlcal acUvlty or other direct dlo Ive wanung 011 the label. apart Bearch studle11 involving metaboli&m dur- effect 1n the dinsrnosis, cure, mttiirat1on, from other labellni'. The 1uggut.ed al*

llut pregnancy f.lld felt that the accept- t.res.tment. or prevention o! cilaeue, or tern ve does not. provide !or thir;.

abllit.,v of performing a specific study on to !llrect the structur, or a1w function augge$ted J>&ri.i?'&Ph <fl <6> 11; no1 i;,regn1l11t. !emllles should be the dec1J;lon o! the bOdY of rns.n or other ananals. The ble since these are not 1.nvest.igr,.*

n! the FDA-approved Radioe.cttve Drug term shall mclucle th01e componen~ tion dr\l~s. as t.hat term is norma.11'*

Reset.rch Committee. which may undergo chemiClll cha.n~e in U&ed (U .. a drui unoer an 1ND1, ,1*.

-Both the International Commission on the manufacture of U1e druz r.nd be pres- th h thue druga are used for ruearclt Ra.d.1ologics.l Prote<:tion <ICRP> and the ent in 1.he 1inished druS p~uet tn o. The ia.tement de&enbed in I 361.lCf > <2,

Nauonal Co\lncil on R4diat1on PTotec-t.ion 1Lnd Me1L6Urements (NCRPl have expressed concern over the JX)f!Slble ad-mcidl.fied fonn intended to tumllh the specified &etiT!ty or ertect." The com-miisioner agrees UlAt ra.dioact1ve cl~

eea; use is P !or tadioacuve drugs 1or re-under t.ll1s aec:Uon.

W th regard. to the suggested par1>-

verse effect& on the human etnbryo IU\d prod\lcts iiltend@d for parenteral admin- ,rap <Cl <7'. tht name and qua~Uty o!

!etw from. radiation exposure to J>?'eS* ist.ration \lllder t 361.1 should be labeled au teriost.atie agents and other 1.nAc-nant. women. The commissioner hu to identify all tnactive 1n117edients In the tive ngred.ient a.re r~uired by 21 CFR detenn1.ned that, becau5 e of the potential ..ame way as other drug pnxh1ets for :Z0l. 00(b) (5) (ill) <formerly 21 Cll'R ruk to an embryo or fetus, the w,e o!

• pa.rentenil administration 1.mder I 201.100 1.10 Cb) <2) (vl <c> > if a drug product ts radloaetive dru~ du.ring pregne.ncy can* <5> <111> <formerly I 1.l0S<b) (2> <v> for arent.eral uae. Section 361.1 <f> <J>ro-not be lfenera.lly reoogna.ed && &&fe; <cl' and has modl.ded ~ 361.l(fl oon'e- 370.lOO<f>) h&S been mod.1.Qed \.o

- there!ore. iracti studJe.,; cannot be eon- spondl.ngly. /ill other lAbel rt,q\liNmenta incl de th1a reqU1l'ement. Section 502 <h, l.m.posed by sect.Jon 602 lb>* 11.11d <e> of of e &et require& that dr\1gs li&ble tn

=

ducted under 1 361.l. Thia Urnitatlon 1n 110 way refiect&, however. any prejudg- the e.ct which were *t&.ted ln the pre- de oration aha.II bear a. 11t&teinent of ment ~ to whether wch a stud,v may e.mble to the propo&al b.&ve al8o been Prec&Utlon u neceesa.ry tor the pro-be conducted under an IND. The Com* listed under I 361.1 (fl. on of the pubUc bes.Ith. The Com-m.ls&.toner emphasizes that the ra.di&tion The commis81oner aao a.dvu,ec that the oner eonclude11 that, bec&wse of the csose limits, J>harnu.colog1eal dose Junia;, proposal ctn the preamble llld propoeed ~ nature of rMUoactive ~ & . l,e,,

Rad.Joa.ctive Drug Research Committee f 370.lOO<f)) 1.ndicated label .t.nd labelUlit radJoiaetive deuy. the label for such req\l!rement.s, and all other 1'9Qwnment.a requirement.& for radioaet1ve zna.terials. aha1l contain &n expU-ation date.

of f361.l rel&te only to a &JP~c rroup Buell reQulremmta are 11~1t1c label re- toraire conditions ~ neoes-ef radioactive drugs ror certain reM&rch qwrement.11 u 1mJ)Ole4 b:, ecct1on li02 maint#J..11 the drug product's uses. There l.s no Intent thAt. ~Y of these and Ce) Of the ac~ and ce:rt&1n other st.ability for 1t& anUe!oated ebelf li!e, Um.its reprei;ent actual or de f~to limits reqwrements and are to appear on the ~ut11-Cturer.s a.re. responsible for pro-for atudles conducted under an IND. label o! the im:nedie.te coni&.i.ner &lld 'V1dijlst such ln!ormatlon in the labeling.

Therefore. research studie,; 1n 'J)regna.nt shielded container un.leas otberwue spec- I! aJ ndioa.ctive ~ la recoiroiz.ed 1n an women may be permitted wbere the U1ed. The wor~ 1n Ute 1mal order otnecompendlu.m. lt 11hall be labeled aron.sor submit!.; an IND a.nd complies has been re'Vi!ed to refiect this. IMi rescri'ced by ucb compen4.lwn.

with the :requlremen.ts of l 312.1.

• 44. One COJ:nIMnt *UJll'est.ed revising t !rood manu!a.c:turina Pract1Cti

43. one comment requested clarinca- ~ P h <f) o! proD06ed I 370.100 to req

• that the manufacturer usure tion of proposed I 370.l00<d> <7) as to read: "A r&dioaetive drug preJ)IU'ed, th& the drug tlnJ&hed dosare form lla.s

. ... ,e ' ta......- ment 1n *'No etudy in-wh eth er ..... pacltared, diatribU~ and primarily ln- the identlt.Y, strength, quality, and p\ll'lty tended for use in accord&n- -'th .... at.a d 1n the. labeling, For n.dioa.etive

.. TOlVUJ&' * * *, no m11.tter how sm.aU the ....... ** ,...,.

t 0! Uvi _... ,, reqUirementa o1 UU.. aecuon aball be u:- for p&renUT'i.1 use. inanu!a.ctureri;

~~ *

• k .. ,

--  !'7,""::iict ~\ti~~ 1: : '1DDt from section 502 m <1 > of tbe act m \ t.beretore have. eviden041 t.bat the t1ve t>rug Re.,earch Comnuttee approval,* &ml &eetion 1.106 of thil chapter 1! Ule me ho& of manufa.cture and ;terilizn.

t th t pa.ckA4Pnit, llLbel &n4 labellll8 are 1D com- tio employed are adequate to emure or e we O any QOmpound conta.1ning pll&Dce with Feder&l. State. and 1~-* iaw a.eh .t1nal product ls stffl.le anu naturally occurriilg ni.dloisotope.s 111ch * ..._.

a.& potasstu1:n which contains 0.012 per- regarding radioactive materlala and 1f P n rree. It 111 the responalbllity ot cent a::--to. the JJM:kqmg, l&bel and l&bellng re- t.h. ~oa.cti\le Drug Research Com-

'The Commissioner a.dvi!es *'-*t

• 301.l Quited for ra.d.toacttve material$ by the mi tee to det.ermint that rac.11oaetlve rn11-

,......, ~ 'Nucles.r Regulatory Commiulon &lld by te ls for parenteral use under I 361.l rproposcd J 370.100.1 pertains onl~* to Bt.&te and loc&l rMilologica.l health au- prepared in 1urlle and PYro~en-fn:e

<:ompounw; to whlr.h tracer quantlti~ o! thoriUcs bep.r the followtng: * * *."The certain ra.dionuclides have been deliber- t f _... *

• a.tely attached and not to an eleroel'lt. commen u, .. ,er J>roposed tht addiUon he Commi,,;r;loner 1'11.1; s.lso concludec:

such a,; pot.ai;.slum, which cont,.iru; trace of n new paragraph U 1 <61 to ree.d t tbe specific concentration for w:11 "whether the drug ls for tnvestiutiona1 loactive drug 111'lould be expr***ed o1 1 iunounu; of radioisotopes 1n its naturn.l 111,e on1:v; ** an d a. new paragnp h tf.l<7> th label. Section 361.l<fJ 1propose(l* .....,

,tate:. Section ned t.o reflect this. 361.1 <d) <7> has been modi- LO retL d "'I" i t

.. e exp rat on date. epecial ** 3 0.1001!1 .1 ha.& been rev.I.lied to reQ\11r~

st.oraste cond.itions, pyrogenlc:it.~*. specific th t the 111.bel include the to~"1 quo.ntit ).

43. One comment Quutioned the concentrabon aDd 11-dditlon of ba.cterio- of dloactivity 1n the drw: produci-11 lnl*

meaning or the word "active" u w;ed in st.a.tic a(tents" a.nd add!Uon of 11 nev.* m *ate container and the amount or ru*

th e term "active l.ngttdicnt," relative to sentence reading "tn the event Ula!. the di a.cth1ty per unit volume or unit miu::-

~onnatlon required on the label by 11e-c* l.m.medlate container ot any radioactive at a deaignat.ed referer:ced time. Sec-tion 502 <e) of the act and proposed drug is too small to contain the infonnll* ti 381.H! 1 hlLli also been revised to re*

l 370.l00<r> and e::ii::1>ressed the fMllng tion set forth ln pU&grapb aeven <7 > q re that. the l11.bel be11.r th!!! route of 11,cl*

• th at all in~lents ln an inJecta.blc 111.bove, the in!onnation &hall be fUmished !stration Uthe dnie ts for ouier th11.1:

prepantlon ahould be 11pec1.0.ed and listed in the product's accom1>:m:v1.n1t label. or l UM:, as is reQuired ror all prescrip-u1:(ler propoaed l 370.lOO<r> &nd a .deter- The Com!n.lt.sioner concludes that the ti dn.iii; under 21 CFR 201.100. In*

~=~~~o~t~ter on Whether ~ey arc 1nitla.l wordlnR of t 381.l(f) (J>ropo&ed foeation which may be placed on U1E>

1170.lOO<fl) 1a greferable to the IUK* larl of \.he shielded cont.alner only ~f

....... MGonn, VOL'°* NO,,.,_**,, ,u., U, 't"

J....J* J.....J V'-"I "-'111 RULES AND REGULATIONS tne 1mmedla.tt: container label ls too der topi~ A. D. anu C or low: p1-eau1blc Q\ll -=rnenl.:I. and tbat Uie t.ime periods im-11 u, accommoda.t.e 1111 ol t.he ncc1:11* Lo I.he Jul.Y 29, J07i ):ll'O~l, t.1-C: pern11t* e.s 1141l~<l alluulll llO~ nsulL w a lut,rd

• 1111ey 1nrarm11.Uu11 .i.5 ~lbO epeciOed. ted to rni.ve on t.bc.lr label a.cd ln.bcl.lJ:li: eht loO any manufacture1*.

1.nforma.tlon requ.ired by the Nn.C and 1cn:l1.1n:. under tne Federal J"ood.

M1sC'r.1,,.,-,n:ong St.ate and local radiation control author- Dr ii. a.nd Cosmetic Act lsecs. 505. 701 t:i. Oue cu=e11L 11u11!i1::1kd chang~ lt1es, u au or Ll.J.i: l"DA lllbelinK require* 1a1 . :;2 15\.&t. 106Z-.10.,3. u amendetl.

~ n (b1 o{ prcpoaed t 370.100 i.o ments or section 002 or i.he act n.nc1 21 105 121 u.e.c. 36e>, 371 ta,,. t.he PUt:>llc rell4: "n1e ~ucllLiuwi Ullllc.r wh.lch µtse Cl"R :.i!0l,100 ctormerly 21 Cl"1t 1.10tllbJ) Ht: 11.ll Ser\'lt:c Ai:t \IA:C. 351:, ~II Bt.at. 102.

o! i.w** 11'.dlui\C~IVl" di*us for re.r.earch, 11.reml!!l.

O 11.s 1cnded <42 U.8.C. 2621 J, aul.horit:,*

whlch l::w.s been. are nuw ur WW lie r-.:11* 49, one comment i:xprt:ue<l t:u1u.:1:r11 <lt:l 11at.c:d to ll1t: Colil.Ullisaloo1:r (21 C1"R Ula.tea bY i.:ie Food and Drug ,\d.ml.nlJ;* as too t.ne etrect t.he&e reB'\,llaUoru; will 2.1 01. 11,.lld 1ll cuupen1.Uon W1t.h tne NU-t.nitiun or whiclJ u; i.llt.rocluccd U1t.o 1.ULe.r- exert on i:wt.i.1111 cowr.,t,UL.iuu wlth1n the cl .r Re11ul11o1.0ry Couwwm\un, '1:~\.\-c 'l.'.

5't&l.te commerce. ru; 11a.!e and e.tfecttve . racuopnarmaceut.lc::al Industry durmi; the or e Code of Pederal Regula t10ns 1.s u.n:,;". Tl.IC CUUIU1t:11L WIS0 15U!18eli'loe'1 WU* t,raru;lt.loD {n1111 .r1:11ul11.~lu11 Lill IJ.ie NKC W &lll 111.lt:u 111,:1 lulluw:,;

ing a. new paragraph (d> to propOlied re1:1u~tlou by the FDA. l!"urthtr, the com* PART 201--lABELING I 3'10.100 to stat.e "Ttlese reB1,1lations will ment expressed concern regarding the

~

not act to exempt any d.nlg covf!red bY cost of the tra!UltJon &nd 8JlY compeUtlve In 8ubpart D a new § .201.129 *~

Ula piLrt from r.ny other provision of dlsadvll.Iltage or renricUona im~ed dur- ad ed to reM1 u follows:

lu.w u.r ri:1tulu. ~iuu ui,i.1licu.bh: l.hen,tQ. ins ~.1.5 t.nm.&.IL.luu J.JCriUu. Tl.le cuUlllle.11~ § 2 l,1Z9 Dnap and device: f'.lU!zi>ptiun The Comm!Mioner ha.s concluded that emphuJ.r.ed t.ha.t it is es11mtia.1 t.hat for radioaeliTe d1'111ltl for re11C,ard, the suggested changes to proposed ~ !70 .* nothing ln thMe regulatlom create ,. I llfe*

100 11,,ri: wwecl:lSSllrY. Tlw; re1A1111.L.lon 1D competitive a.dVaniage tor one uianutac-no way tmp1ie11 that other provisloru of turer over a.not.her. A rad.loa.ctive drug intended tor at.1-law or reiru}ation a.re not applicable. In The Com.m1.sa1ocer sees no ba&1s i'or mi.Il,iatratioc to hum&n research *ubject.s 1aet. the reB'\,1111-tlon clearly alludes to the the concern eXJ>ressed by t.he comment, t.he course of a resea.rcll J:lrcJect licensing r-eQuirements of the NRC. This 50. TWo comments point.ad out 11. typo- ed to obt&1n* btu.lc rtsearch in1'or-reB'\,llaUon '\l."111 aPPI.Y to all radioactive graphical error In t.he paragraph head- n rera.rd.lri, metabollmi <includlng

'1r\lgiJ ~at are generally recotmlzed u ing tor proposed 11.lOSlr,>. The word cs, '11Btribut1on, and Joeala&t10n >

we and ei!ectlvc until future develop* "radlocative" ahoUld re&d "racUoacttve." ra.d1oa.et1ve.ly l&beled drug or re-merits. ~rience, or knowledge necess1* The typoirraph1cal error u noted 1n r~ hum11on ~ioloSY., p&tbObhYs-ta.~ revision. the commeci has been corrected. 1n &d- i o ~ or b.lochemiatr)" <but not in-411. One comment stated that there d.1 Uon, propoeed I 1.l0Glp> bu bee:l re- te for lmmi:diate theni,wt1e, e11,ag.

were no recommende.tions 1n the pro- cod1:0ed u I 201.129 in the final re~a- n c, or llim1l&r purposee>, \.IDder t.he r:,01ed reirula.Uoru. i:>erta.1n.1ng to the tion tnaccorda.nce w.lth t-he rec-od1.0cat10n oonk:Ution.s aet tortb In O381.1 o! th.ts J)ro-per disposal or isotopes, of I 1.106 into Pa.rt :101, publlshe-d 1n tbe chfl!p(,et, ah11.ll be exempt from aection The Commissioner advises that the l"StlttAL RROJSTH o! M*rch 27, 1975 (40 &02~!) Cl) of t.he t.et lf Uie ~ -

Nn.C and Asreemi:n\ States cODtro! ra- P'R 13996), ~ l . t.nd labeling are Jn CClall)U&nce d.1&tlon safety durln11: the ma.t1ufa,etw,,,

• Wit.ti I ae1.1 m of uus chapter.

uae. and ~Sll.J of radtooctlve ctrun. En"scnn: D.n-m

7. One co1wm:11L asked 1l 11. 1111parale ~1. One co=ent request.d that Ule j _ rART Uo--NE;W DRUGS omce within the !"DA ht.d been uaigned December 31, 197( and Jul:y 1, 107& dead-responatbl11ty solely for ra.diopha.rmAC11u- lines a.s set forth 1n the pfOPO$a] be ex- 21 In I 310 .3 &dd a new J)ll.lqraph <n i t1caln.

• tended b:, t.be FDA OD a Cll'\ll'*b7-drua t o ~ aa follo'W!I:

The eonunu.&ioner advloe1 Ul~L Ior al1 flhll man WIIC ~11n1r*by *.i:mui u..Oict.arff ba-rad.loactjve dru,r products, ineludlnf ra- sis to provide adequate time to com_ply dJoactlve blolo~ca.J products, rniew or a witn t.ne 11naJ ~t10n&, f0UOW1Dg &IlY "NoUce or Claimed Invutlptional Ex- -.ny *modtftcatfon resuUtng from com*

0 5~0..3

<h>

. . The Defillll1Jon1 ud ia.lerpt'10~,

term "n.dioa.cttve ~ ..

emption for a New Drug," amenclmenta uients submitted. m ~ &DY mblltanc. deftned u a ctrug to 111ch notice, " new druir api:,Iie&tion, in tion 201<r> Cl) of the Pedetal l'ood, "nle pros:,oaa.l lden~ed e!ff!Ct1'Ve data

• and Coametic: Ailt. Which mubtta aznenwnent.s and cupplementa ~ ,uch tor apec!Ac changes to 1mpl~ment PD.A ,1J>O taneous dillintarn,.Uon ot un.sta.llle ar:,plie&t1on, and e,pprovtnir and monJtor* regulatJona retrard.it>,J rad.loact1ve new lng the RCth1ties of the Radioactive Orul drugs. Due to- the letllrt,b of time needed nu eJ witll tbe ein1Aion of nuclear pu-Research CammJtl.ee"ellalJ be the respon- to review the comments and prepue the tlcl , or photons and 1.ncludea Ill.Ill' non-aibll!cy of the RadJD'J>harmaceutlcal final reeuta.tton, thi: COmmtu2oner hae ra~ve ru,ien1, It.I~ or nuclide ren*

Oroui:,. Division of oncology lloZld Radlo- found It necessary to extend t.heH pro* en. r whJch ii Intended to be -uaed In t.he prei:,uation ot &D1 auch ,*ubltance pht.rma.ceu~lcal Druir .Products, CHFD-- posed effective dates as follows: *<l) the t ,.

150), Bureau of Dnie:s, 5800 Fishers Lane, Pecember 31, 1974 date :for 1111bmiufon but does not include drua.s IUch as D-COllt&~ comJ)()U!l(!a or J)OW-llockville. MD 20B52. Elsewhere 1n th1' of an NDA. mn, or t.n ap)l11catJon for a 11 -coz:it&i.n.ins ali.t 1rhlch contain ts.rue of the Fr:trr:uL Rl:cmrn:n, the Com- biological prex1uct llcenae for each dnll' t ,quant1t1ea of n*turally occurring

~torier is lasutnR an order tn.nsrer- containini those radionucl1(1e,; llst.ed UD* ra ODUclldes. "nle 1.emi "ra.dl011.Ct1Ye rtng rest><>nsibWt.y tor n.dloactive bio- der I 310.503 ct, 11 > and for subu:Uulon i

mcludea a "radioactive biolog.lcal logical products from the Bureau o! of t.he information for an 1.nvuturational p uct" u defined 1n I 800.31ee) of this BioloR'ics to the Bureau of Dn.lts to con- new dr\lg a.5 requlred by I 310.S03<1> 1S C ter.

aolldn.te pr~essing of o.ll radioactive drug extended to August 211. 1075: <2> t.he matters 111 one amce.

• October l, 1914 date referred to ln I 310.- In I 310.503 revue ~raph (d 1

48. One com.rriP.nt indicated thnt )'ro* 503 ls> is extended to JUly 25, 1975; (3> a &dd Dl!!W pBMIC&l)ha (C), (If), and p(llled 13'70,10011'.l permits the la.bel and the January l, 1.975 date referred to In (h>r to read M foJlo11'15:

le.bellng ot "t.agtr~d" comPoUndll to con- I 310.503 <f> C4> and 15> and Chl .15 e,c- S aio.503 Req,ai.remenu ...,.i:11rrtin,: ttr*

t.a.in tnfonn11,tlon required by the NRC or tended \.o after Augu.st 25, 19'15; <4> the  : l*ln nidiolcliTe dl'llf:11, State a.utho11tie11. but. thi~ ie not men* effectJve date tc-r delef.irui Ule "Note" that t.ioned rei,?e.Tding t-hose radioactive dru,s 11,ppe11,ri; aL the end of I 312,1 ii; extended * *

~overed under topics A. B. and C or the to after AuiUSt 25, 1975: and (5l tlle <~) Cl.* In view ot. the ext.ent of ex-preamble to the r,roposa.1. Juh* 1 lll75 date referred to In f 310.503  ;,etjence w1th the l.soto~ U.Sted ln J;)Clra-1rra.~ (c> o! tbis section, tbe Nuclear Tllc Comml.AA.loner ha~ determined <d1'c31', (f*1 <5), and Cg> Is ext.ended to Re atory Commi,sion and the Food 1.ha.t a.II radioactive druitS, .In.eluding Februnry 20. 1'116. The reErUl..ations ha.ve those which r~u1re ~e submission of an been revised accordingly. The Comma* an Drug Ad.ministra.t.Jon conclude t.ha ~

NDA, IND. or 11,n 11ppllcatlon tor a bJo- 1loner concludes that Uu!re has been ade- su~ iao~pe& should not be d.1£t.r1buted lulriclll prod ur.t license, e.s <1.1Scw11ed un- quate c11,cuss1on 11-ml noUce of t.heiie r~- un er tnvest1g1Ltlonal-we la.t>e11ni= v.-hen PECIIII.AI. UOIITH, VOl, 40, NO. 1<14--fllDAY, JU~Y 2ll, I J

.,.. 15: 14 DUPONT 012 31308 RULES AND Ut;l,ILATIONS they ._re a,etuallY intended for us1: ill l::o'oOd and Drw,; Adm!u.lstr11,tton, 0800 lh) The exemption l"eferred to 1n p:1r.

med!Clll Pl'ILCtice. Fishers *Lane. Rockville, MD 20852,

• new agn.ph Cai, LO; applled to rmy drug rior c21 The exemption referred to 1n drug applicatioti or 11 "Notice of Cla.lrned referred to in pa..rairraphs <di. <f 1, and i,arll,imph <a) of this section, u applied lnvestigaUona.l Exempt10n for " New. . <e I of th1J .section. u tenninat~ a!ler to an)' drug or biol~c cont&in1ng t.nY Drug" for each such drug for which the Aug:u.st 25, 19'75, ol the lsotopei; 11.sted ln pan.gl'll,ph <cl manu!a.cturer or d!strttiutor does not ,

or this i;ection, In the "chemical Iorm" hl\ve an 11.pproved new drui appUcation / PART 312-NEW DRUGS FOR 11.Dd intended for the UM!!; stated, 1.~ pursuant to ~tlon 505CbJ o! the act.. I!: INVESTIGATIONAL USE terminated on March 3, 1972, e:itcei:,t DJ; the drug i& 11 bioloi'lc, a "Notice o! j provided tn* paragraph <d> <3> or this Cla.imed Invest.Ura.tion Bxem1JUon for a 4. In I 312.1, a.mend pa.ragraph l& * ,:: ,

section. New Druii" or an appllCiLtlon !or a UceDBe in Form FD-15'll by a.ddtna: a net1

<3) The exemption referred to in para- under section !&1 of the PubUc Health tum 8.d 111.nd two new sentences to Heu graph <a) ot this 11ection, as o.ppliecl to service Act sh..U be :rub.mitted to the Bu* 10.a and delete 1n lt.s entirety, etl'ectiv, any druv. or biologic eontainl.ng a.ny o! I reau o! BloloBics, Food and Druir Admin* J.~t 25. 1975, lhe "Note" regardinr the isot.opcs listed 1n PllTll.lll"BPh ICI o! lstration, 8800 *:RockvUle Plk.c, Bethesdo.. an order of the Comm1ssioner of Fooc this section, lu the "ehemlcal form" and MD 20DH, in lieu of a.ny 1ubmts,ston r.o the 1 -.nd Drugs p~bl1Shed in the F'ZDu.>.1 intended for Lhe uses L1tated, for -which Bureau or Dnla's. / Rsoisn:11 on Ja.nuary a, 1963 <28 FF drug a new drug application or a "NotJce <(> The exemption referred to in pan-I 1'3), a.a It a.ppee.rs at the end of I 31:?.J o! Cloimett lnveaue:a.tlonal Exemption e:ra.ph ,a., of this section. as appUed to, to rea~ M follows:

for a New Drug" wu wbmltted prior to any drtii or biolorlc contA!nmg any ofi 6 312.l (:OnditioJ1* for ""ra\lplion ,,.

Mo.rch 3, 1972, or tor which biologk an the 1Botope.s listed in pnragraph tf) (1 J ' n** dru11:~ fvr invce1i,r11Lional mw*.

application for product Uceru;e or "No- or this section, t.n the "chemlcal form":

tice of Claimed lnve.st111:a.tlonal Exemp- and intended for the wies 1tat.ed. la ter*I tion !or a New Drug" we.,; IIUbsnlt.ted m.in.e.ted Aurust 25, UJ't!i except aa pro 1 prior to l\4areh 3, 1972, is terminated vided 1.n paragrap}l m of t.b1a sectloni J"ou.t 1"0-18'71 eiU:ier uoon lsotla.nce of a nonax,provable <51 The e:umpt>On referred to tn para-i notice for the new drug appllcation or "ra.ph <a) of t.!l1I 11ection, u applied e. * * *

• .,pplication for product license or ter- 11.tlY drua- or b!ol(l3'1c confA!ning any o 11. It th4' drug u a radla&ctln clrug, au.ff', .

minaUon o! the. Notice of Claimed ln- the l.sotope.s l.i&ted 1n P&r&'1'&Ph <fl (1 I ctent da~ 111uat b4' aYall&l>le from &IU.mi vestigatton.a.l E;,cemption tor n New or this section 1n the "chemlcal form' *tudlea or prevtoua hunu.n lltudJH to 11.llo'

& l'eUOnablc M..lculatlon Of radl.llUOtt ~

Pru,," or on February 20, 1976, whlchevl.'r and 1.ntended for the iues Btated, fo

• 90t!Md d ~ upon '4ml.nl.wtnUon to a bu.ma:

OCC\lra drat. which drug a new dru&" applieation *or being. *

• * * * * "NoUce of Clalmtd In*M~*~nal Ex (f) (1) Based on its experience in re,- empt.tog tor a New Drua" WM 1111bm1tte 10.* *

• Ul&t1ng lnvestll(atiorial n.d1oaeuve phar- t.o the Bureau ot Drup*oi:i or before Au ma<:eutlcals, the Nuclear Regul.a:tory &1,Uit 25, 1975 or for which biologic an apl u

a. * * *

• uru,: I*

• l'&d!o&eil'llt drug, tbe CllnJc.

Comml.AA1ori hu compiled a list of reae- plication tor JmXl\leC. license or "Notice o pllann&co~ phaae muat. Include ~Ud.l, tor~produced Isotopes for which it con- CIA.imed InYest.iptionAl ExempUon fer W'bJC'll 'Will Ol)t.,.ln salllcltDt data for <SOIWI sSders that appJlcanta may reaaonably New Drug" WU .submitted to the BUl'M *tl"'Y -1cul&t.10na., 'nine. atudlaa 12:touj be e,;pec~d to submlt adeciue.te evidence of BlolOric& on or before Au,uat. 25, 19i ~ u a u tho tseret.ton, "'bole bod,- retei of safety and errectlveneSi for wie as rec- ls termin&~ either upe,n ilaua.nee of "°n, and orp,n CU.tnbutlon of t.ll* "'1l; actJ u ma wr1&.l.

ommended 1n appropriate labeling; ffll!h nonapprovable notice. for the new CU'U UBe may include, amonr others, t.he WJeJ, 1.ppUcat.1on

• or appllca.tion for produ .*

1n this t.at>ula.Uon: 11een&e or te.rm.1.natlon of the "Notice o Clit,.imed lnvest.li&t1onal Esemptton tor PART 361--nESCRIPTJON CRU<rS "fO New Dtua'," oi:: on P'ebruary 1!0, 1117 t4UMAN USE GfNEAAUY RECOGNIZE 1.IOIOi>(' CIINDlaw lofln u ... whichever OQCU1'II fini. AS SAFE AHO EFFECTIVE AND NC 1g1 The exempUon n'fen-ed to in para MISBRANDED: DRUGS USED IN R irrapn (S.l of tba secUuu, 11.1t *PpJ.i~ SEARCH any dnw Intended solely for invesUea 5. Add o. new !'a.rt 361, consisting-tioD&l lid u pe.rt a! a researcb projec ,

1.hia time of one Met.ion, to read ,

Whlc.tl 'l.1ff .bad been apprvved un 01*

fore July 21i, 111'75 in accordance 'fl1 Collows:

~D~

crum lluman!IM11'ffl alt,ur,un mi,.r,,- 10 CPR 35,11 <or equivalent tt.eU,.lation A"OTJIIOalTT: Pea~ Jl'ood~ Pr1.IS, IUld ~

119m, IJ)h,r...., au ~ m i t State) b tennim,ted Dl'Clc Act, e.oc. 1105, '701 (a), all Stat. 106~10(

Do ** , *. n1111.h:,leneuiaml11P Xldo~ imnclns:: February 20, 111'76 l.f the m.anufactUNJ' _. &IIM!Dd*d, JD~II (21 U.S,C. SM, 871 (Ii J1P.n'-Lkl a.cl<! lrldl'.1"7 fun*Uuu J'Utlllc Healt.b eet'Tlce Act, 8-C:. &&l, 611 Bt:

n (Sni. H11d1r*. such drug or the *Pomar ot the lnvestl '1'02, u ameneled (f.2 tr.s.,c. 202).

a *********. d,:, *************** nn1n lm-,ni,. t.ion of such ~ sulmlJta on or befo Da ***** l'OIJ'l)l>~l'l&WI **.** llnl"lf' l.,._j11s:.

l>o ***** 'l'~netai.eo *rr** Luu,: UW1f111~. Au1rUSt 2s, 1975 to U1e Fooq and I 361,l Radio,icth*e cb-a,r~ fur r.c-rh, If 6"41 al bun>*,, Aclmin1strat1on. Bureau ot ~ s . rc.carchllt'eJI, l.>o ***** n!~~>-

• Bu1wiWMC:i111,:

150, 5$>0 F'iahers Lane, Roc,lcvllle, 1a> Radioactive drugs <u defined .

e,idrum~tl!. 2D852, the followi.ne l.ntormat.lon: <<310.31n*, o! thls chapter> a.re gentra..

(2) In View of the extent of experience

<1> The raearch proJect title:

< 2 *, A brle! e1escrtPtiOn of the pur recoenized ~ 111,fe and etr111Ctlve whe-n a 1'1\tn.lat.ered, under the conditioru t With the isotoJ:lel! 1.1.sted 1n Pt.ranaph m or t.he proJect; forth In paragraph <b.t of thLF; tt Cl) of thil. section, the Nuciur Regula- <3, The. name of t.he lnv~Uiio.tor r~- Uon. to hum.an research subjects dur1 tory Commission and the Food and Drug ,;ponsiblc: the cour-&e of a research project Lntend Adm!nlStratJon conclude t.hat tney should '"' The na.me and llcetlAe number ~r to obtain b~ic information f'e£'Rrdl not b4! dil;tributed under investigational- the inKtJtutton holdiug the spec!Oe - the zneta'oolism <J..ncluding lc.11Jet1cs, d use la.be~ when they are actually ln- cen!ie under 10 cm 36.ll 1or eQuivale t. t.ribution, $.nd localization> of a rad.

temle"1 for use 1n medical practice. reguia.tion ot a.n Agreement State); a.cuvely l&beled drug or regarding hum

<3, Any 111iLnufacturer or cUJ;tributor (5) The name and me.ximwn a.mo~t physiology. pa.U'lophysiolog;r, 01* :b.

interested in contln\\ing to ahip in lntcr- per i;ubject ot the radionuclide u..ct: ~ chemi.!try, but not 1ntended for lmn*

&I.A.t.e commerce drugs containing t.hr <(l'I The num'oer o! rubJecta involver: (ta.~ t.herapeuuc, diagnor;Uc. or ii.mi*

I.sot.opes listed in paragraph <f .1 1 1 *1 of Q~  ! pUrpo,es or to determine the u.!ecy a this &eetion for a.ny of the lndicatiom; l 7, The d11,.te on which the adml.n1$l* e1%ec:tlvene..& of the drug ln humai:i.s listed, shiLll submit, on or before Au- tra.Uon of the radioactive drugs is *~- auch purp(llles Cl.e., to ca.ny out a cli:

gust 25, 1975 w the Bureau of Drugs, P<<ted to be completed. j cal trial l, Certain basic reeeareh stud; ffOJl'"- HG15TU, VO~. 40, NO, 1o4.._,.IDAV, :n, 19,s

15: 17 DUPONT 014 II I

i I

RULES AND REGULATIONS At nm* ume n prc1J.)0~~~1 i1- upPt"oved 'lllhich 1 i, *, Tl,c ilwestigait.or uUllZe a.d£que.t.e li.11.~*l* to resul~ !rom thl\t r.tucl~*- 'II,,, .*

involve,; P.xposurE' either or more t.hll.n IUld l\pp:ropnsne iratrurnentauon !oi- the !ore t.he pl'otocol en.all be based up:i,,

• 30 research i;ubjects. <1r at u.ny research detection and Trn!aJ;urement of the spe- sou d ra.tiona.Ie derived Irom approm 1:-.l~

subject under lA years-or a.,:e, the com- cific rad1ouucllde. -a

• 11.l ritudie~ or published litl'ra ! \Jrc mit~ shall immecl!lltely submit to U\C , 2

• Pharmacoloalcal dosage. To de- andi.s.hnll be of sound clc.s.iirn sue:~ t11::.:

Food and Drui:: Admhili,tration a special terml1ll: tho.t tbe amount or a.dive ill* huo ma.tion o! 5cientl!l.c value ma:* rr,.

1>1.11:nmar\' or 1n!onna1.io11 ill the format ,n-ed.ient1; to be e.dminu;t.ered docs not !\Ult. The nu;illl.tion do~e shall bC! Utl\i, 1;ho'l'l"11 £n t.hi,; µo.ra.s-raph. Content.G o! exceed the limH:,.1.tioPJI set forth in pa.rn

• sum 1ent nnd no ,::renter than necc~~ar*.-

these reports an:1 ll.Vo.llablc tor public STaPh <bi r2., of trus t1er.tlon, \.he corn- to t.aln vo..lld mea.surcmcut. The i.::::.

cl1.Sclosure. unless con!l.dentJa.Jlt~* i.s re- m1ttee shall reqU1r$ that the 1.nve5titta.tor jec d number ol subJect6 5hllll be su::..

qu~ted b; the lnvestigat.nr and it 11\ adc- provide phB.rIIln.cologjc11.J dose ealcula- cle but no greater thlill necessar;* k~

Qut1.tel:, B,llO\Til by \.he 1nve5t.1(i?iltor thlH t1on..~ based on dat.a. a.ve.ila.ble from pub- t.nc 1purpose ol U1c studr. Thi\ nwnnt*:

t.hc reoort constitutei:; .a trade isecret or lisned literature or !rom 0Ulc1* valid of 4ubject.~ shall also reflect the !M~

<"on11dentiCll commercial lnlorm11.t.1on o.s human studiP.~.

• th~t.he study 1s intended to obtain b:i~:c ctefmert tn t t.61 01 this chapter. (3, Qualifications o/ in&,e~ttaators, re.s ch information re'ferred to in par ...

14, ,Approml, Each RndioactJvc Dru!; En.ch 1nvest1i.s.tor sho.11 ~ QUalified by itrn h Ca I ot this section a.nd not a .*

Re.search Committee i;ha.ll be specifically t..ra1nin~ n.nd exPe'l'ience to conduct t.hc ten ed for imrnedla.te therapcullc.

fl.pprnvcd by the Bureau of Dru1n1 of the 11rop0&~d re1;en.rch 1tudies. di oat.ic or lilmilo.r purpoof.i; ot to ti,,.

Food and Drug Admlnistration. APPllC!l- *c,p Lice11.?1e to handle ratfjoactive ma- U!~e the sa.lct~ IIJld efl'ectivene~r c!

t1ons shall be submitted to the Food and tr.rials. The respo'D.Blble 1n1'e&Uire.tor or the I Oru:r in human., :or such purpose.,

Drur. Administration. B11rta.u of Dnlits, inst.itut1on..~ shAll. in the ca.se o1 rea.ctor*

RF'D-150, 5600 Fii;hcrs Lane, Rockville, produced isotopes, be *licen.eied by the li.et to cu-ry out a clinical tr1A.1 >.

< 1 Adverae rta.cttons. The inve1t1i:r::1-MD 20852, and shall contain the no.me~ Nuclear ~llUla.tory Co.mmls&lon or tor hall unmedJately repOrt t.o lhe Rad1.

and <1ullllfic11Uo.r11; o! the member11 of the Agreement State to possess a.nd tae the oac ve Drug Research CommJttee all cotnm.lttee, and a 1t&tement that the sped.fie rad.ionuclides tor re5eaTch use or adv rr.e effects auocui.t.ed with the u,~

committee ar.rees tn comply '11th the be it llstcd investigator Wlder a broad U* of he radlo,i.etJve drui in the ruu.rch NQuirements i;~L forth in this aect.1on. cense. or in the case of nonr"$.Ctor-pro- stu . All adverse reaeuon.s proba.Dly at-Approval sho.11 be ba.sed upon ijJ.Q U!re56"* cluced !.sot.ones. be licenaed by *othei- ap* tn ble to the we of the rad.io1.ctl\'e ment of t.hc aua.l!tlcaUoM of Ule mem- propri.a.te St.t.ui or local a.uU>orit1es, when d.ru 1n the reiaearch study shall be lrn-bcra or the committee, and the MBUr- regul.red by State or local law, to P(lll,NSS t.ely reported by the Radioact1 ve ance that all neceeiiary fields or expertiJle and. U.&e Ule &pec!fic r&dionuelides for~ Research Commlt.tee to the :Food are covered. Approval o! a con:un!ttee search uae. Drug Adm.lniatn.Uo.c. Bureau ot may be withc1rawn at any time for fail- <5> .H1tman ruearch iNl>i1cts. Each iD* B, JD"D-150, &600 Fi.um, une, ure of \he committee t.o comp!y wlt.h &ll.Y V~tigv,tor ah.all odect. a.ppropriA,t,e hu.m.an kvil.le, MD 20852.

of the reQUlrement.5 of th.ii, sect.Ion. Ap-

• sub.le-ct& and shaU obta.1n t.he COORnt o!

proval of a committee &ha.ll remain such buman bemsa or UJ.ir NPrM4!lnta- J ) A ~ !,ii 1Mtft1'ti,on.i,l ~

m:tttec. The !.n¥*t1rat.or llhJiJ..l ob--

effective unless ancl unW the FOA with- t.i.ns in aceon:lance with f 310.lOZ of tll!.e ~ tlle review and apptoval of an ln-draws BUch approval. Ch&nJcs 1n ~ - Cha.pt.er. Tbe research 1ubJfft8 lh&ll be stitµtianal Review Committee -.hlch bersh.ip and a_pplle&t1ons fot new mem- at lee.$t 18 7e&n1 of aae 11.Dd le<<ally com- co~orms to the rt,qUl.rell1e:nta ot o CFR ben wall be submlt.~d to the Food a.na petent. E:l:ceptJona are permitted on);y 1n Pa 48.

Drug Adm.inl!tra tion N aoon as, or ~-.. t.hOAe 11oec!a.l IJ.tuationa when it can be * < > The n!!flllt.B o! 11,ny re~cb con-tore, vacancle1. occur on the commit.tee. demorutraud to the committee thtl.t t.he du ted s:,urswmt to thJs aect.1.on a.a pa.rt

<&l Monitorinp. The F'ood and Drug study present.s a. unique opoortunity to of he eva.lus.tJon o1 a. d.rui Ptll"B'1J&nt to Admin1stra.tion mall condu<:t periodic a-s.1.n in!ormation not presentJy availa.ble I St2,l of tbis chapter ahall be included reviews of approved committees. Jdoni~ and requ!ns llie use of reses.rch 11ubJects in the e-ubmiastons re<Juired under I J 1:;?. 1 tor~ of the actJv1t1es of ~e commlttee less Ulan 18 yea.:,,~, ~e 1?.nd I.a without of t.ha chapter, ahall oo conducted throuim review or lt.s &~cant rt&k t.o the 11ubject. Studies

In ana.lc.1nir the de~&t.loll8 re- mittee. Each female research su.bJ.eet of .f aection &O~lCf) 0 > ot the a.ct and quired in ~ a p h <bl <l l of t.hia eec- clilld-bea.ring patent1a.l shall 11t.ate s.n ..5 a.nd 201.100 o! thu cha;,t,n- l! t1on, IL Radiation &i'et;y Comin!ttee ahall ~t.tng 1,h.$t &ht 4 not i:>t'eKD.a..nt. or, on pacb.g1l:ig, JAbel. and I A ~ art coruiider t.he !ollow1ni reQU1rementa Uld the be.Bis of a preenancy test, be con- pJ..i&nce with ~ . St&~. a.nd &.&Sure that each 1s met.: firmed a.s not llZ1len&nt befare .a.he i:nay la.w rqa.rd.ln.- nd..loa.ct!ve lllA.Url..a.ls <1 l .RcuUattcm dOl'C tl'J mb;cct$, To p&rt.1c1pe.ui 1n &llJI' atucty. the l&bel of t.he 1.rmnedl4te con* ll.6&UT~ thnt t.he radia.t1on d°'"' t,o re-C6) Qllaltt1,1 ol rac:tki4cti~ tlrufl. The tat er and llhlelded conta.tner. l.f &nY,. aeo;rch t1ubjects is as low &$ r:,rac~ca!Me rad:ioo.ct!ve drug used 1n Ule research elt et' HP&Bte :from or u P8.n oJ anr to pcrfonn Ult! 6tudy a.nd mHt the cri- 1tudy &lall meet approprta.te chemical, la *and l&t'>ell.ng required tor rad.lo*<"* teria ot I 361.l <bl <31, t.he Ra.dl.oe.ctive r:,ha.rmaceut1ca.l, radlocllem.Jcal,

• and t1 materials by t.he NUCltu JU,rulatcn*

Drug ~Sffrch Conun.lttee 11h&ll req1,11n! ra.d!onuclldic 1t&tldards o! ldent.lty, CO ion orby State or local ra.dlolor* that: stre~t.h. quality, a.nd purity u needed 1c huaUh authorities be!ll' the follo" * <i, The inve.stiila.wr provide absOrbed for safety and be o! aU<:h tm.l!orm and 1n dose cs.lcula.t1011s bMetl on biologic w.~- reproducible quality u to rive siintfi* i l The sto.tement "Caution: Federal tribution data. ave.ila.ble !rom publi&hed cance to the rcsea.rc:h &tudy conducted. prohlblt.e r:UsJ:)ensing w1t.hou~ pre* literature or ll'om other valid at.udies. The Radioa.etlve Dru& Re.search Comm.IL* i:,tion": <l11 The 1nvestiirator prov1de for an tee i;hll.ll determine thn.t radioactive ma- l The 1tatement "To be admJ.ll.l** acccpl.O.ble method o! radioll,.ISl:ql.y o! tllc teMals !or pa.rcn~ra.I u,;c arc prepared te~d in compliance with the req u ,rr

• radioacUvc drug prior to 1~ use to MSU"n! in sterile aod PYTD8'en-free form. n'l ts o! Pedera.l regulJl.tloru re,ard:ni; that the do11P. ca.lculntion.s actually reflect <'7> Research protocol, No matt.er hO'I\' r toa.euve drugs for research UJ<t * ~ 1 the a.dm1ni11tered dose. sm11,ll t.he a.mount ot rn.d1oe.ct1v:!ty, no C$ 361.l>";

(iii I The rn.clioi\.Ct.ive drur. chosen for study involving 11,dmin.1.stra.Uon or a ra- (3> The est.lilbl!Jihed name or U"ae dn.i

• the st.ucty lH11; thnt combina.Llon o! half* t11oa.et1ve drug, as defined 1D A3l0.3<n> II ny; me, type~ of nuila.tlons, rndi11t1on ener2~*. o! thi.,; cha.pl.Cr, to research 1ubject.~ 4) The iee~bl.1.shed na..ine and r;ua*

• mot.uooliam, c11,.,11kal properlle:;, e~ ..

'll;lUch ruult.5 in I.he lowest dOBe to thP. under tll.i6 l'ect.ion. srui.J.l ~ pennJtteCl Ut ot ea.ch active 1Dgred.ll!D~. wllole body or specific oriau11 with which unless the Radioact.ive Drue Rae.arch 5> The name and h$.11'-U!e or I.be r~, it. j~ P<')Mlble to obtain th!!! flf!CCs.snJ"'Y commlttc(! concludes, 1n ltl Judrmmt, dl ucude, t.Ot&l QU&D.tity ot n.dloa.ctJr.rr in!orma tlon. that scientific knowlcdl!r. and benefit is In the drui: proaucl's imrned!a~ eo,:* J.,_1* J.0 ltULJiS AND REGULATIONS ~1311 wner, and .aO'lll.n.t or rl!.<11oa.cuv1t1 uct:.a (includiu!I 11u.Lo:11t,l11i et1tabl~hme1n blolo 1~ pruduct. under Ult> l"\lbllc per u.uJt. roJume or unH au,,M &~ a de>>* a,1.11.I product licenM: appllCAUoD.51, All Heal h Sc-mcc Act. ~~d n:Ccn,uued ,,1r.11e, h1turc corrCl!PQndenee t.nd l\.lbmlal.ioil3 T Cozn:nu.,loner now coDcludc:5 ~hat, UP 'l'he rO\lt.e a! anrntnlstrat.lon, U St regarding ra.die>t>c\.lvc ululuailcw pruduc~ ai.hcc radlu11cLlv-e dn.tfll. lncluClng radlu-15 Iur ot11er than oral u,;e; 1!1111.ll 1.11: <llrected \Q ~ Burea.u of Orup. actlv . blolopc~ prollucl.s, an: ~ 1n <7> 'J*nc net quantity ot contenu.: Thu; order uccuwt:ll c.Q'ecttve IU.l8Ull~ 25, whlc tbe ~dlOMctivc component is or 1 81 ~.n ldet:1t.lJ:,1.12g lot or control num- 1975, pn.m ey interest., all ~toac~lvc ~ t,cr rrom 11'b.lc.J:l n u posslbll! t.o deter~

• The Dhl:!luu c,f 1'1ologli.:., et.andt.rdb ahu 11 be rarul~t.e<l tllru1.1&h only um:

mmc Lhe comi,letc i:nanutactunng h.l~- (OB$l "-"II.I\ tr1LUS!errct1 !rum l.llc Nu.* bure u Lo a.ch.ievc willorm.lty o! t.ree.L-tor~* or tne pac.k..a{:c ur Lhc uruK: Lluuul IlatltUU:b ot Hee.Ith to t.be Food n11m tllrough a 1,mgle con~1, pomt. The (II) Tlle name and a.ddresa of Lhe ma.11- and Orug Admin.l.st~Liun <FDA> lillU rt:* Cocnntl.a~ouer rur~ln:r i;un1:,\uu,:-:, \\\"eo\ \\\-.: ufaciurer, pac.lt.er. or ullsLrlbuLor; nu.wi:u U1c :eurc:111.1 ur 5101<1g1~ lnc,i.tce ot 5 ~ u u! Dru":s lllloul'1 be re.epow.lblC' UO, Ttle e::,;ptrauon tta.Lc, II u.n:;: whlr.h 111*11,1; µublliJ1l!tl w Ll1t2 F.t:D.EllAl. tor ~ rad1011,ctive Llrul(~ bcciiwsc u! IL~ , 11 > 1f the drug 1s lnte;pdecl for par- REGISTEP. or June 29, 197.:: (3'1 l'"R e:iwtµii O?'i'aIUZatlonal strucLUJ1;! u.m.1 ent.crul use. n statement e.s t.o whether 12a6::i1,. A!; the tu-st. step 1n etrectlnl' an 11~. The Bureau o! Biologics wUI the eont.enL,; are sterlle: orderly t.rans!er, tl1e DBS was appended prov¥e the Buruu or Drugs needed ex-C12l If the clrug Is for other Ll:l&n oro.1 to u1e l"DA as a Bureau wi~ou, an~ pa~e wtt.n respect; to _tne blol()f:lcal IL'ie, thP. no.mes of all inacth*e ingredients. i-ee.11gnmeot of overlapi:,in1r or rela.ted com~nent o! radioe.ct1ve biological peep!. Ula.L: functions t.hM had developed between S>rod*ct.s and will tes, all aamples o! such (i) TrlloCe amomtu; or he.rtnler..,; aub* DBS and FDA based on historical, 11tatu- prod cts that are submitted in support wry, suid orgaD..1zationa1 dist1nctiona. of n w drug ~pllcat1ons, stances added .solely for individual prod- Since the transfer ol DBS to FD.A., the ur.L ldenu.!lr.auun need not be no.med. As a result ot th15 decision to trs.ruter Conunissloner hAs reviewed those acti v- :re ~Wty for ra<Uoacttve b1olog1c:a.l (Ii) If Ule drug i,; l.n~nded for par- 1tiei; that ht.storle&llf have been con- prod eta from the Bureau or Biologics to enteral use, the auantity or proportion or ducted by DBS and the Bureau or l31o-- the ureau of DruirS, all !uturt appllce.- all J.no.dtvc 1.n,:re<11cnu, except that in* log1c:;; w\der section 351 of t.he Public Uo gredJents added to adJust pH or t.o make Md 11ubmwtons for radi0111ettve Health Sertice Act M well aa thoee eou- drug , inclucilntr radioactive biol<>lrtCAl the druR 1BOtonic may be declared by ducted by the PDA, principally the Bu- prod ct.s, shall be in the format and n~e and 11, 111.aLP.menL or U1e1r etl'.ect; 1! re:iu of Dr\,lgs, under the lPederaJ Pood, foll the procedures i,rescribed in 21 the vehic:le is water !or injection, It need Drug, and Cosmetic Act, He conclude.ci CFR Part 3Ho. For radioactive b.tolog1~ not be named. Provided, how~er, That tha.L then 1s 11 need for aome reusiirn* prod cts. the new drug applic&t..lon pre-ln \.be ClloM o! containers t.oo amall or men~ or act1v1t1ea n~ardl.ne radloacuve llC otherwille una.ble to acr.ommoi,&te

• label in 21 CPR 314.1 will be deemed druss between tJ:le Bureau ol B1ologtca to

• tu~ the eatablillhment and with sufl1c1ent space to bear all such 1n- a.nd the Bureau of Drusa t.o provide uni~ prod ct license appl1cat1om reauired tor fon:nat10n, the 1.n!orme.uon required br Jormlty 1.11 proce.&&1n8' And & foeal point biol paragraph <n <l l and <12) or t.hlJ. eec- products; &pproval o! t..he new

.. for 11oCtion within FDA for t.hil cat;esory dr\11 appllct.Uon shall be in lieu of 1:ssu-tlon may be 1>l11ced on t.he shielded con- o1 products.. tainer onl,-. ing s,roduct and an establ..lAhmant

• The Bureau of Biolortcs cw-rentb' ex- lice e. Th* requu-ement to subina new R.t,~ttue d.aee. 'Ibis rt~a.Uon wll ercl.aeA primuY control o-rer t.hoae radio- drug &ppl1cat1ona I.I not eXJ:)eeted t.o lm*

bec:oine etr~Uve on July 25, 1975. Thia aetlve c:truea, which contaID a b1olo,1cal POiie laD.Y hard.!.h!D on m&nu!a.cturen or date 1s necessarJ because or the various product in add!Ur;,n to a rad1onuclide; ra.di~tive blologl.c.a.la. Toe evtdence re-effective da.tes set torth !or gpeeific 1uch product.a have been subject t.o U- .quir'qd to establlah l!&!ety and effective-changoo reh1tink to t..he transltlonal regu- cenziure under aecUon 351 of \he PUbllc: nms fare auent1&111 the .a.me for 'both lation of radioactive new druirs from the Health Service Ac~ The Bureau o! Drwra biol leal product.I and De"W druKz. These

tiuclear RegulaLon Commwion to the regulates all other r&dl~ttve CU-U.s. rma now holdinJ biological pt'Oduct Pood and Dnut Administration. uid the RILdioacUve bioloctcal products, how- 11 tor radioactive bl0loll1cal prod-need tor thlti r~a.uon to be ln toroe as ever. in addition to beln61! subject t.o aec- uct.!, and all o! them also ma.nw~tu~

800n a,; P()5,lllble "° that there wlli be* tion 351 of the Public Health S.rvic, Act, othe 1>rodu.cts reQu!ring new drug ap-reB"UlaLory control over the safety and are also "Cltug11" and "new druirs" as s,11 om. The impact on the reirulated eJfectiveness of all radioa.ct1ve ~ s . those terms are defined 1n section 201 <e> 1nd r)' should, Lherefore, not be t1gnt. (8-, 80&, 't011*1. 112 eut. 1002-1063. u a.ne1 lP>, respect1vt1r. or Lhe .Federal nca . The Com.m1Mio1:1er admes tnat. u amend.a, 100:; (:ll u.e.c. 81111, S71 l*l); tbo .P'uod, D~. and Cosmetic 11ci anel are an,. penwm ia preparing 11, bicl0ttical Publtc BAlth e.nu," llci (.C. 361. 68 e~t. t.hererore 11ubJect to the druii provisions 'Prod ct lleenae appJ1cat1on. he 11bouid TO2, u amendtH1 (42 u.e.c. 202, > of the Federal Pood, Dru,:. and Couoettc IIUb it tt within 30 dayg In order t.o ha.ve Dlltea: JuJy 18, 1915. AcL, includJng t..he Jlew drug provtaJona, U pr<<:ealled 1ti that torw. ltecocnizing t.h15 dual Jurllidlouon over ln addlt1on, compUAnce With the pro-A, M. ScmcmT. blol~cal products, the Department o! visio of 21 CFR Part 314 &hall be Commiuloncr o/ Food and Dru.as. liealth, Educe.Uol.l, and Welfare decided d ed to comtitute complla.nc:e wit.h IPR I'xlc.'tG-1C1~1e P119d 't-2~'16:8:f& amJ many yean aso <prior to the transfer of the vuiom of subehapter F, the ODS to M:IA) that t.o lnl.1'11:et ._ blolo,1~ tJlul. i'<"IILI pn>duct regula.tJons, unleu the fDoC1u1t Nn. 75N-<>Oeal product 11, m.&?lW&eturer should not. ~ Co hmer 111a.tr.e1 a dat.ermlnatJon required to 11ubmJt both a license appli* that a particular regulation in Bub-RADIOACTlvE BIOLOGICAL PROD\JCTS cation under sect.Ion :131 of t.be t'UbUc cn&p r F shall be appllca.ble to ,-.cUc>- Ru11lgnment of Respon1lbility Health Service Aet and a new dru1 ILP* acth- 11ruw;i; co.nl.&1n1ng a biological plication under uctlon 505 of U'le Federal pr:od ct. Appllcauon of a Subcha.pter F By this reRUla.tii:m, tl1c comml.a.sioner Food, Drur. and Cosmetic Act. To re- re,ul tton w1U onlY be made when Lhc o! Food and Drugi; il'i rll!&ll&iµilng nv,pon- quire such dual iiUbmlSSlons wollld. nave Com i.uloner concludes that It bl nece&- sll>lllty within the Food and Drug Ad- resulted ln unnecesta.ry duplicatJon o! sar.v usure the eafety or effectiveness m1nlstre.tion 1or regula.tinp; radioactive effort. both. bf the manufacturer and b)' ot product, 14 not duplicative ot thr biological produr.t.5 from \.he Burea.\.l of the Department. lnltead, to avoid such reciut ements in Pa.rt 314, and 111 i.o IL"* Blol0111cs to the Bureau of Drugs. AA a duplication. only Ucoru;e applications Wl* l!ure e ssune degree or reg"'Ulat.ory con-rtRUIL or t.hti; rea,;slirnzn1mt. rue.nu!e.c- dcr i;ect!on 351 of the Public Health Serv- trol urrently exercl.sed over such prod-turers of rodJoBCtlve biological products ice Act WOUid be reQUl.rCCI. Tllt new Cl.rUg ucts, e Commi.&&.loner bas ~viewed I.he ,.,.lll be rc-gllired tr, comply with the rl!- n:101laU0Tll'I <21 C'l"l't 310.4! were amend- prov loru or aubchapLer l anc1 con-quir-emr.nt., ror- d~11 <1neludlnl!' 11ub- e'1 w a~~ 1..1111,L is uew ur~ wou.lu uoL 1-"' clut1 at Ull11 time that the provu!o1u; mittlng new dru(: applications IUld ~- aeeme<l rubJeet to the new e1rug proV1* of I 10.2 RC<Iuesu tor samples and pm. rlodlc 1*eport.s1 for such producLG 1r1 l!P.u 11ion:i o! the l"ederl\l I"ood. Drug, and t.oc<>l : official release I.hall ttma.ln a.p-u! Llu: n:quin:mc.nL:; Jtlr u.lulu~lr.111 prod- cosmetic Act u 1t a a <lrur ucellJle<l aa a pUc le to rad.loaet1v11 ctrult11 cont.ll.l.nl11i: rtD[lAL ltG1$TElt, V01. 40, NO, 144---f'IUM'I', JULY 25, 19)' RULES ANO REGVLATIONS

-. biologli:t:l prod11c-L Appi*opriaLe fo,lcd producL mn:r be hitroduc.cd t.o th~ 111 ~rl;. 2u:,1 tconom.iwl tr11ns1tin:: :*,

• ch::rntce!\I h:we bf:en mo.de u., this .i;ect.ion market r.i.e., fu.ll **J1ew drui:: a:pplicatlon, v.* rdir.(: li'Lb<:l~ *and labelmlt o: 1narl:c\A*

to retlecl that thl! Direct.or of the B\1- nbbrcviatP.d n"" drill' .nppJictt1,1on11. OL' p oduct.~. thr Com.mir;sionr.r 'l\"ill cc):-* 1*~u nl Dnigs mar use this 11ectJon !or other C0Dd1Llons, ,;,;-ii] be detcrmine:1 111, t.l e etlective di.te on v.hi!'ll rrinrketed 1:. r11cHo:ir.tive dl"\1":ll cont.41.ni.nB' a biolOiica.l th:i.t time. *ct 11.ctl,*e hinlor.ic:o.l produr.u: mus:. con,. 1Jroduct when it i,; deemed necus11ry 1or A ne'I- drur. applicatio:1 doe~ nnt have p.

• with lll~ rc:qutrcments c,! Part :!lJ.

t.11~ 1111.feL)', puritr. or p0tencr of the to bt. submitted tnr nnr radioacti\'e 'bi- u ~il Ul" c!:H" or, ,;\'hMl *nP.w ]llbcls. 11.1~:-' prcdur.t.. ological product llr:crucd a!ter Jul~* 1. ,, lat.*e1ing is printed by thr: m11.nu111 *. 'l'o etfect t.he tr,ms!cr of resPonsibU1t~*, 197:!, and before the et!:cetlve date o! this t rr.r of such pmducL,. or Ju!~* 26. 1!J'l* omcndmc11ts must be tnade in ~l CFR order. The product license tor 11uch a ra- "l hknever occu.r-s ~nL. Pnrt..,; 310. 31~. 3H, 800, 601, o.nd 610. In dioactlve biologic!l-1 product, toiether . Therefor~. 1.mu1.:1* U-,..: F~t\lrn1.l Foo Part 310. : 310.4 provides the exemµtio11. with portions ot the utabll3bment license g. and Co~mcLir Art r.~ec~. 60:i. 1r* prev!ousW dl.licui;i;ed, that. n licensed relevant to the re<imrement! tor o. neo;i.*. , , . ~2 Sta:. 1052-1053 (\.'; amended. 10~: blolo[:!Cnl prod\lCt Dl!ed not al/lo be &\lb* drui;: kpplkatlon, now conslltutes an ap~ ( J u.s.c. 3u5, !l7l 1n,). the Public. Hex t::* ject to nn approved new drust appli- Proved nc~ dr\lg applic1Ltion under e<<'* rvlcc Act <sec. 351. 58 Stat. '10:! ti** c::.tion; that i.e<:Uon i,; a.mended to e,-;* tiun 505 or the Federal Food, Orui:. and ended *42 u.s.c. 262i 1. and under au-cludr. rai:uoacUve bioloficn.J t>roduct.-, Co!omotir: Act. 1ot1tY dele1taLed to the Commiss1nne:* from thi11 exemption. In Part :n::. Any- racliollctive biological product for l CFR 2,120.1. c11apter I or Title 21 o;* ~ 312.Hg, currenus provides Ula t. a v.*Wch a license appUcnt1on is pending on l' Code of Federal Regulation~ ;. "NoUce cf Claimed Inv~UgatJonal :E.'X- the effective date of thi11 order w11l be itmended ...~ follows: emptto11 for n :New Prug" <IND> for a* J>roce~ed and approved or disapproved / PART 3lo-NEW DRUGS biologten.l product. be i;ubmltted lO the 8,1\ 1ubmltted, .Anin, no new dr\lJ aP* Burenu o! Blologici;: th.ls r-ection ii. Plication n!HXi be irubmJUed !or these I 1, In Subpart A by 2uis1nJ l :no.4 tc* a.mended t.c, :prnv1de U1at &n IND ror Products. It the product. 1& found &e* tead a& follows.: ., radioactive bloloitlcal product be sul>- ceptable tor Ucensure. it will be approved inltted tn the Bureau of Drugu. In Part M I!- ~ drug t.P1>lltation in Ueu of j11-f , 310 **1 B.t0l~~= pl'(l(ia~" *uJ.-c-1 ,,. , !14., G31Ul0<a> C7' movides that a new suance of e. product llctmae. . liceJU<: matrol. druK application wW be refused for Future cba.nne in ,.u aps,roved radio- ~,.-, Excei,t for ra.diO-active bl0loinc11.1 .filing 1f Lhe drug is subject to llcem!.ng a.etive biological products Will be 1ubject. roducU intended tor human u.se. a ne"* under the PUbllo Health Service Act: thli; to WP1>ler:nental new drug appllcatiom &hall not be deemed to be SUbJeet section ts amt-ndeel to permJt .t'U!.ng or a <21 CFR 31-t.a> rather than amendments .aectJon 1505 of 1.he act it it *ss 11. drtl,; new drug 11.ppUcation :ror a radloa.ctive ~ t.be UceD.M. utewise, &11 radioactive censed under the Publ1c Hetllth ~mrc blologie11.l product. Part eoo 1& amended bioloa'ical proet., a.re subject to the ct o! JulY l, 1944 <58 Sta.t, 43:?, as ht I 600.3 to 1nclUde a deftnition o! a record.a &nd n:porta reqwre=ent.a of 21 ramencled <42 U.S.C, 201 et 1eq.>) or un-ra.d1oactlve biological product. whJcb lS CP'R 310.JOO after the eflecUve cu.te of ~er t.be &nlmaJ virus, serum, and tox1.11 deftned u a. biological product labeled tb~ eeeUon. law of Mateh 4, 1913 (37 Stat. 832 c21 wj{.h a ra.d.lonucllde or a btololri<:;al prod- Ever,- curreni °'Notice ot Cl&lmed In* .s.c. 151 et M,q.) >. uct intended solelY to be l&beled wtt.h a vestip.ticmal lti.empt1on for* New Drug"' A re.d!oactlve blol08'ical proouc( radionuclide. <Elsewhere 1n this iBaue for* ~ " b1olotrlct,l EJnX1uct will cas deflned 1n I 600.3<ee> or t.hl5 chap-ot the F'DDAL lb:Cl:S'J'ZJl, 1he Commtn- be tnmferred t.o the Bur.n of Drugg. ter> intended for htmlall uu u subJect tc sioner b* tegumg a 11z2al regulation on Any anu:.:odrnm~ of or 11Upplementa to section 50$ o! the act. ADY Hcenu to: radfoa.ctlve dnll11 wh1ch 1ocludes add- tJlY aueh Dottce, and all ~ rePON such a r..dloaattve b1o1Qfical J:lrodue* n1t1r,n of "radi~tive drug"' 1n Part. Sl0; reprding sacil JlOUCe, *l:Wl. be ft.led sn Wbich is issued. under the Public HCGJU this de11mt1on cnJ&S*referencea the new the future with the Bureau of_ Druga, , 8trvtce Ac~ ot Jwy 1 1944 <58 Stat 88~ de:t1n1t1on 1n Part eoo.> In Part eo1, .IUJY new ~Notice of Cl~ed Invest!<<*- ! u amendud <t.2 'U.S.C. 201 et leQJ ) 0 an7 , I eo1.2 currently outlines the procedures tioD&l l!:zemptwi:i for a New ~ " for- a I which hu not been n,yaked or IJUSJ:)ende, tor dl1ng e.ppllcat1om for mtablillhment ra.dioacttve btolotnoa.l Pl'Oduct ahall be .., of Au,u.st. 2S, 1975 ahAll COl1Bt1tut and product licensee or biologies: th1s sul>lllitted directJy to i.b.e Bureau o! an ap:proved new drulf a.ppllca.t.ton to er aecuon 1s amended to provide that radio* .t>ruo. .  ! feet under these.me terms and condJUon active biologiclll -product.I ah.all be For all r&diO&Ctive b1olosteal product6, / u aet forth l.n ,uch lice~ ILild auch 'PO covered by new d:r\lg applications and including an.Y .uhJect lil pe:1d1ng M>* 1tions o! the Mt&till8hment J.teense reJa~ not by b1oloittca1 r,roduct licenses. Part Plic.&t1on for Uceusure on the d!ectlve inr to au.ch product. which include dat 810 is amencled u dlacUBSed &hove. date of this order, all co!'l'MP<>nde.noe, a,nd.inform.ation requ1nd under Part 3 i These change! are p~pect1ve ln "Notices ot ClaJmed Inv*ttnt1onal Ex- of Uus ehapi.er for a ne-w dnzg *PPlici nature. Every biological product lJ* emption tor t. New DruB5," and onirtnal tion. Anr such rad.la.cUvt btologtcj I censed prior to JulJ' 1. 1972, is eurrently and sur,plemen\al ne* ~ .,s,pU<:atioIUI product for whJcb Uceiuure undu u under revtcw for afety, etfect!Yenus, &hall be ,uhmltt.ed to the DM&lon of Public l'Iealth &rvioe Act a pending c: I and 11,J:)propria.te labeling, u described tn Oncology t.nd R&diophannauut1cl>J AU&'USt 25, 1975 lhall. upon dettrmjnr 21 Cl"R ~1.25. The product Ucense for Drui Produda (HFP-150). :Surea.u of tlon that lt Ls ac~tab!e 1or Ucensure. '.' such a "4loe.ctive b1oJo,-1cal :product.. Drugs. Food IUld Orur Admmi.strat1on, a.wrove<1 as 11. Dew drus: e.pplica.t.Jon . together with portions ot the establish- :;soo Fallers JA.ne, RockvUle, MD 20852. lJeu ot ~a11ee of a b!ol°'"cal rodu: ment 1icerue relevant to the reqwre- JUl aamples ol rML!oacti~c b1oloiocal I ucense. P inent., for a new drug appUcat1on, now Procluct8 submitted in support o! 11 nev.*: consUtutes. 111,n a.:pproved new drUg ap- drug a,ppl.lce,tion ghal), 'fl.hen notified by j plication under uction 505 of tbe Fed- tlic Bure&U ct .t>rug,;. be &ent d.lrectlY the Buree.u of Biologics. Food and to/ Drug PA.Irr 312-HEW DRUGS FO~ INVESTJGATIONAL USE eral Food, Drug, and cosmetic Act. ~

• 2. Iu I 312.l by nt\1sing p&tll.if1'aph ,

• such product,;, even thl'OUi'h new subject ~dministrat.lon. Bldi:. 2PA. 5800 Rock-to new drug appUca tions, will remllln ville Plke, BeLhasda, MD :ZO0H. , t.o read as follov:s:

r;ubject to the biological product review. The Cotnmis&1oner notes Uiat ttie la-i § 312.1 Condition* (or nhnp1ioT1 I because they were Ueeru:ed as blolt>glcal beling standards undl'1' Pe.rt 010, SUb-i nc-w druj!t~ for lnw..ni,mtinnal u~*** Product.& before July 1, 2972. Thoae prod* part o. of Subehaptcr F wm po lODJCl'! uct., whlch are found to be unsa!e, or o.pply to radioact.tve biological prod~ * *

• inetlecgve, or ni!Rbranded will be 11ub-- instead. the re<2uirements o! 21 <e> A ".Notice o! ClaJsned lm-csti1 ject to regulatory action. Those whlch Pa.rt 201 of Bubchaoter C wUl be &pl ~on&l EumJ)t.ioD for a. .New Prug" '\l"h plica.ble. 1n particular, this me*tu tba. pertaJn,s to a product subJect to the are det.enn!ned to be sa!e, e!!eetive Md the tDo.nu!aeturer's license number ap Dot mhbmnded may cont1nuo to 1>c eens1ng JJl"Ovislona ot the P1¢llc He.a pea.nnr. or> the container and pack.a.ir ma.rlteted; tn &Lddltion, U*1e conditions 1&0ei,; <21 CFR 610.60<&> <2J and 610.6~ Service Act. ot Jul)* l, 19*U (58 St.a.t. t under whlch s.n 1dent1~l, e1rnllar or re,. <b 1) 1.s no longer reqwred. To permit ~ 11-'1 a.mended ((2 tr.S.C. 201 ct seq. l I sl PtoillAL llEGISffl, VO~. 40. tlO, 1,U-,tlOAV, JUIV ~.5, 1975 I

I ' 1JUt-'UN I l!JJ. r I RULES AND lllOULATIONS I 31~1:l be subrn!~ lmt1aDy t() the .Director. Bu-niau of Btc,tc,rics, 8800 Rock\'We Pike, J:&bOra.tor;v aoo cl1nleal ~ demon.9tra.te th&t. tht manufactured which df:emt nt:eesiary tor* \he "1ct7, pur1t:v. or po ncy of U\e product. . BE-1.hes.dA, MD :10014. ~oactJve biologi- producL meet., Pte'Crtbed ~ r d a d. <b, Radioactive biolopical J)roch,cta. cnl produeL~ for bum11-n \VIC are not aa.fety, ptl.M.ty, and potency; a. tull de- Sam es of ADY lot ot a radioactive b1o-Ut"CU\ed to be IUbJeet to the licel'Ulll" pro- ecl'1Pt1on o! manwacturtll{! metnodl;; logic product. u d~ed 1n 11100.S1ee1

• isil,ns of ttle P~Uc H~t.h Service Ac1. da.t& Mtabl!ahlnt% &ta.btllty o! Ulc prod* O! t~ chapter. toll

  ether with the proto-

• ~~-e f 310,4 of this chapter, fmd a.* "No- uct throu~n the dating period: sa.m- cola ~owuur reaul~ of ,-ppllca.ble teat.6.

i..,. o~ Claimed Investi~tlonal Exemp- plc1s, repreise

o'll&trn or the produet tl> mayft an)' ume ~ reQulred to be sent to 1 inn lor a New On.Ii wl'l.lch pertainll to be i,Old. bo.rteTe<!. or exch11.nge(l or of- the ood and I>rwt Admlni!t.ratlon !or l".*dioocth*l' biolo,:icri.l product.~ *shall be ferecl. eem, carried or br-oU:gM for -.le, omci nleue. Upon noWl.catlon b;'I' tlle

• • 1hm1tt.co to tbe Dtv1Slon or oneologr ba.i-ter, or exch11.nic: 1umm{lt'l.es

, . ,,~1 R...'\diopbanna.ceu~cal Drug Product.~. llul'tl- o! tests performed on the lot of *re- Dirir. Bureau of Drugs. a mB.Dufa.c-ture ah..U not distribute a lot of a ?MllO-ll"J1°i:au o! PrtU?l!, 5600 ~ e t i Lane, represented by the submitAed sample(111; aetiv biok>trlcs.l product unW the lot l.! r~,ickvillc. MD 2()8.lj2, Amendments or or 1mcl specimen!\ of tb11 labels enclosu.re6 rel d br the Director, Bureau o!

a1mlemenl.s i.o IJ\lc

h notice, and proirres.~ and col:'ll!lal.ners propor;ed to be used for Drug : Pro11uiet!, That I.he Dire<:t.or, Bu-n-,mrL.~. conaultations, or other com.mu- the Product. An 11,pplica.t1on 1or lice~ tea.ult Drugs shall not Issue such notltl-nic;\tJon11 with re<<an1 t.o Ule J.Dvestlp~ "hAll uoL be consk.lered M filed untll Ml ca.tJo except when deemed neceSBary 1.ian shnll be dlrecud to the i,a.m!! office pert.inent infomwi.tion and da-tA ~ for e safety, purity, or potency ot the L:* which U1e cri.Ftioal notice wa.q sent A have ffln i-eceived from the manUl'ac- .i:,rodict.

mon.sor for n "Notice of Claimed Inves- t.urer by the Bureau of Biologl.c.s. 1n lieu t1tr11.Llonn1 :Exemptfon tor o. New Prug" or the procedures demieribed in th.I.a i:-n.- Si ce the.~ chang-ei; concl'rn internnl submitted to the Bureau of Biol.ogic,; graph. 11,ppliea.tioru !or tadi08iCtive ~o- ~rnmen~ of activities ~d will pro-i.hnll substitute 1n read.Ing thi5 section l~ical productJi shall be landled 88 set . mo~ unUorm hand.llnr of all Tad.loaetive "Bureau or Biologic&" ror "Bureau or forth 1n para.imi,ph (bl of th1as .eotion. <U'Ui' products, the Coauriiu1ouer Ands l)J*uits** wherevC!I" U avpeo.rs. (bl R4t11.oactt11e blolO(Jlcal ~uct,. In that \he changes covered b'Y tha order lieu of subm1ttui.a a.n est&b!.Wmient and are ch t.h.lit. under 5 u.s.c. 553. the

• p1*oduet llcenae for f.be manut~ture o! not.1 11.Dd comment procedure tor rule 11 rad!oa.ctlve bloloslcal product, u de- S' are unnec~ and are not PART !l-4----Hl.'W DRUG APPUCATIOHS :fined tn f B00.3<H> ot this chapter. the uiaite1 to tha promulJ&tion, In

I. In § 314.110 by reVU;ing parairra,ph m1mufacturer o! ,uch a product &hall nr \b.11 decision, Ul.e CommJ..se.loner ctll C1l to read U toHOW'S: submit* new drwt aµs>UoaUon to the Di- ba.s D.&idered. \lie !acts that les11 than rector, DivWon of Oncol()ff and R&dio- ten :rma currently hold biological J)t'Od-G31',110 "--a for tt,(uaini lo tilt' pha.rmaceutlcfl.l Dnli' PrOC1ucb. J!lureau uet cenaas for radioacttve blolOldcal appliMlaMu. of orurs, Pood aud Dn18 AdnunlAtration, pro , and that all of these f1nl1D alao I.a) * *

• 6600 Jiahers Lane, Rockville, MD 20852, hold approvlld new dru<< 1,ppueat1om.

171 The IIPf!W drug i& a drUJr. other on !orm FD-358 CB> aa ut forth tn The omm.Luloner alDo adviaca that any than a radioa.cthe bio~oa.l product <as I 31U<c> (2) o! th1i5 chapter, Por euch pen cuznntl:, preparing a bioloineal def1Ded ln I &00,3<ee> of th15 cha.pt.er,

• products, tbe approval ot the new drug Pto4,let license for a radioactive blolog*

l\1t.en.ded for lt~man ~. subjflCt to JI* application w1ll be 1n lieu of w~ a n ical Product ana1 submit within 30 da:,t; ceml.ng under ~e PUbllc Healtb Service produc:i and an esta.bl.LAhment lJeenae. and ~ereafter will ilOt be reQ\l.1Nd to re-Ac.t of July l, 11>44 (58 Sbat. 682, as Complia.nce with the provisions of Pan ,ubl$.it a new drug application for the amended <'2 v.s.c. 201etaeq.11. 31' of this chapt.er ah.all be, dee.med to 1>r~cL constitute compllanoe with the prcrvi,ions irasted peraon.a mllY, hoWeYer. on or

• of Bubcbapt.er " o! thb chapter unless bef & ~ r 23, 1975, Ale with thr.

the Comm!Mioner Dakes a detennlnat.lon Be Clerk. Jl'Ood a.nd Ona Ad!nin1&- PART C500-0ENEftAL PROVISIONS that. a parUcular rea-ulaUon from Sub- tn. Rm. 4-65, HOO P1&ber11 Lane.

4. In I eoo.:s b)" ~ a new para-cb,.pter P shall be appllcable ~ r&d!o- Ro e, ~ 20852, written eammcit..5 STa'Ph <ee, io rsd BB folloWS! .** ac~ve dru,a coutalninr a biolol1eal 1n tul)licate on t.1lY portion of the product, e-1t,, 1 e10.2 of t2l1D ch$.pter. ord~, COmDJenta received will be avan-

{I 600.3 U,1.£ahi-. &blei !or pablJc lnapectton at tbe office

• PART 1510--GENERAL BIOLOGfCM.

no *d a.bon duri.na wor~r hours, Mon- <ee> "~dtMcUve btoloincal product" l'RODUCTS STANDARDS day U:iroucb Prid&y. AD.y cha.n,ea in this mea,ru; a biololtical product wtdch 1s 6. In f 610,2 by rede'1gnatin8' the pre11~ ord r juatUled bJ' ,ueb comments wW be labeled with a radionucl1de or intended ent text M paniiraph <a> Gener~ and the ubJed of & .turtber order amendmg 110lcly to be la.b~ed 1Vith a. radio11uclide. revislnii it, and by adding a n1w pa.ra- ~ Hie rerwationa involved. en,ph (b). M revisecl, I Gl0.2 readl 1111 ~ ecth,e date. Tha rerulation &hall be PART 601---LICENSING follows; de Uve Alll'UBi 2~. 11175, except fot the

s. 111 I GOl.2 by redeslima.tinii 'IJle J)l'el;* § 610.2 Rcqu""t for 11&111p~ and JIN)lo- re<i enu tor label.II and, l.abeliDt: or cob; offic.iMI N'Jea..c:, . r& oactive blolortcal producu. The ent. text a.s pa.ra,mi.ph <a I Genere&l and addiog at. t.he eod a new sente~e and b:v . a.nd labellng of any m~keted.

111 > Ge~a.l. samples o! any lot of

i.ddtng a l"lew pa.rai

,,i.ph <b, , As rt-vised. nny lieeraed product., except for radio* J'.l active biological product must com-

~ 601.2 reads as rollows; th the requirements of 21 Cl"R Pa.rt active biolottl.ea.1 -products, t.o;ether wltb 20ijon the date on whlcll 1uch labels and the prot.ocols ahow1n, result.D of appU- la Unr are next printed or JUly 26, 1915, ~ t,01.:? Appl.iC!llllicMI" fo,- Nlabli .. hmt<ul eable tests. rna.y at a.ny time be required wb hever 0¢¢\ll'S first, uud prcHMtrt Ii~,...,.; pl'CK'etlur**~ £or to be sent to the Director, Bureau of Bi-liHnj:, olog!Cll, Upon notifioatlo11 by t.he Dlrtct.or, ( S t ~ '°6, 701/a) 62 Stat. 10152-1053 u m c,d, 1D&S 121 V.S,C. US, 8'71 la)): ll&C. , 11 , Gt"n.cral. To obt..i.in a llcenae for J3ureau or J31oloincs. a rnanufacturtr r., _, _,. . . . ,. . ., . . ., 351,1 08 l~t. 702 u 1:DtDdee2 (42 O.15,C 262)) llll)' est,al)ll!ihmerll OT prDduc1., the manu- ahall not. 111.St.rlbut.e a lot of a i,roduc'f facturer ebllll make llpJ)lica.tion to the until the lot Is relea.eed by the Otrector, Qated: July 18, 1975. Direot.or, Bureau of Blo10!1'1Cl;, on form,; pre,;cribe<1 for such purpose,- and 1n tile Bureau of :e101011cs: Provided, That the A. M, S<'BKD>T, c11,.c;" of 11,n appllca.tion for & produot. 11- Director. Bureau o! Biologics. shaU not I Comml.uJoner oJ Food at\d Drugs. . cen.c;,,, ~hall 9'1,bmJt da..~ derived from issue such notifica.t.lon except when PIDl'RAL llGIS'TEJl, VOL 40, NQ. 144---flllDAY, ,ULY 25, r I 15:22 DUPOtT 018

n:n.1 DEPARTMENT OF HEALTH, ~ ra.d.101M:t1ve dru1t11, includlne bJo- d to belcnr, ~ numcrow corr.,

EDUCATION, AND WELFARE 1081eal J>l"IX1ucu., because ot U.ir &hon e11 or problem.a ~uae of 1.hP .b.aJ!.uves. mu.si be s,repared in the nna:i m.ture of operauona 1n DUclcar **: Food and Prue Administration dosa&"e ronn !hottcr be!on they ue to be pha. ru:iell. f D,,,clcet Ne,. 7&N--0009 J used for dt~oola ar tnaune:nt or dis* To clarlfy the obli1ra.t.1ons oz nuclear RADIOACTIVE: DRUGS, tNCLUOING eue in man. In &dd1t10n, the s,repa.ra.tton pha St$ t11:1der the Federal Food. BIOLOGICAL PRODUCTS of rad.ioacUve dru1i1 re<JUires a special Dnllt and Coaznet.lc Aet and the Publlt: knowledge of radioaetlve mAterials. in* HeQJ Service Act, ~e Food and Oruc Notice to Nucl&ar Pharm.clH Reg1nlini voJves the use ol S1>eellll eqwpment a.nd A traUQn t& dr~tl.Dir regul.AtJon:* the Development of Propovad Regula* facilities, and, wllere ructor*produeed wh1c will de1me those cpent.tom COJ"l-tion,_anc:1 Interim Enforcement Polley radionuclkles are h:1volved, l'!IQUU'es l1- nec With the preparation of radioac-This notlc, p;tn,~ the tnte.Un ep!orce- cen.&1ng by the Nuclear Regula~r,y com- ttn r\.lfs and biol~ct.l pl"Qducu- whil.!1, me.nt P0licy of the CommJ.&sloner of Food mission or an Agreement Sta.te. Cert.a.in wUl NPrt'led M UJ.anufacturing pro-and Oruss rcg11,rdlm: nuclear pharmacies Pha.rmuies. referred to as "nuclear ced u and not Part of the practice oi until dennitlve regulnttons on U1~ matter pharmaaes." conduct o~rations which P'UAJ[JUIM;'Y, Nuclear 1>~mu1.eies en1ta{ret.: arc i.ssuecl by the Food and Drns Admln- ve.ry from :rei:ia.cka.<<1nR or pre-parmz ra- in ch o~ra.t.lona will then be rubjtct t(, lstration. Under the cond1tion.r. set .forth dioll.ctive (irug5 :tor adznl.n.ist.ration ta regu at.lon.s reslU'di.nir re£1l;t.ratloll. ciTUI' in this notice, t.ne agency Will not ta.ke more extensive aDd complex ma.nu!11e- llatilti, inspecUon, new dnli a.!)plica.t.i.om reirula.tor:; atctlon !or the t.a.1lure of o. turtng e.nd ;compounding prooedures. lll or ~iolorical Produc, licenses, compll-nuclear pha.rmA.Cy to comply with the re- m0&t cases these nuclear pho.nnacies ue anc41 with cUl'N!nt goo(! ma.nu!a.c:turinr quirement,; ot the Federal Food. Orug, afflliated With, or operated i,y, hocpi~. Pr&dUceG. and rel.a.~ requirements. Op-and Cosmetic Act. or the Public lleal~h mecucal KTOllPS, clinJcs, un.lven1tie5, med* en4on.s not deemed to be manura.ctun.u 1: Service Aet. except. where gucb regula- Seal schoola, and J)ublie health Nencles. i,~ures will alao be ident.Wed ant.: tory action 11; neceuary to sate1Nard the Some of these pbarmadea ~ not eo wlU thes-ea!ter be tre&ted ~ PAl't of thE: public health. am!l.Ated, a.re S>rlfttelY owned, or a.re P tice of pha.rmacy, It is antlclpateci El&ewllere 1n thJ.s 1Mue of \he h.Dnl.L OJ>tl'ted by aeveral inl~tution.s on a co- 'Ula these regulations wm be proJ)06eli RzarsnR, the Comm.lsaloner ta 1115\U,ng a C>PeratJve buls. The n.d.109,Qtl.ve dnlgJ; in  !"GSLU. ~lSTZa 1n the nea.r f\1-final regulation ~rml.llntlng the ex@lJ:>* prepared by a nucleu ph&:-macy may be . Interested J:>n80ns will be aiven 60 tion f.rom new ctrug 111QU1remenus ror intended solely for we Wlt.hin t.be ilutitu- da.y to comment on Ule P!'OJX)Bed regu* radioactive druis, 1ncluc11Ilg rad.Joe.ct1ve tion l.n whleh the pbanna.cy ts loca.ted, la.ti m and all 1uch coounenr., wlll bP bio)ogicaJ products. AS a tmlllt, manu- or t.hey may be r,r-epllred tar datnbution co lde:-ed in the prepan.tton a.nd pro. ta.cturers and distributo:-s of t.hese i>rocl- to other 1rut1tutlon&, 1'or eumple. a nu- mu ra.tlon of the 'final ~lAtion, uct,; m~t comply w1Lh the HQU!rement.s of the Federal Food, ~ . and ~eUc Ac\ and the PUbllc He.lt.b Service Act, and t.he regulations Ulereunder, .lnclud-clear pharmacy 1n a university hospftoJ me.y prel)are radioe.etive drugs tor dJa* tributlan to other hosi,tta.Ls and clln1ea. At present, Pharmaeles are subject to A ~"7""' ............. .,. , ,. ,_ he Co:min.tmoner ad'V1aes th.at, until and zz:ui.de nna.1, the Pood &nd Prug \ratio!\ w1ll not blke reruls&or,* ~ regtatn.Uon. dru&' U.,Ung, complJ&nce

• the m!SbrBDdinir &M adulter&tJon sec- ac . on for the to..llure o.f a nuclear phar:.

w1ill current good manutaeturtna prac- t.ions or the Pedeni.J Jl'ood. Drua. uid to comply with th~ reQUlrt:ment.s of tices, tnarlce~ Ullder NJ. approved new Cosmetic Act and to the s,rovt.cions ot the Federal Pood, Drug, &nd COiUJetk . dnlt apJ)UCSLtlon or blolo<<te&l Product li- Public Hee.Ith Service A c t ~ the Ac or the Public ilea.Ith Service Act. eeDBe, rescm:ch under* the NQUirementa lleeilllinl o! btolC)f;ical products. I! they so lon, u the phs.rma,cy (l > complie~ for 1nft$ttgatlonaJ dru&'a. anti lir.bellllg e ~ e 1n the ma.nutM:turt of new drurs, w1 h apP11e,.ble local la.ws regulattna' t.hc an<l advert1.!mg reQU.i.reUlent.&. In com- they ma:v also be 1UbJtct to the new d.rue Jl ti~ of pharmacy and <2> I& lice.tUed. mec tJ.na on the prol>084\l vubl.labed 1n \.l1e proviafom c( the Pederal Pood, Dru,:, &nd *w re applieable, b, t.he Nuclear Re~a-f'nimAL Rsotsn:11 ot July 29, 19'lt C39 Coa:n~e Act. Ph.:m&c:iM a.re rmerailY to Comm.t.uion or an .Aneement etaw PR 2'1538>, which Preceded \b1I ftnal re~- exempted under &ecUOJ:)I &lOCg) and 7o-i to P<>MMI. U.lle, or tra.nder radioactive ulati@, aeveml persona mqu.ired about Ca> ot the Fed~ Jl'ood. Drur, and Coo* s, except where the cornmwioncr the lega.1 oblilre.tlooa of "nuclear Poharma- met1c .Ac.t fram ~tiona rep.z-dlnir d rminu that tuch recralat.or., act.1on is cies" Wlder the Jl'ederal Food, orua-, and rea1z;tra.t1on., drUg ~ . JJUs)ecUon. and oeaaarJ' t.o Wegu&rd U'le public .be&lth. CO&meUC Act and the PubUc 'Health compliance with current Jood ma.nutac- e .Food and Drua- AdJ:ninilltr&tion 1~ Berv1ce Act llJ>Oll the e.1!ecUve date of turtng practice.& where 'thetr operatk,,ns a optinJ' this l>OlicY M an in~rii:o inea1<- th~ final regulation. euJ)eCially in.llo!ar aN bl oomplianoe With app~le local u1e tot.void. UlY dluuptton 1D t.he s;irac. as these "Due.leer pha.nna.cl.es'.' may be i>ha.rma.cy law& and do not. involve ma.n- t1j:e of 11uclear phartnaey and nuclear deem~ to be manufacturing or dutrtb* ufaeturtng procedUJ"'e5 other th&n 1n the ttjediciM Uiroughout the United State.*. utiog these ProdU<:t& other Jba.n u pm reg-ular COW'lle of their bwineu 01' dis- II)Qt.ed: JUly 18, 111'15, of the compounding and 111.apen&ing ot pens1ni or 11ellmt' C1~* at r-eta11. .l\ppli-drugs 1n tnc ordina17 practice of ph11rmncy, cat1on of these rules and exemotiow to nucle11.r ph~ee, wh.leh would be an 1.mmed1o.te result of the ~nal ree-ule.tion I A. M. SClrKtllt. Commv,ume,- ol Food. a114 .Dr11.1>s. {n\ Doe.'7~l!n1t l"U~ 7*2~'15:t:45 am) APPENDIX IV. Chapter explaining transfer of responsibility.

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RADIOPHARMACY Edited by MANUEL TUBIS and WALTER WOLF A WILEY-INTERSCIENCE PUBLICATION JOHN WILEY & SONS, New York London Sydney Toronto

Copyright © 1976 by John Wiley & Sons, Inc.

All rights reserved. Published simultaneously in Canada.

No part of this book may be reproduced by any means, nor transmitted, nor translated into a machine language without the written permission of the publisher.

Library of Congress Cataloging in Publication Data Main entry under title:

Radiopharmacy.

"A Wilcy-Interscicnce publication."

Includes bibliographical references and indexes.

I. Radiopharmaceuticals. I. Tubis, Manuel, 1909- II. Wolf, Walter, 1931- [DNLM:

I. Nuclear medicine. WN440 Rl31]

RM852.R36 1975 615'.8424 75-28385 ISBN 0-471-89227-0 Printed in the United States of America 10 9 8 7 6 5 4 3 2 1

CHAPTER 23 REGULATIONS AND LEGAL ASPECTS OF RADIOPHARMACEUTICALS SECTION A: FOOD AND DRUG ADMINISTRATION (FDA)

EARL L. MEYERS*

Director, Division of Oncology and Radiopharmaceutical Drug Products Bureau of Drugs Food and Drug Administration Rockville, Maryland

.3.1, HISTORY OF RADIONUCLIDE REGULATION, 686 23.2. FDA REGULATIONS PERTAINING TO RADIOPHARMACEUTICALS, 687 23.3. CONSENT OF HUMAN SUBJECTS, 690 23.4. RECORDS OF DISTRIBUTION AND PRODUCTION, 691 23.5. PREPARATION OF IND AND NDA APPLICATIONS, 692 23.6. THE RADIOPHARMACIST'S LEGAL RESPONSIBILITIES, 693 REFERENCES, 695 SECTION 8: .ATOMIC ENERGY COMMISSION (AEC)

RICHARD E. CUNNINGHAMt Division of Materials Licensing U.S. Atomic Energy Commission Washington, D.C .

• 3.7. REGULATION OF RADIOACTIVE MATERIALS, 697

• REFERENCES, 710

• Now retired.

tPresent addr~*ss: Acting Director for Division of Fuel Cycle and Materials Safety, Nuclear Regulatory Commission, Washington, D.C.

685

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686 Regulations of Radiopharmaceulicals PREFACE Both sections of this chapter were recently revised. However, on January 19, 1975, the U.S. Atomic Energy Commission was superseded by the U.S. Nuclear Regulatory Commission (NRC) and the U.S. Energy Research and Development Administration (ERDA). All the regulatory functions of the AEC were transferred to NRC. Just a few months later, on July 25, 1975, the FDA lifted the "temporary" exemption on radiophar-maceuticals, which had been in effect since 1963. As discussed below, radiopharmaceuticals had been temporarily exempted from the provision of the Food, Drug and Cosmetic Act. The lifting of this exemption returned to the FDA full regulatory author.ity on the pharmaceutical aspects of radioactive drugs, whereas NRC and the corresponding state regulatory agencies of radiological health regulate the radiological health and safety aspects of all materials containing radioactive nuclides.

The presentation of this chapter, while somewhat predated due to the constantly changing governmental regulations, is presented as back-ground material to show the development of the present regulations. It is therefore imperative that the reader consult the most recent editions of the Federal Register and the publications of the FDA and NRC to determine the present status of radiopharmaceutical regulations.

SECTION A: FOOD AND DRUG ADMINISTRATION (FDA) 23.l. HISTORY OF RADIONUCLIDE REGULATION Ther,e have been. three major steps in Federal drtig control legislation. The first was the Pure Food and Drug Act of 1906, the so-called Wiley law.

The next was the 1938 Federal Food, Drug, and Cosmetic Act. The third was the passage of the Kefauver-Harris Amendments of 1962. The latter two events effected radionuclide regulation.

Prior to the 1938 Act, the *Government had no control over the intropuction of new drugs. It was only after they were .in interstate commerce that they were subject to such provisions of the then existing Act that covered adulteratipn and misbranding.

The Act that was passed in I 938 required clearance of a new drug before marketing. The clearance, however, applied only to its safety when used as directed in its labeling. The 1938 law also provided for the

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FDA R£_J!Ula_ti!)nS _o! Rac!_il>P!~rmaccuticals 687 promulgation of regulations to allow the shipment of a new drug for  ! '

investigational purposes before it was approved for marketing.

The Kefauver-Harris Amendments of 1962 required an approved new drug application not only for the safety of the drug product. as previously, but also for effectiveness. This has sp~cial significance for prnccssors and distributors of radiopharmaceuticals because the Food and Drug Ad-ministration (FDA) regards all radiopharmaceuticals as new drugs.

Under the Public Health Service Act of July I, 1944, (Title 42, United States Code (USC), Section 262) the Bureau of Biologics, Food, and Drug Administration, formerly the Division of Biologics Standards, recom-mends to the Commissioner of Food and Drugs the licensing of specific biological products, including radioisotope-tagged drugs, that are defined in 42 USC, §262 and the applicable regulations (Title 21, Code of Federal Regulations (CFR), Part 273).

Radiopharmaceuticals are subject to regulation by the Atomic Energy Commission. Under the Atomic Energy Act of 1954, as amended, the Atomic Energy Commission (AEC) is authorized to license the posses-sion, use, and transfer of byproduct material, that is, radioisotopes

. .oduced in nuclear reactors, including byproduct material used as drugs .

• The FDA and AEC have worked closely over the years to assure adequate control of radiopharmaceuticals. In recent years, the AEC and FDA have been working toward an agreement under which FDA would assume the same control over investigational radiopharmaceuticals as it exercises over other investigating drugs. They are in agreement that FDA should resume control over all radioactive investigational drugs. Because of the manpower needed to handle the anticipated workload, a two step approach is being used. The first step is being implemented, using generally AEC's "well-established" list of the chemical forms of radionuclides and stated indications. The second step will be undertaken in the near future.'

23.2. FDA REGULATIONS PERTAINING TO RADIOPHARMACEUTICALS e Federal Food, Drug, and Cosmetic Act of 1938, as amended, applies f radiopharmaceuticals as much as to any other kind of drug. In general, the drug provisions of the Act are applicable to radiopharmaceuticals.

The Act prohibits interstate commerce in drugs that are adulterated or misbranded and in any new drug unless it is the subject of an approved new drug application. This includes a prohibition against doing anything that causes a drug to become adulterated or misbranded while held for sale after shipment in interstate commerce, e.g., in a hospital*.

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688 Regulations of Radiopharmaceuticals The following are a few of the significant definitions of adulteration, (21 USC§ 351) and misbranding (21 USC§ 352) affecting radiopharmaceuti-cals:

1. A drug is adulterated if the methods, facilities, or controls used for its manufacture, processing, packing, or holding are not operated in conformity with current good manufacturing practice to assure its safety, strength, identity, quality, and purity.

2. A drug is adulterated if it purports to be a drug recognized in an official compendium and its strength differs from or its quality falls below the standards set forth in the compendium.

3. A drug is adulterated if it is not an official drug and its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess.

4. A drug is misbranded if its labeling is false or mi,sleading in any particular.

5. A prescription drug is misbranded, and all radiopharmaceuticals are prescription drugs, unless its labeling contains a quantitative declaration of its active ingredients and certain other ingredients.

6. A prescription drug is misbranded unless its labeling bears ade-quate "full disclosure" information for its safe use by physicians, including indications, dosages, routes, frequency and duration of ad-ministration and any relevant hazards, contraindications, side effects and precautions. If a new drug application is approved for the drug, its labeling and advertising must be in accord with labeling approved in the new drug application.

7. A drug is misbranded if it is manufactured, processed, repackaged, or relabeled in an establishment that has not been registered with FDA.

8. A drug is misbranded if it is recognized in an official compendium unless the drug is packaged and labeled as prescribed by the compendium.

The Act prohibits the shiprrient in interstate commerce of any new drug unless a new drug application is approved for it (21 USC, §355(a)) or it is exempted for investigational use in accord with the New Drug Regula-tions (Part 130, Title 21 CFR). The term "new drug" is defined in Title 21 USC, ~32l(p).

Persons holding approved new drug applications are required to keep records of clinical experience, (21 USC, §355(j)). They are required to make reports as experience accumulates and advise FDA when they receive reports of adverse reactions, untoward reactions, contraindica-tions, and the like, when associated with use of their new drugs.

Except for the specific preparations for which new drug approvals are 111 effect, radiopharmaceuticals may legally be shipped in interstate_

- - *-* --*------- - (,89 FDA Rci:ulalions of Radiopharmacculicals commerce only in accord with the inves,tigational drug provisions of the law and regulations. Under the Act, the FDA is authorized to promulgate regulations exempting drugs intended solely for invcstigational use from the requirements of Section 505(a), (21 USC, § 355(a)). Section 130.3, 21 CFR, specifies the conditions under which new ;drugs for investiga-tional use may be distributed.

Under the New Drug Regulations (Section 130.3(a), 21 CFR), a ~ew drug intended solely for tests i11 vitro or in animals may be shipped interstate for such uses provided the fopowing conditions are met:

1. The drug is labeled "Caution-Contains a new drug for investiga-tional use only in laboratory research animals or for tests in vitro. Not for use in humans."

2. Animals used in such tests or their products, such as milk or eggs, are not used for food purposes.

3. The new drug is not intended for in vitro use in the regular course of diagnosing or treating disease.

This exemption for the investigational use of radiopharmaceliticals for studies in laboratory animals or in vitro requires no prior notice to FDA.

A In 1957 an amendment was published for the purpose of making it

-..illfnnecessary for the shipper of radioactive new drugs intended for investigational use to obtain a signed statement from an investigator when the shipment involved had been authorized by the AEC through its licensing system. Shortly after the Kefauver-Harris Amendments of 1962, the FDA and the AEC agreed to an extension of the ex~mption fvr investigational use of reactor-produced radionuclides from the New Drug RegulatiO{ls (Part 130, 21 CFR), until further notice, if shipped in confor-mance with AEC regulations. This exemption was the only e~emption to the investigational new drug regulations that was permitted. However, the exemption did not apply to accelerator-produced isotopes, to naturally occurring isotopes, to nonradioactive drug products used in conjunction with an investigational radionuclide use, nor did it relieve any person from the obligation of obtaining an approved new drug application before distribution of the drug product for other than investigational purposes.

The exemption, in part, is still in effect. As noted under Section 26.1, a two-step approach to lifting this exemption is being used. The first step Agan with a proposal published in the Federal Register on January 27,

~71 to revoke part of the exemption. The. proposal contain'ed those radiopharmaceuticals which were on the AEC "well-established" list, with the addition of 201 Hg. The final order resulting from the proposal was published in the;Federal Register on November 3, 1971 as a new section to the New Drug Regulations (Section 130.49, 21 CFR). It covers drugs

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690 Regulations of Radiopharmaceuticals which are on the AEC "well-established" list except for teletherapy and brachytherapy sealed sources or which may appear on the list in the future, and for which applicants may reasonably be expected to submit adequate evidence of safety and effectiveness for specific uses. The radionuclides listed in Section 130.49 of the New Drug Regulations (Part 130, 21 CFR), in the "chemical form" and intended for the uses stated, are no longer exempt from the Investigational New Drug Regulations (Sec-tion 1130.3, 21 CFR).

The preamble of the final order assures the industry the FDA will work 1

with all interested parties to define the kind of data required for each product. The order provided 120 days, to March 2, 1972, for submission of the required INDs and NDAs. Notification was given that FDA would permit continued commercial distribution until the applicants were notified otherwise. The commercial distribution of these drug products under the investigational drug legend has been the pattern under the AEC regulation of reactor-produced radiopharmaceuticals. As NDAs are ap-proved, this situation will be corrected.

The second step in the plan of FDA regulatory control will be lifting the remainder of the exemption granted by agreement with the AEC and published in the Federal Register of January 8, 1963 as part of the Investigational New Drug Regulations (Section 130.3, 21 CFR). This will allow regulatory control of all reactor-produced radionuclides used as radiopharmaceuticals for clinical investigation.

23.3. CON~ENT OF HUMAN SUBJECTS A very important provision. of the Act (21 USC, §355(i)) provides that regulations on the use of investigational new drugs on humans impose the condition that investigators obtain the consent of such human beings or their representatives, except where they deem it not feasible or, in their professional judgment, contrary to the best interests of such human beings. These regulations are found in Section 130.37, 21 CFR. This consent, where required, must be in writing during Phase I and II testing (clinical pharmacology), but may be in other than written form for Phase III (clinical studies). If written consent is not obtained, the investigator must obtain oral consent and record that fact in the medical record of the person receiving the drug. Failure to comply with these provisions of the law and regulations may be the basis for declaring an investigator ineligible to receive an investigational drug or the basis for termination of the sponsor's exemption to use an investigational drug.

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Records or Distribution and Production 691

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23.4. RECORDS OF DISTRIBUTION AND PRODUCTION It is' important that artificial radionuclides for drug use be manufactured or otherwise handled under exacting controls to assure their identity,

_purity, and potency, and their proper labeling to supply adequate informa-tion for safe and effective use. This entails certain record-keeping requirements since there has always been a need for records in connec-

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tion with sound scientific work.

Persons holding approved New Drug Applications are required to keep

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records of clinical experience, (21 USC, §355(j)), and report this experi-t:*:t*-.*

ence at stated .intervals (Section 130.13, CFR). Approval of several New  ;.

Drug Applications have been withdrawn, mainly on the basis of the failure to keep records and submit yearly reports as required by Section 130.13 of the New Drug Regulations.

Accurate records for drug processing and accountability must be maintained. The preparation of a radiopharmaceutical is a "custom" undertaking, where a batch is usually one unit or dose. The receipt of the order by electronic means may be detrimental to accuracy, the half-life of radioisotopes demands speed in handling, and labels must be com-

• sed in part at the time of processing. The maintenance of records under these operations is time consuming and very often laborious. However, should an undesirable response occur following the administration of a radiopharmaceutical to a patient, the legal involvements may reach staggering proportions.

The practice of good radiopharmaceutical manufacturing procedure requires that .the manufacturing process be adequately safeguarded and documented throughout all stages of the operations. The records should give the complete history of each batch from the receipt of incoming materials to the final dispensed product. Essential in controlling the manufacture of a 'dosage form of a radiopharmaceutical is the master-formula record (Section 133.7, 21 CFR) for the quantitative composition.

the manufacturing and processing instructions, the packaging. the labeling and the storage instructions, and the sampling and testing applied to the product during and after manufacture. Each time a drug product is made, a batch-production record (Section 133.7, 21 CFR) should be prepared .

.Accurate copies of the master-formula record, usually produced by

...,notocopying procedures, are prepared to cover the production and control of each batch of the radiopharmaceuticals. Laboratory control and distribution records are "tied-in" to the batch-production records.

The radiopharmacist must ensure that the processing, packaging, labeling, testing, storage, and distribution methods, controls instructions, and precautions described in his records are complete, a-:::curate in detail, and so clearly stated that they will not be misunderstood.

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692 Regulations of Radiopharmaccuticah 2J.5. l'REl'.-\R.-\TION OF IND AND NOA APPLICATIONS The new drug section of the Act, (21 USC, §355(b)), states the purpose and substance of a new drug application. The new drug application form (Form 356H) is found in the New Drug Regulations, (Section 130.4(c), 21 CFR) and is available on request from the FDA. It furnishes a detailed outline that should be followed in assembling the data for the application.

To allow for clinical investigation, a means is provided whereby drug products may be evaluated for safety and effectiveness, prior to the time of a new drug application approval. The Act (21 USC, §355(i)) and the New Drug Regulations (Section 130.3, 21 CFR) provide an exemption for investigation of safety and effectiveness of use. This exemption is in the form of a "Notice of Claimed Investigational Exemption for a New Drug," Form FD-1571, or IND. Form FD-1571 is available on request from FDA. The IND should furnish assurance that the individuals selected as investigators are in fact qualified to investigate the safety or effectiveness of the drug, or both, depending upon the nature of the experiment (Forms FD-1572 and FD-1573 available from FDA on re-quest).

The investigat.ional drug regulations pertaini1rn to clinical pharmacol-ogy phases of a drug test permit submission of a general outline of these phases as the claim for exemption. The FDA developed the follmonng simplified procedures particularly for the physician-investigator who sponsors an investigational drug including its use solely as a research tool.

He could meet this requirement by submitting a Notice to FDA of:

I. His intent to use the compound or compounds proposed for study.

, 2. Identification of the compound or compounds, together with the facts that satisfy him th~t the agent may be justifiably administered to man as intended.

3. The purpose of the use and the general program of the activity proposed.

4. Appropriate background information, including a brief statement of the investigator's scientific training and experience and the nature of the facilities available to him.

It is not necessary that these requests for exemption be lengthy and comprehensive. However, such things as the consent of human subjects provision and the requirement for reporting adverse reactions would still apply.

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693 23.6. THE RADIOPHARMACIST'S LEGAL RESPONSIBILITIES The law prohibits the doing of an act that results in adulteration or misbranding. This includes a prohibition against doing anything that causes a radiopharmaceutical to become adulterated or misbranded while held for sale after shipment in interstate commerce, e.g .. in a hospital.

A clear-cut policy should be established in every hospital \Vith respect to the procedure for processing radiopharmaceuticals. Each radiophar-maceutical to be prepared possesses its own unique pharmaceutical aspects. If a radiopharmaceutical is needed, the rndiopharmacist should prepare it or supervise its preparation. He is then in a position to determine what constitutes a safe and effective product.

The FDA has no program for regulating hospital practice. This does not mean that provisions of the Act do not apply to radiopharmaceuticals once they have entered a hospital, but simply that the regulatory activities of FDA are not currently directed toward hospital practices. It is reasonable for FDA to expect that radiopharmacists and the other professional personnel associated with hospitals will do a creditable job A of maintaining the integrity of radiopharmaceuticals in the hospital until W' they are accurately dispensed. If any government regulation is required to assure this, it may be an area of activity more appropriate to State rather

,. than Federal officials.

• A radiopharmacy. in our opinion, is exempt at present from the establishment registration requirements in accordance with Section 132.Sl(a) of the regulations promulgated by FDA, (Section 132.5 l (a), 21 CFR). This regulation, which expands the exemption contained in Section 5 lO(g)(l) of the Act (21 USC, §360(g)(l )), states that it is not necessary for a pharmacy to register if it is operating under applicable local laws and does not compsmnd a drug for sale other than in the regular course of the practice of the profession of pharmacy. The regulation also provides that the supplying of such pharmacy of a prescription to a practitioner licensed to administer such a drug for his use in the course of his professional practice does not require registration. FDA has for some time been concerned about this exemption from registration for "com-pounding pharmacies," and is considering a change in these regulations.

A The law is somewhat more complex with respect to the IND/NDA W' provisions in Section 505 of the Act (21 USC, §355). Every radiophar-maceutical is a new drug which, when shipped in interstate commerce,

• must be the subject either of an approved NDA or of an 1ND. except for some reactor-produced investigational radiopharmaceuticals. Thus, radiopharmaceuticals shipped from a manufacturer located out of the state to a pharmacy must be covered. Since the IND or NDA must relate

694 Regulations of Radiopharmaceuticals to the intended use(s) of the drug, it must cover whatever compounding will be undertaken by the radiopharmacy. If the radiopharmaceutical shipped to the pharmacy originated from within the state, and the compounded drug were not shipped out of the state, no IND or NDA would be required. Even if the raw material originated from within the state, however, if a radiopharmaceutical so compounded is shipped out of the state, or if there is reason to believe that a physician or patient to whom the drug is dispensed is from out of the state or intends to transport the drug out of the state, an IND or approved NDA is required.

If a hospital engages in radiopharmaceutical manufacturing, it will be confronted with the same scientific and technical problems encountered by commercial suppliers. If a hospital undertakes such operations to supply not only its own needs but those of other institutions, its operations may fall outside of what may properly be considered hospital practice and may invite application of Federal law with respect to such operations. However, if such operations are undertaken within its own facilities to meet the hospital's own radiopharmaceutical needs, they are recognized by FDA as normal hospital practice in dispensing drugs or prescriptions.

The radiopharmacist must obviously bear full responsibility for the quality, identity, strength, purity, and appropriate labeling of the radiopharmaceuticals issued by his department. If he manufactures some himself, he should maintain a quality control" system in conformity with good manufacturing*practice (Part 133, 21 CPR). In the preparation of radiopharmaceuticals, he must be constantly aware of the intricacies in manufacturing techniques, formulation incompatibilities, operational fac-tors, tests and standards, packaging, and stability of the finished product.

The radiopharmacist must be the guardian of radiopharmaceutical

• quality. The quality of the products manufactured in the hospital must equal that produced by pharmaceutical firms having modern equipment, advanced technologies and methodologies, and competent technical staffs. If the hospital is unable to produce products of quality equal to the pharmaceutical firms, the radiopharmacist and his staff should not engage in manufacturing radiopharmaceuticals.

It must be emphasized that the hospital or clinic is legally implicated in all studies involving human subjects in which staff members utilize hospital or clinic facilities. The adulteration and misbranding provisions of the Act apply to investigational new drugs. Even though the radiophar-maceutical is made and used within the facility, the State and Federal rulings apply and impose legal responsibilities upon the radiopharmacist, investigator, and the appropriate hospital or clinic committees .

695 ADDENDUM On July 25, 1975, and after extensive hearings and reviews, the FDA published a notice in the Federal Register lifting the exemption that had been granted to the AEC in 1963 on.the requirements of INDs and NDAs for radiopharmaceuticals. The full text of these regulations is on pages 31298-31314 of the Federal Register of July 25, 1975, and it is too early to review and discuss them at this time. The following key provision is reprinted here:

§310.3. Definitions and Interpretations (n) The term "radioactive drug" means any substance defined as a drug in section 201(g)(I) of the Federal Food, Drug, and Cosmetic Act which exhibits spontaneous disintegration of unstable nuclei with the emission of nuclear particles or photons and includes any nonradioactive reagent kit or nuclide generator which is intended to be used in the preparation of any such substance but does not include drugs such as carbon-containing compounds or potassium-containing salts which contain trace quantities of naturally occur-ring radionuclides. The term "radioactive drug" includes a "radioactive biological product" as defined in §600.3(ee) of this chapter.

REFERENCES I. Federal Food, Drug, and Cosmetic Act of 1938, as amended (Title 21, United States Code), U.S. Government Printing Office, Washington, D.C., particularly these Chapters:

II-Definitions, Sections 201 (g), (h), (j), (k), (I), (m), (n), and (p).

III-Prohibited Acts and Penalties, Sections 301 (a), (b), (c), (d), (e), (f), (h), (j), (k), (I),

(n), (o), and (p).

V-Drug and Devices, Sections 501, 502, 503, 505, 508, and 510.

VII-General Administration Provisions, Sections 701, 702, 703, 704, and 707.

VIII-Imports and Exports, Sections 801 (a), (b), and (d).

IX--,-Miscellaneous, Section 902 (c). ,

2. Code of Federai Regulations, Title 21; Part I, General Regulations, U.S. Government Printing Office, Washington, D.C., particularly these Sections:

1.1-General.

I.lb-Packages; definition; presence of mandatory label information.

1.2-Labeling; label; definitions.

1.3-Difference of opinion among experts.

LS-Guaranty; definition, and suggested forms.

1.100--Drugs; name.

I.IOI-Drugs and devices; labeling, misbranding.

1.102-Prescription and insulin-containing drugs in package form; labeling re identity.

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696 Rc~ulations of Radiopharmaceuticals 1.103-Drugs and devices; forms of making required statements.

1.104---Drugs; statement of ingredients.

1.105-Prescription-drug advertisements.

1.106--Drugs and devices; directions for use.

1.107-Drugs and devices, exemptions.

3. Code of Federal Regulatio11s, Title 21, Part 3, Stateme11ts of Ge11eral Policy or Interpretatio11, U.S. Government Printing Office, Washington, D.C., particularly these Sections:

3.36--Thorium dioxide for drug use.

3.45-Sterilization of drugs by irradiation.

3.62-Established names for drugs.

3.73-lmmincnt hazard to the public health.

3.74---Labeling for prescription drugs used in man.

3.501-Mailing of important information about drugs.

3.507-Location of expiration date in drug labeling.

3.508-Significance of control numbers on drug labeling.

3.514---Statemcnt of dosage on prescription drug labels.

3.515-Exemption from certain drug labeling requirements."

4. Code of Federal Regulatio11s, Title 21, Part 130, New Drugs, U.S. Government Printing Office, Washington, D.C., particularly these Sections:

130.1-Definitions and interpretations.

130.2-Biologics; products *subject to license control.

130.3-New drugs for investigational use in human beings; exemptions from Section 505 (a).

130.4---Applications.

130.5-R.:asons for refusing to file applications.

130.9-Supplemcntal applications.

130. 12-Rdusal to-approve the application.

I 30. I J-Rccords and reports concerning experience on drugs for which an approval is in effect.

130.27-Withdrawal of approval of an application.

130.32-Confidentiality of information contained in new drug application.

130.33-New drug application approvals; availability of informatio11.

130.37-Consent for use of investigational new drugs (IND) on humans, statement of policy.

130.38-Designated journals.

130.49-Requirements regarding certain radioactive drugs.

5. Code of Federal Regulatior1s, Title 21, Part 132, Registratio11 of Producers of Drugs, U.S.

Government Printing* Otfice, Washington. D.C.

6. Code of Federal Reg11/atio11s, Title 21, Part 133, Drugs; Current Good Ma11ufact11ring Practice Ill ,Wa1111facture, Processi11g1 P11cki11g, or Holding, Sections 133.1-133.15 (inclusive), U.S. Government Printing Office, Washington,. D.C.

7. The U11ited Stares P/111r111acopeia. 18th rev. U.S. Pharmacopeial Convent.ion, Inc.,

Washington, D.C., 1970

8. The National For11111lary. 13th ed. American Pharmaceutical Ass., Washington, D.C.,

1970.

'). lfr111i11gto11 *.,* l'li11m111c<'11tical Scic11ces. 14th ed. Mack Puhlishing Co .. Easton. Penna ..

1970. Char~ .1.1-.15.

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Regulation of Radioactive Materials 697

• SECTION B-ATOMl*C ENERGY COMMISSION (AEC)*

On January 19, 1975, the USAEC was superseded by the Nuclear Regulatory Commission (NRC) and the Energy Research and Develop-ment Administration. All regulatory aspects of AEC were transferred to NRC, and the Code of Federal Regulation Title IO AEC became NRC-CFR Title IO. The following text has been left as originally written inasmuch as not all former AEC regulations have as yet been relabeled as NRC and many considerations, written in the past, apply to the former AEC.

23.7. REGULATION OF RADIOACTIVE MATERIALS The Atomic Energy Commission's authority to regulate radioisotope-containing drugs is derived from the Atomic Energy Act of 1954, as amended. Among the provisions of the Act for such authority, Section 161 establishes a broad basis for regulation by stating in part:

In the performance of its function the Commission is authorized to A b. Establish by rule, regulation, or order such standards and instructions to

. . , govern the possession and use of special nuclear material, source material, and by-product material as the Commission may deem necessary or desirable to promote the common defense and security or to protect health or to minimize danger to life or property.

The atomic energy materials which the AEC is authorized to regulate under- the Act are source material (natural uranium and natural thorium),

special nuclear material (plutonium, uranium 233, or uranium enriched in the isotope 233 or the isotope 235), and by-product material (radioisotopes

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I yielded in or made radioactive in the process of utilization of special }::~~:: .

nuclear material such as occurs in the operation of a nuclear reactor). ~.~... ~; ..*

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Practically all radioisotopes used in medicine that are regulated by the ., .

AEC are by-product materials. The AEC does not regulate radium, accelerator-produced radioisotopes, or radiation-producing machines L

such as x-ray machines.

The AEC has adopted regulations that set forth the conditions under ri hich atomic energy materials may be obtained and used. Regulations of i;*

• articular interest to the radiopharmacist or physicians engaged in the use of radioactive drugs are IO CFR Part 30, "Rules of General Applicability to.Licensing of Byproduct Material," 10 CFR Part 35, "Human Uses of

• The views expressed herein are the author's and do not necessarily reflect those of the Atomic Energy Commission and the Nuclear Regulatory Commission.

• 698 Regulations of Radiopharmaceuticals By-Product Material," and 10 CFR Part 20, "Standards for Protection against Radiation." These regulations prescribe, among other things, the criteria for approval of license applications for the use of by-product material; rules pertaining to the transfer of licensed materials; record-keeping requirements; the kind of information that must be submitted to the AEC for licenses to use radiopharmaceuticals in man; and the criteria for radiation protection.

Control over the use of atomic energy materials, including pharmaceut-icals containing by-product material, is exercised through a system of licensing carried out by the Commission's Division of Materials Licensing and an inspection and enforcement program conducted by the Division of Compliance. It is necessary in most cases to apply to the AEC and be issued a license before by-product material may be obtained and used.

Under certain well-defined circumstances, where the use of by-product material may be placed under a general license or .exempted from regulatory control, the user does not need to apply to the AEC for a license. However, for certain categories of general licenses, he may be required to register with the AEC.

The regulations in 10 CFR. Parts 30 and 35 allpw only physicians licensed by a State to dispense drugs in the practice of medicine to be authorized users of by-product material in licenses which permit the administration of radiopharmaceuticals to man. The manner in which a radiopharmacy may be licensed will depend on its relationship to the institution that possesses the license authorizing administration of radioactive materials to man. The radiopharmacy could be a separate commercial enterprise just as pharmaceutical manufacturers are separate commercial enterprises. In this case, a radiopharmacy may provide services to one or more hospitals or physicians in private pr~ctice. The radiopharmacy, itself, would then have a separate license. If the radiopharmacy is a department within a medical institution whose prim-ary work is to provide radiopharmaceuticals to the departmei:it of nuclear medicine, the license for the pharmacy may be issued separately or.it may be combined as part of the medical license,' in which case a clear dis'tinction would be made between that portion of the license which authorizes prepar'ation. of radiopharmaceuticals and that which allows their administration to man under the supervision of a physician.

Part 30 of 10 CFR contains the basic rules pertaining to the licensing of by-product material. Reduced to its simplest terms, the essential require-ments that must be met for a license are that the applicant have appropriate training and experience to use the radioactive materials safely, adequate equipment and facilities for the safe handling of radioac-tive materials, and operating procedures that define appropriate radiation

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l{e,1uh1th>rJ of_ ~:1_dio:1cli_vc~~hltcrials (,99 safety practices to-be followed during the use of radioisotopes. To meet these requirements in the operation of a radiopharmacy, the staff must i'nclude a person responsible for radiation safety who has worked with types and quantities of radioactive materials similar to those intended for use in the radiopharmacy and who is also familiar with the precautions that must be taken to assure safety. The equipment and facilities necessary for the operation of a radiopharmacy will ordinarily be typical of those found in radiochemical laboratories. The operating procedures should specify safety practices which employees must follow in the course of their work, such as wearing of protective clothing, requirements for radiation surveys, personnel monitoring, and waste disposal.

The control that the AEC exercises over the type and quality of radiopharmaceuticals that may be administered to man is applied at the point where the license is issued to the medical institution or physician for use in man. Licenses issued to pharmaceutical manufacturers or radiopharmacies take into account only the radiation safety considera-1 ions and the methods by which employee health and safety are assured during the manufactu!"ing or preparation of drugs.

The AEC's regulatory program for the administration of radiophar-

-aceuticals to man included considerations of patient safety and drug dficacy as well as radiation safety of the physician, technicians, and members of the public. In general, the requirements for approval of an application for a medical license are that (1) the proposed radiophar-maceutical is one that has been demonstrated to be safe for the patient and effective for diagnosis, therapy, or obtaining desired investigational information; (2) the proposed equipment, facilities, and procedures are appropriate for the effective use of the radiopharmaceuticals and are adequate to protect the health and safety of the patient and the public; and (3) the drugs will be used by physicians whose training and experi-ence in the basfo principles of radiation and the clinical use of radioisotopes are ,sufficient for safe and effective use of the drugs.

A license issued to a medical institution authorizing the administration of drugs to man might specify the source from which the physician may obtain the drugs. If so, information about the drug which serves as a basis for authorizing its use is usually supplied by the organization that

~epares the drugs. In other instances, licenses might simply require

.ysicians to procure drugs from a supplier who assures the pharmaceuti-cal quality of the drugs.

In AEC medical licensing, a distinction is made between those drugs that are well-established for routine clinical use and those that are nonroutine and are still undergoing investigation. The uses of radiophar-maceuticals that are considered to be well-established are those for which I:

700 Regulations of Radiopharmaceuticals the pharmacological and radiological action; preferred route of adminis-tration, safety, side effects, contraindications, dose range, and effective-ness are well known. In general, they have been investigated widely and are used routinely for diagnosis or therapy. Physicians having proper qualifications, such as appropriate training and experience, facilities and equipment, and operating procedures, are readily licensed for these uses.

The current diagnostic or therapeutic procedures that are, in the opinion of the Commission, safe and effective, and satisfactory for routine clinical use are listed in Table 23.1. \

The short-lived radiopharmaceuticals present some unique problems in licensing since they are frequently partially compounded by the user institution. Where they are, the AEC prepares licensing criteria for drug preparation and use. Thus far, criteria have been developed for the use of molybdenum/technetium generators to prepare sodium pertechnetate 99 mTc for brain scans and technetium-labeled sulfur colloid for liver and spleen scans. As the safety and efficacy of more radiopharmaceuticals

. utilizing short-lived radioisotopes become established, it is anticipated that criteria will be developed for additional routine uses. When criteria are p:*epared, they are normally sent to all AEC medical licensees.

All other uses of radiopharmaceuticals are consi'dered investigational by the AEC. Persons proposing to administer radioisotopes to man for investigational purposes are required to submit a research protocol that contains information similar to that required by FDA under its investiga-tional drug regulations. The protocol must include, among other things, the rationale for conducting the study, the plan of investigation, an outline of related work previously conducted, the number and types of subjects to be studied, radiation dose calculations, and the qualifications of the investigators to conduct the study proposed. The radiopharmacy, whether it is a separate commercial enterprise sponsoring an investigation or a department within a medical research institution, will normally work closely with physicians ca*rrying out clinical investigations in man and will be best able to provide much of the information required by the protocol.

After completion of the investigation, the licensee is required to submit a report from which it can be determined whether or not it is appropriate to proceeq with further investigations, and, if so, the manner i~ which the investigation should proceed.

The AEC has appointed an Advisory Committee on the Medical Uses of Isotopes to advise on policies and stam;Iards for regulating and_

licensing' the medical use of radioisotopes in man. It provides guidance in establishing clinical experience and training requirements for physicians, safety procedures related to medical uses, and criteria for the evaluation of proposals to use radiopharmaceuticals. The members review and

i I I

mes Encased in needles and/or applicator cells Interstitial or intracavitary treatment of cancer.

Teletherapy source Treatment of cancer.

Chromate Spleen scans; placenta localization; red blood cell labeling and survival studies.

Labeled human serum albumin Gastrointestinal protein loss studies; pla-centa localization.

lier Labeled red blood cells Placenta localization.

i*co or ""Co Labeled cyanocobalamin Intestinal absorption studies.

roCo Teletherapy source Treatment of cancer.

roCo Encased in needles and/or applicator cells Interstitial or intracavitary treatment of cancer.

Colloidal Liver scans; intracavitary treatment of pleural effusions and/or ascites; inter-stitial treatment of cancer.

Seeds Interstitial treatment of cancer.

Iodide Diagnosis of thyroid functions; thyroid scans; treatment of hyperthyroidism and/or cardiac dysfunction; treatment of thyroid carcinoma.

'-"I Iodinated human scrum albumin Blood volume determinations; brain tumor localization; placenta localization; cardiac scans for determination of peri-cardia] effusions.

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"'I Rose Bengal Liver function studies; liver scans.

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~ Table 23. J (Continued)

Isotope Chemical Form Uses Iodopyracet, sodium iodohippurate, sodium Kidney function studies and kidney scans.

diatrizoate, diatrizoate methylglucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate

'"I Labeled fats and/or fatty acids Fat absorption studies.

"'I Cholografin Cardiac scans for determination of pericar-dia! effusions.

Macroaggregate*d iodinated human serum albumin Lung scans.

Colloidal microaggregated human serum albumin Liver scans.

Iodide Diagnosis of thyroid function.

Iodinated human serum albumin Blood volume determinations.

Rose Bengal Liver function studies.

Iodopyracet, sodium iodohippurate, sodium Kidney function studies.

diatrizoate, diatrizoate methylglucamine, sodium diprotrizoate, sodium acetrizoate, or sodium iothalamate I

ml Labeled fats and/or fatty acids Fat absorption studies.

ii "Fe Chloride, citrate and/or sulfate Iron turnover studies.

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"~Kr Seeds encased in nylon ribbon Gas Interstitial treatment of cancer.

Diagnosis of cardiac abnormalities.

I 'I 19'Hg Chlormerodrin Kidney !-cans; brain scans.

I '"'Hg Chlormerodrin Brain scans.

I p Soluble phosphate Treatment of polycythemia vera; treatment of leukemia and bone metastasis.

I

Colloidal chromic phosphate Intracavitary treatment of pleural effusio-ris and/or ascites; interstitial treatment of cancer.

,2K Chloride Potassium space studies.

nse Labeled methionine Pancreas scans.

"'Sr Nitrate or chloride Bone scans on patients with diagnosed cancer.

90 Sr Medical applicator Treatment of superficial eye conditions.

99mTc Pertechnetate Brain scans.

99mTc Sulfur colloid Liver and spleen scans. .

133 Xe Gas Diagnosis of cardiac abnormalities; cerebral bloodflow studies; pulmonary function studies; muscle bloodflow studies.

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704 Regulations of *Radiopharmaceuticals provide day-to-day advice on all applications for the use of radiophar-maceutica!s undergoing investigation. They also review information

• about drug investigations to determine whether or not a drug is safe and effective for routine clinical use. The Committee currently consists of IO members whose specialities cover a range of disciplines, such as internal medicine, radiology, medical physics, and pharmacology.

Most medical licenses authorize specific radiopharmaceutical proce-dures. Any signiticant changes in the program or additions of new procedures must be retlectecl by an appropriate change in the authority granted by the license. In an effort to simplify the licensing process for both the AEC and applicants, all but a few of the diagnostic procedures using by-product material have been divided into two groups based on similarity of requirements for physician training and experience, facilities and equipment, and radiation safety. The diagnostic procedures! contained in these groups are listed in IO CFR Part 35, §35. 100. Group .I includes the diagnostic uses characterized as uptake, dilution, and excretion studies.

Group II consists entirely of scanning and tumor localization procedures.

If a physician applies for a single diagnostic procedure within a group and if he is otherwise qualified for all the diagnostic procedures within a group, he will be licensed accordingly.

Institutions with extensive programs for medical research, diagnosis, and therapy with radioisotopes need more flexibility than is usually allowed by. a license, which authorizes only specific radiopharmaceutical procedures. Operations must be rapidly adjusted in such an institution in order to meet new goals as research and development programs progress or new programs are undertaken. This would be difficult to do under the usual medical license. To allow greater flexibility, licenses granting broad authority for the use of multiple types and quantities of by-product material are issu'ed to medical institutions that have demonstrated a high level of competence in nuclear *medicine and clinical investigation, and are actively engaged in research activities. Most medical institutions whose work in nuclear medicine is sufficiently extensive to have a need for an in-house radiopharmacy operate under a broad licens_e.

Control of proposed medical uses of radioisotopes within the institution that has been granted a broad license is under an in-house medical i~otope committee. which applies criteria similar to AEC licensing standards for the use of radiopharmaceuticals. In essence, the in-house isotope commit-tee is the administrative body that carries out responsibility fo*r the safe use of radioisotopes within the institution. Its membership should include physicians. such as internists and radiologists, and others, such as medical physicists and pharmacologists, who have broad experience in the various aspects of utilizing radioisotopes in clinical research or investigation.

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• • Regulation of Radioaclh;i 1\-laterials 705

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Clinical uses of radiopharmaceuticals within the institution, research protocols for investigational medical procedures, and the qualifications of the users must be evaluated and approved by the comrri'ittee in accor-dance with criteria and guidelines that it has established and the AEC has approved. The committee must ~!so adopt administrative procedures associated with procurement, use, and disposal of radioisotopes and assure that written records of all phases of the program are maintained. A formal set of rules, recommendations, and procedures for procurement and safe handling of radioisotopes should be established and distributed to personnel under the jurisdiction of the isotope committee*. A radiation protection .officer who reports to the committee should be appointed to implement the overall radiation protection program for the institution.

The AEC maintains surveillance of the performance of the isotope committee and operations conducted under a broad license through inspections carried out by its Division of Compliance.

In addition to specific and broad licenses, the Commission has also issued a general license as specified in 10 CFR Part 35, §35.31 which authorizes the use of small quantities of radiopharmaceuticals for certain diagnostic purposes. These include 125 I and 131 I for measurement of thyroid uptake and blood volume and blood plasma volume determina-tions, 58 Co and 60 Co for measurement of intestinal absorption of cyanocobalamin, and 51 Cr for determination of red blood cell volumes and studies of red blood cell survival time. U oder the general license, the physician does not need to apply to the AEC for a license to use these drugs. Instead, he files a registration form with the AEC on which he provides his name and address, confirms that he is a physician licensed to practice medicine, and states that he has appropriate equipment to carry out the diagnostic procedures he proposed to conduct. The physician may procure th~ generally licensed drugs after he receives from the AEC a validated copy of the registration form with a registration number. Drugs procured under the general license may not be administered to a woman known to be pregnant nor to a person under 18 years of age. The supplier, i.e., a pharmaceutical manufacturer or radiopharmacy who distributes radiopharmaceuticals to general licensees, must be licensed by the AEC to do so in accordance with the provisions of IO CFR Part 32, §32.70. The supplier must also hold an effective new drug application from the Food and Drug Administration for the drug or, in the case of a biologic, must hold a license issued by the Secretary, Department of Health, Education, and Welfare.

As applied to the operation of a radiopharmacy and practice of nuclear

• Now referred to as the Radioisotope Research Committee(!).

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706 Regulations of Radiopharmaceuticals medicine, the standards for protection against radiation set forth in 10 CFR Part 20 are designed to control the radiation exposure received by physicians, radiopharmacists, technicians, and* members of the public during the use of radioisotopes. They do not apply to the radiation exposure of patients resulting from the administered radioactive drugs.

The standards contain many specific requirements such as those for surveys, personnel monitoring, and waste disposal, which are intended to lead to control of radiation exposure. The regulation also contains record-keeping requirements related to these activities.

In developing its regulations on radiation safety, the Commission is guided by the recommendations of the Federal Radiation Council (FRC),

the National Council for Radiation Protection and Measurements (NCRP), and the International Commission on Radiological Protection (ICRP). The ICRP notes in their recommendations for permissible dose to radiation workers that any exposure to radiation is assumed to entail a risk of deleterious effects. It also notes that the quantitative relationship between dose and risk is not well known, but the maximum permissible doses can be set such that there _is low probability of radiation injury without undue restriction of the benefits of ionizing radiation. In applying these two views of ICRP to exposure of radiation workers under the provisions of 10 CFR Part 20, applications for licenses are examined to determine that exposure of radiation workers will be minimized even though operations will be conducted within permissible limits. Efforts to minimize exposure rn,ust be compatible with achieving the objectives of the procedure and accomplishing them without undue sacrifice of time, money, or quality of results. No attempt is made to weigh the benefit that might be derived from any specific radioisotope procedure against the risk of deleterious effects to the radiation worker when operating within the exposure limits. Applying this, principle to the practice of nuclear medicine, the physician is free to choose radioisotopes and follow the radioisotopic procedure which he believes will best serve the patient even if his choice might result in a slightly higher dose to radiation workers since the primary consideration must be that the patient's interest is paramount. A procedure that minimizes dose to those handling the radiopharmaceuticals at the cost of compromising the medical value of the procedure to the patient would be considered unacceptable. All

• exposures must, of course: remain within the limits set by 10 CFR Part 20.

Radiation safety is the licensee's responsibility even though the AEC is responsible for deciding whether or not an applicant is properly qualified to be licensed for the use of radioisotopes. To discharge its responsibility, the licensee's management must make periodic checks on its program to assure that employees use radioisotopes safely and in accordance with

707 requirements of the license and provisions of the regulations. Mainte-nance of appropriate records is essential for managemenfto assess the quality of its program. Of the records that AEC regulations require, the ones of particular interest in the operation of a radiopharmacy include records covering the receipt, transfer, and disposal of radioisotopes; radiation exposure of persons working in the program; and surveys made to evaluate radiation safety.

In discharging its regulatory responsibility, the Commission conducts an on-site inspection program carried out by the Division of Compliance.

Compliance inspectors review licensed programs to determine whether or not they are being operated in compliance with AEC regulations and license requirements.

Section 274 of the Atomic Energy Act authorizes the Commission to enter into an agreement with a governor of any State whereby the State assumes certain regulatory responsibilities for the use of atomic energy materials, including the regulation of by-product material in nuclear medicine. To enter into an agreement with the AEC, the State must demonstrate that it has a regulatory program compatible with the Com-mission's program and that it has appropriate technical capability to operate the program. Persons using by-product material for medical

& purposes within Agreement States apply to and are licensed by the State

• rather than the AEC for such programs, except for institutions operated by the Federal government, such as Veterans Administration hospitals. In operating their programs, most Agreement States exercise regulatory authority over the use of other sources of radiation, such as radium, x-r_ays, and accelerator-produced radioisotopes, which are not covered by the Atomic Energy Act and, therefore, not regulated by the AEC. A part of an agreement with a State is the requirement that both the AEC and the State put forth best efforts to maintain continuing regulatory compatibil-ity, and in actual practice the Agreement State regulations and procedures are essentially identical to those of the AEC. The AEC thus far has entered into agreements with 25 states (Table 23.2).

The AEC has prepared special licensing guides to assist in the prepara-

. tion of applications for licenses to use by-product material. Two guides of particular interest to the radiopharmacist are "How to Get a License to Use Radioisotopes" and "A Guide for the Preparation of Applications for the Medical Use of Radioisotopes." The former provides background

& information about the regulatory program, how it functions, and the W *safety responsibility of persons who use radioisotopes. The latter in-cludes the specific requirements for training and experience of physicians who administer radiopharmaceuticals, information to be included in protocols for investigational uses, and a list of drugs that are considered

Table 23.2. Licensing Officials in Agreement States Alabama Kansas Division of Radiological Health Radiological Health Section Alabama State Department of Radiological and Occupational Health Public Health Program State Office Building, Room 313

• Environmental Health Services Montgomery, Alabama 36104 Kansas State Department of Health Topeka, Kansas 66612 Arizona Arizona Atomic Energy Commission Kentucky

.rn East Thomas Road, Suite 107 Radiological Health Program Phoenix, Arizona 85012 Kentucky State Department of Health Arkansas 275 East Main Street Division of Radiological Health Frankfort, Kentucky 40601 Arkansas State Board of Health I Little Rock, Arkansas 72201 Louisiana Division of Radiation Control California Louisiana Board of Nuclear Energy Bureau of Radiological Health P.O. Box 44033, Capitol Station Department of Public Health Baton Rouge, Louisiana 70804 2151 Berkeley Way Maryland Berkeley, California 94704 Maryland State Department of Health and Mental Hygiene Colorado 610 North Howard Street Radiation Hygien,e Section Baltimore, Maryland 21218 Colorado Department of Public Health Mississippi 4'.!10 East I Ith Avenue Radiological Health Unit Denver, Colorado 80220 Mississippi State Board of Health Jackson, Mississippi 39205

• Florida Radiological Health Section Nebraska Division of Health Division of Environmental Safety P.O. Box 210 Nebraska State Department of Health Jacksonville, Florida 13220 I Lincoln, Nebraska 68509 Georgia Nevada Gwrgia Department of Public Health Department of Health, Welfare and State Health Building Rehabilitation

.-\tlanta, Georgia 30303 Carson City, Nevada 89701 Idaho New Hampshire Radiological Health Section Radiation Control Agency Idaho Department of Health Division of Public Health Services Statehouse New Hampshire Department of Boise, Idaho 83707 Health and Welfare 708

709 Table 23.2 (Continued) 61 South Spring Street P.O. Box 231 Concord, New Hampshire 03301 Portland, Oregon 97207 New Mexico South Carolina Environmental Improvement Agency Division of Radiological Health State Capitol Building South Carolina State Board of Health Santa Fe, New Mexico 87501 J. Marion Sims Building 2600 Bull Street New York Columbia, South Carolina 29201 Division of Industrial Sciences and*

Technologies Tennessee New York State Department of Industrial Hygiene and Radiological Commerce Health Services 112 State Street Tennessee Department of Public Albany, New York 12207 Health Cordell Hull State Office Building North Carolina Nashville, Tennessee 37219 State Radiation Protection Program Texas North Carolina State Board of Health Division of Occupational Health and Raleigh, North Carolina 27602 Radiation Control North Dakota Texas State Department of Health Division of Environmental Austin, Texas 78756 Engineering Washington Radiological Health Program Radiation Control Section State Department of Health Division of Environmental Health Bismark, North Dakota 58501 Washington State Department of Oregon Health Radiological Health Section 1510 Smith Tower Oregon State Board of Health Seattle, Washington 98104 safe and effective for routine clinical use. Single copies of the guides as

• well as copies of pertinent regulations and application forms may be

• obtained by writing to the Isotopes Branch, Division of Materials Licensing, U.S. Atomic Energy Commission, Washington, D.C. 20545.

Multiple copies may be obtained from the Superintendent of Documents, U.S. Government Printing Office, Washington, D.C. 20402(2,3).

The field of nuclear medicine is relatively new and is still growing rapidly. Each year, greater numbers of persons are diagnosed or treated with radioisotopes, the list of nuclear diagnostic or therapeutic proce-dures available for routine clinical use expands, and the number of physicians and paramedical personnel engaged in nuclear medicine in-creases. At the same time, the Commission's program for the regulation

~~~'"'!:.*.:~-~-t_:'71.'.f~-~-~-*7,--:.~:T:;r.nn~~":*J\'!.tc"::."-~"li.'."-"'"Yr\.-:-,e~ .. ,,.. . . . :sy-,1:1,:"m""'l-.-n-r**-*r--.....- ... ,--e*-.-.-.... - .. * - - * - - .

710 Regulations of- Radiopharrnaceuticals of nuclear medicine is undergoing study to determine what its future role

. should be to best serve the medical community and the public. It is anticipated that in the coming years this role will change from that which has just been described. At the time of this writing, it appears that the eventual regulation and other controls applied to radiopharmaceuticals and to the practice of nuclear medicine should develop along the following lines: '

I. Radiopharmaceuticals should be regulated on much the same basis as other drugs and by those government agencies that presently have.

similar responsibility for nonradioactive drugs.

2. Physician qualifications to practice nuclear medicine should be established and controlled by the medical community itself or by state and local examination boards that make similar judgments in other fields of medicine.

3. The AEC should limit its role in the regulation of ~ticlear rdedicine to considerations that govern the radiation safety of employees and the public during the manufacture and the use of radiopharmaceuticals as the AEC currently does for other uses of by-product material.

Future changes that might occur in the AEC regulatory program will be made with these long-range goals in mind. However, since the problems are complex, it is unlikely that all these goals will be achieved soon and probably not in one step.

I REFERENCES I. JO Code of Federal Regulations. Federal Register, vol. 40, no. 144, Part II,July 25, 1975.

Part 20--Standards for Protection against Radiation.*

30--Rules of General Applic;ability to Licensing of Byproduct Material.

31--;-General Licenses for Certain Quantities of Byproduct Material and Byproduct Material Contained in Certain Items.

32-Specific Licenses to Manufacture, Distribute, or Import Exempted and Gener-

. ally Licensed Items Containing Byproduct Material.

33-Specific Licenses of Broad Scope for Byproduct Material.

35-Human Uses of Byproduct Material.

2. How to Get a License to Use Radioisotopes. U.S. Atomic Energy Commission, Washington. D.C.

3. A Guide for the Preparation of Applications for the Medical Use of Radioisotopes. U.S.

Atomic Energy Commission, Washington, D.C., 1972.

APPENDIX V.

FDA Nuclear Pharmacy Guideline

NUCLEAR PHARMACY GUIDELINE CRITERIA FOR DEI'ER11INING WHEN 1D REGISTER AS A DRUG ESTABLISHMENT D:l. te: 11:ly 1984

• Office RespJnsible for Guideline: Division of Drug Labeling Comliance Office of Compliance (HFN-310)

Center for Drugs and Biologics Food and *Drug Administration 301-443-7281

The FDA has legislative authority ynder the Federal Food, Drug, and Co.srretic Act to regulate drugs for human use. section 510 of the act (21 u.s.c. 360) re:;ruires drug establishments to register with FDA. Other provisions of the act provide ci1e authority for FDA to regulate the manufacture, sale, and distribution in j_nterstate commerce of new drugs, to assure that they are safe and effective for their in~enaed use (secs. 501, 502, 505 of the act; 21 u.s.c. 351, 352, 355). section 20l(p), of the act I *

.. oofines the term "new drug"" generally to mean a drug not generally reC'Ognized by qualified experts to be safe and effective. It has been the agency's position that all radioactive drugs, including radioactive biological products, are new drugs except for those* generally reC'Ognized as safe and effective-when administered for research Wlder the conditions set forth in§ 361.l(b) of the act (21 CFR 361.l(b)).

unaer section 510(g)(l) of the _act, a fharrracy, including a nuclear i;:har~cy, is exempt fran canplying with the need to register as a drug establishrnent if (1) it operates in C'Onforrrance with any applicable local laws regulating the practice of fharmacy and medicine, (2) it is regularly engaged in dispensing pres er iption drugs upon the pres er iption of

- practitioners licensed 'to adninister prescription- drugs to p:1tients under their care in the course of their professional practice, and (3) it does not manufacture, prop:1gate, canpound, or process drugs or devices for sale.

other tha~ in the regular course of their business of dispensing or selling at retajl. Thus, to the extent these re:;ruirenents are met, a nuclear pharrracy rray prep:1re a radioactive drug without being required to register with FDA 2

as a drug esta~lishrnent under section 510. Onder other circumstances, however, registration of a nuclear pharrracy will be reg:uired.

As a matter of pracbce, in addition to nuclear fharmacies, nuclear medicine laboratories under the control of a fhysician rray also pre_pare radioactive drugs. section 510(g)(2) of the act specifically permits licensed practitioners to rranufacture drugs without I-~aving to register as drug manufacturers provided the drugs are solely for use in t11e course of

• • the practioner 's professional practi.ce.

Because the NRC has legislative authority to* license and regulate all aspects of the possession and use of radioactive by-product (i.e.,

reactor-produced) rraterials in order to protect health and minimize danger to life or property, it also has certain regulatory authority over radioactive drugs. Both radioactive drug manufacturers and nuclear pharrracies are required, therefore, to comply with applicable regulations of the NRC as well as those of FDA.

In a sep;i.rate notice also p.iblished in the FEDl;:RAL REGISTER of July 25, 1975 (40 FR 31314), FDA announced its intention to clarify the responsibilities of nuclear pharmacies under the act. The notice o:mtained

- an interim enforcement *policy pertaining _to nuclear r:narmacies. It stated that FDA would not take regulatory action against a nuclear phanracy that did not canply *'with the re:::i:uirenents of the act, except when regulatory action was necessary to protect the p..1blic heal th, provided the fharrracy (1) canplied with applicable local laws regulating the practice of pharrrac.1, and (2) was licensed, when applicable, by the NRC or an Agreement 3

'i . !

I state to possess, use, or transfer ragioactive drugs. (An Agreement State is one t.l-iat, under forrral agreement with the NRC, is authorized to license, under Federal law, persons engaged in the possession, use, or transf,er of source, by-product or special nuclear rraterials in that State). FDA adopted this interim enforcement policy in 1975 to avoid any disruption in the practice of nuclear p,.,arrracy and nuclear medicine throughout th~ United States. FDA concluded that, al though radioactive drug manufacturers would

.. be subject to the act, it -would not take regulatory action for the failur.e of nuclear i;harrecies to canply with the requirements of the act, under the o:>nditions specified, until the status of nuclear pharmacies was further clarified.

DEVELOPMENT OF NUCLE-i\R PHARMACIES Since 1946, when artificially produced radioisotopes became available in quantity, there has been a rapid growth in the medical use of radioactive drugs, including ra'dioactive biological products, to diagnose and treat a.tsease. Radioactive d!;ugs are administered for two different

- purposes: as a radiation source, and as a radioactive tracer. As a radjation source their princip:11 role is i~ therapy; as a radioactive tracer they are** used primarily for diagnostic. purposes.

When *radioactive drugs first became generally* available, they were usually prep:1red by canrnercial* ,drug manufacturers under approved new dr~g ai;:plications (NDA's) and shipped to users in a form suitable for direct 4

. -**- ad'ninistration to patients. As the use of radioactive drugs increased within hospitals, units within hospitals were often created to receive and store all incoming radioactive drugs. In most hospitals--where, in fact, rrost radioactive drugs are administered-those units often became p:i.rt of the p,anracy depar trnent. Pharmacies employing registered p,arrnacists and other personnel having specialized training and exper:ience in corn_p:mnding, preparing, storing, and dispensing radioactive drugs became kr)own

• specifically as "nuclear pharmacies."

Initially, the activities of a nuclear pharmacy included 'Cl) purchasing a canmercially prepared radioactive drug from a drug manufacturer who held an approved NDA and dispensing the drug in its original unopened container, (2) dispensing a single dose from a multiple-dose container of a C'Olilril=rci.ally prepared radioactive drug, a.nd (3) diluting (including adjustments of buffers, bacteriostatic agents, and stabilizers) and repackaging a cornrrercially prepared radioactive drug for subsequent use or distribution. As the training and experience of n~clear fharrr.acists increased, some nuclear pharmacies began prep:i.r ing their own radioactive drugs.

Orn method used by *nuclear :EX)armacies to pre:i;are radioactive drugs was to add a radionuclide to a nonradioactive substance, usually a drug product, resulting i.n what :is referred to as a "labeled cornp:>Und." In nuclear medicine the ter~ "labeling" refers to the process of addjng a radioisotope to a suitable nonradioactive substance. In this document,.

this process is referred to as "radiolabeling" to avoid confusion with the term "labeling" as defined in section 20l(m) of the act.

5

M technology developed, and in order to reduce the radiation dose to patients, radioactive drugs with shorter-lived radionuclides were introduced. Because of* their short half-lives, many of these drugs must be prepared in a final dosage form shortly before they are to be administered to patients. Thus, these drugs had to be prepared at a facility close to where they would be administered. Otherwise the deli_very time cx>Uld be so lqng that significant radioactive decay would take pl_ace befor_e the drug

• • was administered. The ability to *prepare _radioactive drugs with short half-lives became possible, in part, through the* use of a radionuclide generator. A radionuclide generator contains a glass or plastic colurm filled with an adsorbant; such as a resin or alumina, in which the long-lived "parent" radionuclide is retained. Radioactive decay of the long-liv,ed parent radionuclide results in. the production of a short-lived "daughter" radionuclide which* is eluted by p:i.ssing an appropriate liquid or gas through the column. These radionuclides are then used by a nuclear pharrracy to prepare- short-lived radioactive drugs, often by using a nonradioactive kit. A "nonradioactive kit" or "reagent kit" contains all the necessa~y ingredients, except_the radionuclide, for mking a.

radioactive drug product. By adding the radionuclide to the nonradioactive kit according to the directions accompanying the kit, a radioactive drug product of S,Pecified purity* can be produced, often just prior to administration. Most nonradioactive kits are prepared by a rornmercial manufacturer under an approved NDA, but sane nuclear J_:harmacies are now prep:iring their a,m kits.

6

~

Another aspect in: the aeveloµnent of nuclear r:harmacies has been their physical location and extent of activities. M:Jst nuclear r:harrracies are located in hospitals ana dispense radioactive drugs only within the

institution in which they are located. As the practice of nuclear p-1arrnacies has matured, sane nuclear p-1armacies, although located in a particular institution, may supply radioactive drugs _to other institutions that do not have nuclear p-1armacies. In other instances, som~ nuclear

• pharrracies rray be completely independent of any institution and may supply radioactive drugs to a nurrber of institutions and practitioners.

Distribution of radioactive drugs by a nuclear pharrracy may thus be limited to (1) one institution, (2) a few institutions and *practitioners in the vicinity of the nuclear i;:harrracy, or (3) a large number of instituttons and practitioners in a large metr9politan or _geographic area, which may be located in rrore than one state.,

ACTIVITIES OF NUCLEAR PHARMAC.IES Activit~es of a nuclear :p1arffi?cy rray include:

o Purd:iasing a canmercially prepared radioactive drug product whid:i is marketed* un*aer an approved NDA and dispensing the drug in its original unopened container.

o Repadcing a radioactive drug product which is the subject of an approved NDA for subseg:uent use or distribution.

7

o Dispensing a single dose, or seri~s of single doses, from a multiple-dose container of an approved radioactive drug product. For example, dispensing single capsules of radioactive sodit.nn iodide_,

drawing a single dose of a ;:adi.oactive drug into a syringe, or dr'awing a nurrber of single doses of a radioactive drug into syringes.

o Diluting and repackaging an approved radioactive drug pro~uct, such as adding water for injection to reduce the concentration of the active_

comp:::ments, and adjustment of buffers, bacter iostatic agents and stabilizers.

0 Eluting an approved radionuclide generator and using the eluate to radiolabel a nonradioactive kit to prepare a radioactive drug product.

o r*~ufacturing a nonradioacti.ve kit for subsequent use in preparing a radioactive drug product.

o Preparing a radioactive drug product by using a commercially prep:1red radionuclide or a radionuclide obtained from a nuclear reactor or particle accelerator to which 'the nuclear pharmacy hap access.

Some activities of a nuclear fharmacy clearly* involve J;harmacy practice*

that qualjfy for the statutory exemption available to J;harmacies. Othe~

activjtjes, however, are operations that would require the establishment to 8

register under section 510 of the act. NUclear fharrracies that are re;;Iuired to register under the act will also be subject to the drug listing provisions of section 510 of the act and FDA's regulations under 21 Part 207, the current good rranufactur ing practice requirements of section ,501 of the act and FDA's regulations under 21 CTR Parts 210 and 211, and the factory inspection provisions of section 704 of the act. A nuclear:

p,arrracy, particularly one that is required to register, may ~lso be

-* subject to the new drug provisions of section 505 of the act and FDA I s regulations under 21 CFR Parts 310, 312, and 314.

-* All pharr.acies, including nuclear pharoocies that qualify for the statutory exenption, are subject to section 501 of the act. section 50l(a)(2)(B) of the act deems a drug to be adulterated if the facilities or controls used for its manufocture, proces_sing, packing, or holding do not conform to or are not operated or administered in C'Onformity with cur;ent good.manufacturing practices. Al though nuclear piarmacies are required to comply with section 50l(a) (2) (B) of the act, it has not been the p::,licy of FDA to apply the current good manufacturing practice regulations under 21 CFR Parts 210 and 211 to rnarrracies as these regulations are not e specifically applicable to many fharrracy .operations.

All pharrracies, including nuclear rxiaroocies, are also subject to the factory inspect"ion provisions of section 704 of the act. This section authorizes, arong other things, the fospection of any factory, warehouse, or establishment in which food, drugs, devices, or cosmetics are r.anufactured, processed, packed, or held for introduction into interstate 9

ccrnrnerce or after such introduction 'into interstate canmerce. Thus, as

~tablishrrents holding drugs after their introduction into interstate ccrnrnerce, all i;:harmacie~, including nuclear fharmacies, are subject to inspection unaer* this provision. In addition, nuclear pharrracies that are required to register as drug establishments under section 510 of the act are subject to rrore extensive provisions of the ~nspectional authority of-section 704. Although subject to inspection, th~ agency is not required to j_nspect, and except for reasonable cause norrrally does not inspect fharmacies, including nuclear fharmacies, operating entirely unaer t.l-)e piarmacy exemptions in the act. However, the agency will be

- required, under section 510(b) of the act (21 u.s.c. 360(b)), to inspect pharr.acies, including nuclear pharrracies., that are registered as drug establishments under section§ Sl0(b) of the act.

DEVELOPMENT OF GUIDELINE To better understand the nature of the practice of nuclear fharmacy, including the types of activities and organizational settings in which these* activj ties are performed, FDA has met with a nurrber of professionals, professional organizations, and Federal and state agencies having an inter_;!st in nuc~ear medicine and fharmacy. A meeting, join~ly sponsored by t.l-)e State of Wa~hfogton Radiation Control Unit and FDA's regional offl.ce in Seattle, was held in Seattle on Noverrber 12 and 13, 1975. ~epresentatives of a number of State radiation control agencies, 10

.f

two state boards of i;:harmacy, the American Pharmaceutical Association,.*

and sever al practicing nuclear rxiarm:icists and others attended this meeting. Issues discus.sed at this meeting were: (1) ~at is a nuclear pharmacist, and what kind of qualifications should he/she have for preparing and dispensing radioactive drugs? ( 2) ~at credentialing requirements are appropriate for nonpharmacist dispensers of radioactive drugs? ( 3 )' ~tla t is the def in i. ti.on of r adior:harmacy or nuclear_ rxiarmacy, and what constitutes a pr.escr iption for a radioaGtive drug? ( 4) What are the requiranents for the preparation *and supply .of radioac~iv.e new drugs including those for investigational purposes? A summary of this meeting is available for inspection at FDA's DOd<ets Management Branch (HFA-305),

Food and Drug Administration, Rli1. 4-62, -5600 Fishers Lane, Rockville, MD, 20857, under DOd<et No. B0D-0069.

F-DA believes the ffrst three questio~s involve primarily state and local laws regulating the practice* of rxiarmacy. However, under the* act the answers to the.se questions may determine, in a given situation, whet..:"'ler a P'}armacy is exffilpt from the registration provisions of the act. Thus the licensure procedures ci1at designate a person as being a r:harmacist, the extent; that a p-larmacist may delegate authori.ty, and the type of order that qualifies as a prescription are all matters that are determined ~d~r state l~ws, but they may also affect t.."'le application of the act to F,harmacies.

To aid the agency in establishing er i ter ia to determine what activ{ties of a nuclear r:harmacy require registration, a subccmmittee of FDA's Radiop1armaceuticals Advisory Corroni.ttee was appointed in o::tober 11

. ... 1975 to consider and report on issues relating to nuclear y;harrracy .

Specifically, the subcommittee was rtquested to consider the following

• . _ two questions: v-tia t types of operations engaged in by nuclear y;harrnacies should be regulated to some degree by FDA? What .is the relative urger1cy for issuing new regulations or stat6Tlents of policy, if they are needed?

The subcornmittee reported to the Radiopiarrraceuticals Advisory Ccrrimi ttee on April 15, 1976. In preparing its report the subccrnmj ttee

.. received suggestions and r:eco!T[ilendations from numerous individuals and organizations. In add~tion, it considered the publi.c testimony presented on t..11ese two questions before the full committee in April 1975, and the statements and discussions at a meeting of the subcanmittee in January 1976. A COP.:f of this report is also available for inspection at FDA's D:>d<ets Managanent Branch (address above) under oocket No. BDD-0069.

In considering which nuclear pharoocy operations should be regulated by FDA, the subcanmittee concluded *that if the radioactive drug was prepared and dispensed under a prescription, the laws and regulations governing the practice of y;harrnacy and medi.cine at the State level should awly and the nuclear pharrracy should be considered as engaging in the practice of y;harrracy. 01 the other hand, the subcommittee stated that the presence of a third party in the dis tr ibuti.on of a prescription drug, between the location where the product is formulated, compounded, or rranufacturec) and the p:)int where it is administer.ea to patients, changes the practice to one of manufacturing. Examples of this type of situation t.i.'1at were cited by the subcommittee included one in which a nuclear 12

i:harrnacy sells radioactive drugs to a second fharrnacy for dispensing by the second pharrracy under a pres er iption, and one in which a nuclear i:harrracy sells to other *fharracies bulk quantities of nonradioactive kits that it develop.s. In each case the fir st pharmacy would be a manufacturer under the act and be required to register under Section 510 of the *act.

The subcolilffil.ttee also recognized that radioactive drugs are often

.. administered by a nuclear*rnedicine unit in a single instjtution. such a.

nuclear rredicine unit 1:"3-Y operate a nuclear phanracy and maintain control over any radioactive drug manufactured or can_pounded within the p,armacy until it is dispensed. Here, the subcorrani ttee concluded that the high level of control exercised over the drug *precluded any need for*

registration.

The subcommittee recommended to FDA that substantive changes in FDA regulations, as they pertain to true nuclear fharrnacies, were not needed. The subcornmi.ttee recommended that individual State boards of fharracy rather than FDA should regulate nuclear fharmacies in the same manner as t:J:ley now regulate traditional pharmacies which do not compound

- or dispense radioactive- drugs.

At the same time, the subcommittee recommended that FDA clarify "the jssue of nuclear fharmacy-rnanufacturing versus traditional fharmacy c:::,mp::,unding with a policy statement; this statement should indicate that the same er iter ia will be used in making th is deterrnina tion for radioactive drugs as those which are used for. nonradioactive drugs. This statement will also affirm that certain of the operational procedures in whj~~ sorre nuclear }?harmacies engage are, in fact, manufacturing, and must be regulated as such."

CRITERIA FOR DETERMINING-WHEN A NUCLEAR PHARMACY MUST REGISTER AS A DRUG ESTABLISHMENT FDA agrees with the subcanrnittee's recc:mmendation that, to the extent practicable, the criteria for registration as a drug establishment for n~clear i:harnacies should be the s~~e as those for traditional pharmacies. The agency further agrees wit.h the subcommittee -that regulations applicable to nuclear i:harmacies contemplated in the July 25, 1975 notice are not needed at this time and that FDA can fulfill its regulatory responsiliilities in this area by issuing a guideline on the subject. This guideline also responds ~o the subcommittee recommendation that FDA notify state boards of piarmacy and other state and Federal agencies of FDA's p::ilicy in the area of nuclear fharrracies.

section 510(g) (1) of the act (21 u.s.c. 360(g) (1)) states that phaqnacies which rraintain establishments in conforrrance with any applicable local laws regulating the practice of piarrracy and medicine are exempt from t.."1e drug registration provisions of the act. For the e;{emption to apply they n:iust be regularly engaged in dispensing 9 prescription drugs or devices, up:m prescriptions of practitioners licensed to ad"ninister such drugs or devices to P3tients under the care of such practitioners in the course of their professional practice, and they must not manufacture, prepare, prop:igate, compound, or process drugs or devices for sale other than in the regular course of their business of dispensing or selling drugs or devices at retail. Because many States do 14

not a:r;pear to have laws that apply specifically to the practice of nuclear rxiarrracy, and rtay not have rnechanisms specifically designed for certifying nuclear fharrracists, and because many nuclear fharrracies require specially trained personnel whose activit_ies resemble those of drug manufacturers more than those of traditional i.:harrracy practice, FDA cb<=:s not believe that the "pharmacy" exemption of th~ drug registration provisions of section 510(g) (1) of the act (21 u.s.c. 360(g) (1)) applies to all so-called "nuclear Itiarrracies." FDA's regulation of n~clear p,arrracies will be bas~ on a reasonable application of the provisions of section SlO(g)(l) of the act to nuclear Itiarrracies and it will treat t.liese nuclear fharrracies as other i;harrracies have been traditionally treated under thi.s section. Therefore, a r::harrracy, including a nuclear i:;harmacy, whose activities are consistent- with section 510 (g) (1) of the act will be exempt from registerin~ as a drug establishment and from.

canplying with other requirements that flow from registration.

Conversely, a piarrracy, includin~ a nuclear Itiarrracy, whose activities are outside the provisions of section 510(g) (1) of the act will be subje~ to the registrati_on provisions of the act and to those

- requirements that are conccmjtant to registration*.

To operate under applicable local laws regulating the practice of i:;harrracy and medicine rray mean that a nuclear fharrracy must be operated under the supervision of a piarrracist, registered i.n the State to practjce fharrracJ, In States with such re:;iuirernents, nuclear medical laboratories operated by chemists or physicists who are not also regjstered fharrracists wHl not qualify for the exemption from registration under section 510(g)(l) of the act regardless of the actjvity in which the facjlity engages.

15

Certain activities of nuclear r,haJ;macies are clearly within the pharrrac.1 exemption of section 510(g)(l) of the act.* For example, in a situation where the nuclear r,harmacJ is operating within applicable.local laws regulating the practice of pharrracy and only prep::1res and dispenses a radioactive drug upon receipt of a "valid prescription," the r,harmacy exe~ption clearly applies. FDA views the term "vali~ prescription" to mean an order that qualifies as a prescription under State law for a

.. prescription drug, from a practitioner licensed to administer the drug to a p:1tient under the care of the practitioner in the course of his or her

- professional practice. FUrther, al though the act does not define the term "prescription," sectjon 503(b) (2) of the act states that any drug djspensed by filling a prescription of a practitioner licensed by law to adninister the drug is exempt fran certain of the misbranding provisions of the act if it bears a label containing the name and address of the dj spenser, the ser j_al nurrber and date qf the prescription or its filling and, if stated in the prescription, the name of the p:1tient and directions for use and cautionary statanents, if any, contained in the prescription. Thus, except for prescriptions for controlled drugs,

- Federal law requires the name of the p:1tient to a*ppear on the label of the prescribed drug only when this inforootion is stated in the prescription by the fhysi.cian. However, without stating the precise foroot of a prescription, the act contemplates that certain inforrration will ordinarily be supplied by the licensed practitioner to the i;harrracist. FUrther, the act implies that a prescription is written with a p::1rtjcular patjent in mind. In addi.tion, many States, as part of their pharrrac.1 practjce statutes, require the P3tient 1 s full name.

16:

In the traditional practice of fharmacy, prescriptions are usually handled differentiy depending up::m whet."'ler the prescriber and patient are in an institutional setting or in a private setting. In the institutional setting, the p:itient's prescription is usually forwarded to the r:oarmacy by the nursing staff and the pres er ibed drug is then sent back to the nursing staff for storage without the in~titutionalized patient ever obtaining possession of the prescription or of the

.. pres er ibed drug. In the pr iv ate setting, the pres er iber usually hands the prescription to the patient, who takes it to their piarrnacy of choice and receives the pres er ibed drug from the Fharrnacist. In either situation, however, the prescription is normally written for a specific patient. Rarely, in the private setting, is a prescription written for more t;:han one patient. Ole example of such a situation would be when.all members of a single family are being treated for the same OJndition with the saJile drug, e.g., pinworrns. In such a situation it is considered awropriate to write and dispense one prescription for the entire family rather than write and dispense separate prescriptions for each family zrember. H~ever, in sudl a situa_tion, a member of the family normally

- obtains possession of the prescription and takes -it to a piarrnacy to be filled.

The agency *believes that, al though traditional piarrnacy practice concepts should apply to nuc1ear i;:oarmacies to the extent possible, the unique nature involved in the prep:i.ration,* handling and administration of radioactive drugs might require sane departures from the traditional p.,arrracy practjce. For example, when dealing with radioactive drugs the 17

patient, whether or not in an institution, normally does not obtain p:::,ssession of the prescription or of the prescribed drug. Usually, the t=hysician orders the drug from a nuclear piarrracy which dispenses it directly to the fhysician for administration to the patient under the t=hysician's supervision. Further, because most radioactive drugs are intended

. for diagnostic purp::ises, they must be aaministered to the patient at a facility having the specialized e:;iuipnent necessary for the diagnostic procedure to be performed ..

The agency is also aware that in nuclear i;:harrracy there are instances

- where fhysicians in private practice specializing in nuclear medicine, as well as t=hysicians specializing in nuclear medicine connected with a private clinic, will schedule several p:,tients to undergo the same di.agnostic procedure using the same injectable radioactive drug on a particular day. Rather than order .a separate container of the drug for each patient, a multiple dose container* of the radioactive drug to be administered to all the p:1tients .undergoing the sarrie procedure is ordered. In addition, the physician or clinic may have a standing order wi t.l-i the nuclear fX'}arrracy to supply a IiiLll tiple-dose container of a particular radioactive drug on a certain day of the week to be administered* to p:1tients scheduled to undergo a corrnron diagnostic procedure. The practice of having one order cover several unrelated, but

• scheduled patients and supplying a m..!ltiple-dose con~ainer for sud1 patients is not normally consjdered to be the traditional p,armacy practice. However, t.,'1e agency has evaluated this practice with respect to the djspensing of 18

radi.opharrraceuticals and concludes that, while it is a dep3rture from traditional pharnacy practice, it is, given the unique circumstances of nuclear medicine, a reasonable variant of it, and thus appropriately oonsidered accepted pharrracy practice. Accordingly, FDA will not re:;i:uire a nuclear pharinacy engaging in such activities to register as a drug

~tablishrrent provided the dispensing pharrracy inaintains a hard copy of the prescription or physician's order as required by section 503(b) (2) of the act. and the pharrracy otherwise rompl ies with all aspects of traditional pharmacy practice. Although the above referenceq practices will not subject a nuclear ,r:harrracy to registration with the FDA as a drug establishment, a nuclear pharmacy should also determine that such practices are consistent with applicable state ,r:harinacy laws.

In certain situations, the fact that *the preparation of t,1e radioactive drug results in the preparation of a new drug or re:;i:uires.

more. technical equipnent and expertise .than that of a nonradioactive prescription drug does not nullify the ,r:harrracy exer.1ption. Likewise, neither the location of the p:itient nor the location or or.-mership of the nuclear pharrra.cy would nullify the r:oarrracy exemption. several different situations involving a nuclear pharrracy operating under applicable State

.r;::harrra.C".t laws and preparing and dispensing a radioactive drug upon receipt of a valid prescription are set forth in the examples given below.'

In other situations, the activities of a nuclear pharinacy will be clearly outside the pharrracy exemption. For example, :i.f a nuclear pharrracy prepares a nonradioactive kit for sale to other nuclear pharrracies which add the radionuclide for di.spensi.ng under prescription, 19

'r the activity of the first i;narmacy clearly falls outside the i;narmacy exemption. The examples below give several situations in which the i;:harmacy. exemption does not apply because there is no prescription.

• Nonetheless, in soma sit~ations, it will not be clear whether the activities of a nuclear i;:harrnacy will fall within the piarmacy ex~mpti:on. Many involve nuclear :r;:har:macies that are _located within a hospital. To determine i~ the i;nar:macy exemption applies, FDA believes it will be helpful to compare ti1e activities of a hospital nuclear i;:harmacy with the activi.ties of a traditional hospital i;:harmacy. In addition to filling and ~ispensing valid prescriptions for both inpatients and outp:itients ,. a traditio_nn~ hospital r:harmacy may also send pres er ipt;ion drugs to a ward or clinic within ti1e hospital upon the order of an authorized person. The drug, when sent to the ward or clinic, is not intended for any specific p:itient, but is intended to be used by the ward 'or clinic as needed when a licensed practitioner orders the drug in a patient's rredical record. The.term "ward or floor stock" has been applied to drugs made available in this manner. Because these drugs are under. the control of the .i;:harmacy" and the institution within which the ward or clinic is located and the drug is prescribed by a licensed practitioner for a p:irticular patient, this activity will be considered to fall within the piarmacy exenption. Under the same rationale, if a hospital nuclear i;:harmacy prep:ires a radioactive drug and dispenses it to a nuclear medicine clinic or department located within the hospital. upon an order for the drug by an authorized person, even though ti1e drug were 20

in a multiple-dose container, the µ1armacy exemption would apply. Of o:,urse, because of their short half-life, it would not be expected that radioactive drugs would.be maintained as ward or floor stock in the same rranner as other drugs.

On occasion, a trad:itional hospital p.'1armacy may, Up:)n request of another µ1armacy, send a drug product in its original_ unopened container to another pharrracy. This situation rro.y arise when the second phar:rracy

.. finds that it is out of stock of a particular drug product. Provided the fir st pharrracy did not rranufacture the drug product, it would not be

- required to register for such an activity. Likewise, a nuclear p-iarmacy can send a radioact:i ve drug product marketed under *an approved NDA in its original unopened container to another nuclear p-iarrnacy Up:)n request wit~out being subject to the registration. provision of the act.

The agency is aware that sC111e ~uclear µ1arrnacies have been instr,1.lm2ntal in the development of new radioactive drugs or new uses for existing radioactive drugs. Nuclear p:1arrnaci.es may also prepare new radioactive drugs that are not commercially available, but whose use and preparation- have been described in the medical literature. Physicians

- that write a prescription for a drug ci1at must be*comp:)unded by a

µ1armac:i.st bear the professional responsibility to base its use on sound scientific rationale or rred:i cal evidence. The agency believes that as long as the µ1armacist does not engage in activities that fall outside the normal pract:i ce of pharrraC'.f, such use of a drug in the practice of medicine does not require 21

an Investigational New Drug Applicati~n (IND) or NDA. However, if a pharmacist does engage in activities that fall outside -the normal practice of J;X1armacy, the J;X1armacy would legally have to be registered notwit:1standing that it rray be filling physician-'s orders. Therefore, depending upon hc:M such a drug is prepared, promoted, and distributed, its preparation may fall outside the normal pracUce. of pharmacy and not qualify for the i;:oarmacy exE!llption. In suc:::h cases, even if the drug were

.. dispensed on pres er iption*, the nuclear pharmacy would have to comply wit.'1-}

the new drug provisio~ of the act even though it may not be re::;iuired to register under section 510 of the act (though it may be required to do both). Because the particular circumstances surrounding the operation of the nuclear.pharmacy "WOUld have to be examined in detail to determine whether the r:harmacy is operating within the practice of fharmacy, such situations will have to be decided on a case-by-case basis. An example where a nuclear piarmacy would have to canply with the new drug provisions is where the nuclear pharrracy has developed a rechargeable generator, such as a generator u~ed in preparing Technetium Tc 99m by being charg_ed with Molybdenum M::> 99. Each recharging of the generator is

- consjdered the manufacturing of a new drug by the agency. An NDA would be required to cover all phases in the developnent and use of this type of generator-, fran its construction to the finished product, including how many times it could be r*echarged.

It is obvious from thts discussion that certain types of nuclear pharrrad.1 activities may be conducted under* the pharmacy exemption while others conducted by the same nuclear p-iarmacy may not. The nuclear 22

fharmacy must register with FDA for activities that are not within the pharmacy exemption, irrespective of how srrall a p:>rtion they are of the fharmacy 's total activities. Under this policy some nuclear fharmacies not now registered will be required to register. Nonetheless, this guideline does not impose new re:i:uir enents on these establishments.

Ra~er, it applies existing requirements to facilitiE:s whose functions have for the first time been examined and quantified. Pharmacies, including nuclear pharmacies, are considered as drug establishments and .

are subject to the provisions of the Federal Food, Drug, and ~osmetic Act to the extent they are not specifically exempt, including the provisions of sections 501, 502, 503 and the applicable part of the factory jnspection provision in section 704. Establishments that are required to register are also subject to the current g(X)d manufacturing practice requirements of section 501 of the act and FDA's regulations W1der 21. CFR Parts 210 and 211, and the factory inspection provisions of section 704 of the act. In addjtion, an establishment manufacturing a "new drug", or a fharrnacy that has itself developed a new drug, will also be subject to the p~ovisions of section.505 of the act and applicable FDA regulations W1der 21 CTR Parts 310, 312, and 314. NUclear fharmaci.es may obtain

-information and appropriate forms for registering as a drug establishment from FDA Regional or District Offices or by writing directly to the Center for Drugs and Biologics, Drug Listing Branch (HFN-315), f(X)d and Drug Aclminjstration, 5600 Fishers Lane, Rockville, MD 20857.

23

The examples that follow cover most activities of nuclear pharrracies. Cbviously, they cannot represent all :i;:x:,ssible situations .

. . In addition, it must be remerrbered that in many situations the particular circumstances surrounding the operation of a nuclear i;:harrracy rray have to be examined in detail to determine whether the p-iarrracy is operating within the practice of pharrracy, and such situations will have to be decjded on a case-by-case _basis. Anyone rray seek an opinion whether a particular activity qualifies for the I_X'larrracy exemption by wr iti.ng to

-* the person responsible for maintaining the guideline named ab~ve.

Therefore, the agency_ rrakes available the following examples reflecting the agency's policy for exami~ing functions of a nuclear p,'1arrracy to determine if they are required to register.

EXN1PLFS OF WHEN A NUCLEAR PHARMACY MUST REGISTER AS A DRUG ESTABLISHMENT source of drug Activities of the nuclear Reg is tr a tion phar:rracy required A. Radioactive drug 1. Dispenses the drug 1. No is supplied.by a under a pres er iption in manufacturer. the manufacturer's *

(Product is subject , original container.

of an approved NDA or IND)

2. After storing the drug, 2. No ships the drug in the mam.ifacturer 's original

• container to another nuclear p-iarmacy or to a i;:hysician with or without having received a prescription.

24

3. F.ills the .:drug into single 3. No or rultiple-dose containers in anticip:1tion of a future

. need and its subsequent dispensing under a prescription.

4. Dispenses a drug that 4. No was diluted or filled into single or multiple dose containers up:in receipt of a prescription.

5. Dilutes or fills the 5. No drug into single- or multiple-dose containers and dispenses the drug without a prescription but up::m receipt of an appropr i.ate order, for use within the same institution.

G. Upon an order from a 6. No physician, dilutes or fill°s the drug i.nto multiple-dose

• containers and shi.ps the drug tb the i:;hysician as part of accepted r::harmacy practice.

7. Dilutes or fills the 7. Yes drug into single- or multiple~dose containers and ships it without a prescription to another nuclear i:;harnacy or insti-

, t'ution that, irrespective of its location or ownership, is* recog-nized as a separate entity by FDA.

B. Radioactive* drug 1. Upon receipt of a 1. No (not involving use of prescription, prepares a nonradioactive kit) a radioactive drug prepared by the and dispenses it.

nuclear i:;harnacy.

25

2. Prepares* a radioactive 2. No drug in antici"p:1tion of a future need and its subse-quent dispensing under a

• prescription.

3. Prep:1res a radioactive 3. No drug and dispenses it with-out a prescription, but u:p:in receipt of an appropriate order for use within the same institution.

4. Operates an accelerator 4. No or nuclear reactor to produce radionuclides and radiochernicals to rranufacture radioactive drugs to be dispensed under a pres er iption.

5. Upon a request from a 5. !b physician, prep:1res a drug in multiple-dose containers and ships the drug to the p.,ysician as p:1rt of accepted 1:harmacy practice:

6. Prep:1re-s a radioactive 6. Yes drug and ships it without a prescription to anOther pharrracy or institution th~t,

• irrespective of its location or o\omership, is recognized as a separate entity by FDA.

7. Prep:1res radiochemicals 7. Yes

• and ships them to other nuclear fharmacies or instjtutions as drug canponents.

C. A reagent kit 1. Radiolabels the reagent 1. No and generator are kit according to*the manu~

supplied by a facturer's directions and manufacturer. dispenses the drug under a (The kit and prescription.

generator are subject to an

• approved !IDA or IND).

26 ..

2. RadiolabeJs a reagent 3. No kit in anticiP3tion of a future need and its

. subsequent dispensing under a prescription.

3. Upon req:uest from a 3. No i;:hysician, radiolabels a reagent kit and ships the drug to the physician as part of accepted piarmacy practice.

4. Radiolabels a reagent 4. Yes k_it and shiJ?S it without a prescription to another fharrracy or institution that, irrespective of its location

-* D. A reagent kit is prepared by the nuclear Fharrracy.

or ownership, is recognized as a separate enti~y by FDA.

1. Upon receipt of a prescription, prepares and radiolabels the reagent kit and dispenses it.

1. No

• 2. PreP3res a reagent kit 2. No in antici~tion of a future need. Upon receipt of a prescription, radiolabels and dispenses it.

3. Upon a req:uest from a 3. No physician, prepares reagent kits and ships them (either before or after radiolabeling) to the

. fhysician as part of accepted fharrracy practice. *

4. Prep:ires a reagent kit 4. Yes an.a shir::s it without a prescription,. either before or after radiolabeling, to another pharmacy or insti-tution that, irrespective*of its location or ownership, is recognized as u separate entity by FDA.

27

E. Radioactive drug l. uses the .. radioactiVe 1. Yes or reagent kit drug or reagent kit to obtained fran perform one or more steps another nuclear i.n the rranufacture of a J,ilarmacy, insti- radioactive drug as a service tution, or for the nuclear pharmacy or pr act it ion er . institution that supplied the radioactive drug or kit, i.e.,

custom manufacturing.

Attad1ment: surnrrary of Comments on Prop::,sed Guideline for Nuclear Pharmacies Describing Activities that Require Registration as a Drug Establ i.shmen t and Agency. Resp::,nses.

28

Attachment

SUMMARY

OF CDMMEN'IS ON PROPOSED GUIDELINE FOR NUCLEAR PHARMACIES DESCRIBING ACTIVITIES THAT REC.UIRE REGIS'IRA.TION AS A DRUG ESTABLISHMENT AND AGENCY RESPONSES

[Dod-et No. BOD-0069, 75N-0069]

In the FEDERAL REGISTER of April 11, 1980, (45 FR 24920) the agency annolliiced the availability of a proposed guideline that would assist nuclear ,LX1arrracies in deterrnin ing if they are required to register as drug establishments under section 510 of the Federal Food, Drug, and CosW-tic Act (21 u.s.c. 360). 'IWelve comments Wre received in resp:mse to the proposed guideline. A summary of the cc:rnments and the agenc-.1's response to each are as follows:

1. Several comments cited specific fact situations and asked if registration was necessary. The specific questions were as follows:

(a) One comment asked if registration is necessary if a nuclear p,armacist purchases raw rrater ials, prepares a radioactive drug product and then dispenses t..11e drug product up:m receipt of a pr-escr iption.

(b) Ole canment asked if registration is required if a nuclear pharrracist prep:1res a radioactive drug in bulk at one location, transfers the bulk drug to a second piarrracy where the same nuclear piarrracist also works and uses the rraterial in filling a prescription.

(c) several cc:rnments asked if registration is required if a pharrracist prepares a prescription using a corranercial r.eagent kit, but deviates fran the instructions accanpanying the reagent kit, sudl as by adding ascorbic acid.

(d) cne caraneht asked if registration is required when a technician prepares radioactive drugs under either direct or indirect supervision*of a physidan and then delivers the drug to the physician at multiple s1 ...es.

Certain activities of nuclear pharrracies are clearly within the i;:harrracy exemption of section 510(g) (l)of the Act (21 u.s.c. 360(g) (1)) *

.. Li ks,,,i.se, certain other acti.vities of nuclear i;narrracies will be clearly outside the i;:harmacy exemption. However, in many situations, the particular circurnstan~s surrounding the operation of a nuclear i;xiarrracy nay have to be examined in detail to determine whether the i;:harrracy is operating wit..1iin the practice of pharmacy and such situations will have to be decided on a case-by-case basis. Therefore, the following responses to the question posed by t.rie comnents are generalized and are not intended to resolve individual fact situations. Persons seeking gJidance on individual situations should contact Division of Drug Labeling Canpl i ance (HFN-310), Office of Canpl iance, Center for Drugs and Bi~logics, Food and Drug Administration, 5600 Fishers Lane, Rockville, MD 20857, {301)443-7281.

(a) Normally, a nuclear pharmacy that prepares a drug product from raw 11\:'.lterials arid dispenses it under a prescription is not re:;iuired to register. * (see B. 1. of the* guideline).,

(b) The fact that the same nuclear i;:harmacist is involved with the drug at two i;:harmacies is not relevant to the need to register, nor is necessarily the fact that both fharmacies have cCJ"(lffiOn ownership. The agency would have. to exarune such an arrangment as a whole. However, FDA would cons J der one relevant factor to be whether the local State Doarc:J of PharmaC'J recognized the two i;:harmacies as a single entity arid i.ssued them

- 2 -

a single license. In such a case tra~~fer \r.Ould likely not require registration. Hc,.,,,ever, if a state board considered the* pharmacies as two

• . - distinct entities, and required separate licensure, then the pharmacy that planned to ship the bulk material would likely be required to registe= as a drug establishment. Because state pharmacy boards may differ on their treatment of such arrangements, other factors would normally also be considered.

(c) 'lbe guideline did not discuss modifications that might be made to an a?f)roved reagent kit because issues apart fran registration are primarily involved. 'Ille agency reviews considerable data before aI=9rovi~g an NDA for a reag~nt kit and concludes .that if the manufacturer's instructions are follooed, a safe and effective radioac~ive drug will be produced fran the reagent kit. 'Illus, if the instructions are follooea, a physician can be assured that the produ~t presc'r i::ied ,.has the properties it purports to possess. If a pharmacist ceviates from the manufacturers instruction, apart* from as a prescriber

~ay have directed, the possibility of misbranding or adulterating the crug product must be considered. *The addition of ascorbic acid as cited here or other uses of a pharmaceutical necessity *in compounding a pres:;:i?tion*aoes not subject the pharmacy to registration, but pharnac:sts are not exempt from the misbranding and adulteration provisi~~s of the act and must rely to a large degree on their profess:onal judgment as to when and the extent to which modifications-to an a~r::*,ed new drug are appropriate.

(d) Registration would not be required if a technician prepares radioac=ive drugs un::ler the supervision of a physician solely for use by

- 3

that physician- in the course qf his or .'.her professional practice.

H~ver, registration w::>uld be required if the drugs are used by other

• .Physicians, or if the dr1J3s are sold to the multiple sites mentioned . in the a:mnent.

2. Several c:omnents asked if practices such as mcdifying a reagent kit :w::>uld make the resulting product a new drug.

If the nuclear pharmacist mcdifies a kit as directed by pr~scription, and dispenses it under the prescription, an NDA w::>uld not normally be needed. (See, however, the response to o:mnent 3 for factors to be considered). If distribu~ed without a prescription, h~ver, the NDA requirements would a:i;:ply. Whenever an~ is not required, however, the pharmacy must keep in mind the adulteration and misbranding concerns expressed in the response to 1. (c) aoove. *

3. Sane carrnents requested the:agency to give examples of specific situations ,.in which a new drug ai;plicatfon (NDA} or exemption for investigational use *of a new dr1J3 * (IND) w::>uld be required. One carrnent stated it was oot conceivable that an NDA or IND would ever be required if an order fran a physician for a radioactive drug is dispensed by a nuclear pharmacy for ;:;e physician's own use (examples B7 and D4 of the draft guideline) or in response to a prescription order of a physician.

Although the primary intent of this guideline. is to describe activities of nuclear pharmacies that require registration as drug establishments, the draft guideline did indicate that in sane situations an nm or NDA may be required. These situations w::,uld ~ unusual and for.

this reason, the parenthetical statements that an IND or NM may be required included in the draft have been anitted fran the ex~les of when a nuclear.pharmacy must ~egister as a drug establishment. SUch situations, nevertheless, could occur. As stated in the text p:::,rtion of

• . -the guideline, c-oncerning the developnent of new radioactive drugs or new uses of a radioactive drug, " * *

• depending up:::,n*how such a drug is prepared, prc:moted, and distributed, its preparation may fall outside the normal

. practice of pharmacy and not qualify for the pharmacy exemption. .

In such cases, even if the drug were dispensed on prescription, the

• nuclear pharmacy would hav~-to canply, with respect to the product? it prcx:luced, with the new drug provisions of the act, even though it may not be required to register under section 510 of the act." Such cirC'UIT'stances are c:cmnonly found when an individual physician is the sponsor of an IND for a radiopharmaceutical. Thus, application of the new drug provisions requ_ires evidence that the pharmacy is performing activities not noonally associated ~ith the normal practice~of pharmacy and is operating

. in a manner that subjec;:ts it to the new drug provisions of*section 505 of the act.

4. One corrment was uncertain of the provisions of section 704 of the act and ask~ about its application to the nuclear pharmacist.

Section. 704 of the act authorizes, among other things, the inspection of any factory, warehouse, or establishment in which food, drugs, devi~s, or o:::,smetics are manufactured, processed, packed, or held for intrcx:luction into interstate carrnerce or after such introouction into interstate comnerce. Thus, as establishments holding drugs after their intrcx:luction into interstate carrnerce, all pharmacies, including nuclear pharmacies, are subject to inspection under this provision. In addition, nuclear pharmacies that are required to register as drug establishments under section 510 of the act are subject to more extensive provisions of .*

the inspectional authority of section 704. Although subject to inspection, the agency is not required to inspect, an:! except for

_*_.reas:::mable cause normally does rot inspect pharmacies, including nuclear pharmacies, operating entirely under the pharmacy exerrg;>ticns in the ac~.

Hc,.*1ever, the agency will be required, uooer section 510 (b) of the Act (21 U.s.c. 360 (b)), to inspect pharmacies, including nuclear pharmacies*, that are registered as drug es~ablishme~ts under this section. The revcx:ation of the interim enforcement :p::,licy, published in the FEDERAL REl3ISTER

-* concurrently with the issuance of this guideline, will mean the sa~e manner as pharmacies generally cl!1d that nuclear pharmacies required to register under section 510 will be regulated like drug that nuclear pha..rmacies qualifying for. the pharmacy exemptions will be regulated in ma.-,ufacturers: The guideline has been expanded (see page 9) to clarify the agenc-t's inspectional authority*. under section 704 of* the act.

5. .

One ccrnnent recc:mnended that th~' agency develop good manufacturing practice regulations specific to nuclear pharmacies.

":r.~e agency does not believe that current gcx:d manufacturing practice (CG*1?) regulations specific ,

for nuclear pharmacies subject to regulation as drug establish~ents are necessary *at this time. The a;z,.n> regulations (21 CFR Part 211,) provide _sufficient detail for drug manufacturers generally and are reasonably._ awlicable to nucle~r pharmacies registered as drug esta!::>lishments. Although sane requiremen*ts in the regulations are rot *specific to all types of ma~ufacturing, the agency believes that nuclear pharmacies will be able to initiate additional good manufacturing practices to insure their _ products meet awropriate standards. With the revor-..ati0i1 of the interim enforcement policy aoo the issuance*of these

- 6

guidelines, it is *expected that many more nuclear :fharmacies will register and be inspected by the agency. If these inspections reveal a proble.i-n the agency will take appropriate action,: including providing further guidance through additional guidelines or prop:>sing additional regulatory re:;1uirenents. In the meantime, nuclear :fhar:macists should, on the basis of ci1eir professional training and experience as well as their

.. i~o-..,ledge of the principles of drug manufacturing, be able to- apply reasonable c:ontrol procedures to insure the integrity of tJ1eir products."

The agency notes that at tjie 1980 American Pharmaceutical Association's (APhA) Ann'Ual Meeting, the APhA House of Delegates adopted two policy statenents regarding nuclear *:fharmacy. These were:*

"The Arner i.can Pharmaceutical Association supp:>rts the c:oncept of state boards of p,armacy retaining their authority to regula~e all aspects of prof,ess ional J_:harmacy practice including nuclear pharnacy practice, 11 and

"~he American Pharmaceutical Association urges state boards of i;:harmacy to promptly adopt appropriate rules and regulations for the practice of nuclear p,armacy

. using the National

. Association of Boards of Pharmacy Hodel Regulations for ~e Li censure of NUclear Pharmacies as a nodel 11

• The FDA supports these policy statements and encourages states to take approp.r;ia.t.e action *. Implementation of these policies along wit.'1-i appropriate action by nuclear :i;:harmacy 9rganizations may obviate the need ..

for the agency to develop any additional regulations specific for radioactive drugs.

6. O"le c:omment recommended that all nuclear pharrracies be r~uired to perform stability and.ccrnpatabiljty studies on their containers.

A nuclE:ar It-iarrecy that pe:r forms *activi tie:s that cause: it to be: a

.. _drug E::stabljsh~nt is r~uirE:d to follow thE: CGHP 1e:gulations. The:se:

• • • rE:gulations include: n:quire:mE:nts for containe:rs and closure:s (21 cm*

211.94) and re:quire:r.t::nts for stability (21 CFR 211.166). Although thE:sE:

rE:quire:me:nts do not apply to nucle:ar :i;xiarrracy ope:rations that fall within t.;e:* p.,arl'i'BC'i e:xe:mption, it is still ne:CE::ssary that a nuclear pharmacy,

. .1 jke: any other !=harl'i'Bcy, observe: s.tandards for containe:rs that, assure: the:

stability of t.~e: final product.

7. One: coliUTf:nt state:d that nucle:ar pbarrracists who rrake: *the:ir CMn colc kits should be re:quiI"e:d to re:giste:r and sugge:ste:d that FDA n.quire:

n_uchar pi"larr.aciE:s to rranufacture: final products from FDA approve:d kits and p:o:libit p:,armacie:s from compounding from basic ingre:die:nts be:cause:

stability of radioactive: drugs is of utrrost imp:,r:tanCE:: *.

?~E: agE:ncy aavise:s that as part of the: practiCE:: of pi"larmacy,

. . I

!):iar::-acists have: traditionally bE:E:n considE::rE:d fre:e: to rtake: use: of .I co;;-.r.ie:-rcially availa!:ilE:: rratE:r ials to practiCE:: the:ir pr:of(::ssion of co~p:,:.:nding _and clispe:nsing pre:scription drug products. Nucle:ar

- p:,a::-r.acjsts t:;at opcrat<: within thE:: p:1arra3.cy E:X(::Iilption have:- this same:

re:e:do;:i. Ho-.,e:-*Je:r, nucle:ar !=harl'i'Bcie:s that routine:ly pre:pare: a partia1lar ty,PE: of re:age:-nt**kit and ship it without a pre:scription*are: no longe:r actjng as pharrecie:s and would be: re:quire:d to rE:giste:r. As note:d in the:

!E:Spo:13E: to co:-:lJile:nt 6, nucle:ar p.,arrradsts, as we:11 as othe:t* pharmacists, ar:E: rE:sponsjbJe: for asssuring that drug products pre:pare:d unde:r a prE:scription r.ie:e:t all standards for that product focluding prope:r stabil j ty re:quirE:lTf:nts as *disJ?E:nse:d.

8. O"le canment referred to a 1978 opinion handed down by the Atto~ney General of C~ifornia, which stated that a r:harnacist may canpound and dispense an indivjdual prescription for an individual's needs if the comp:ments have not been banned even though the product

• might be a new drug if not dispensed under a prescription. The opinion was t.'iat the i;:harrnacist is not creating a rnarket for- a new drug but rather acting on the decision of _a physician who has exercised jndependent judgement as to the safety and effectiveness of a p:1rticular' drug in the treatment .of a p:itient. The ccrnment stated that. the proposed

- guideline indicated tha~ in certain circumstances a nuclear ,EX1armacy may be re;iuired to sponsor an IND for a product even though it is.dispensed

• under a prescription. The comment indicated that there may be a ronflict between the Attorney ~neral 's opinion and the guideline and requested clarification.

• The agency does not believe there 'is any conflict between the Californla opinion ahd the guideline. The agency* recognizes that medical practl ce dictates that .i;:hysiciahs remain free to use drugs accordi.ng to their best knowledge and judgement. This may include the request for a drug product to be prep:ired under a prescription that would be a new drug if prepared* by a drug establishment without a prescription. Physicians that write a prescription for a drug that must be cornp::mnded by a

i;:harrnacist bear the professional responsiblli.ty _to base its use on sound scientific rationale or rredical evidence. The agency agrees "that as long as the :i;:harmaci.st does not engage in activities that fall outside the nonral practi.ce of pharrnacy, such use of a drug in the practice of medicine does not re;iuire an IND or_

NDA. However, if*a p,armacist does engage in activities outside the normal practice of pharmacy, the fharmacy would legally have to be registered notwj thstanding that it may be fillil)g physician *s orders.

The gu1del ine has been m::>dified in order to clarify this point (see i;age 21).

~

9. Q'le comment stated that the example in the last sentence on

.. p:ige 20 of the draft gui9eline stated ~at a _multi-dose vial *filled by a nuclear ~'iarmacist to be administered to severa;t unknown patients may no't be recognized as a prescription, but also stated on page 29 that a physician's order for a .bulk drug for use in the ~ysician *s C1ilrl practice is not cause for registration. The canrnent stated that this appeared to be a conflict.

The agency has reevaluated these two examples and has concluded that the need for registration under circumstances involving supplying m.lltiple dose containers of a radioactive drug intended for administration to several p:itients needs clarification. Because of their short half-life, most radioactive drugs rrust be administered very

- pranptly. Thus, the example of having a Fhysici~ order a pharmacist to prep:ire a radioactive drug in bulk for the Fhysician to store i.n the office as noffice stockn_for use in the physician's practice on ai:proprjate p:itients as they are seen by the Fh~siclan was not a realjstic example. Therefore, it has been deleted from the guideline.

The agenC'.f agrees, hOn'ever, that such an activity, when

- 10

performed by a nuclear or traditional i;:harmacy, should* require registration. The guideline has also been m::,dified (see pages 16-19) to clarify that since prescriptions represent a professional relationship between the prescriber, pharmacist and patient, an order written for a multi-dose vial intended for administration to several patients is_

o:msidered to be a prescription, if the dispensing pharnacy or pharnacist

• • maintains a hard copy of*the prescription or physician's order as required by section 503(b) (2) of the act and the pharnacy otherwise complies with- all aspects of traditional or accepted pharmacy practice *

.l\lthough such a practice will not by itself subject a nuclear pharnacy to registration with the FDA as a drug establishment, a nuclear pharnacy should also determine that such practices are consistent with applicable state laws.

10. cne comrrent stated that FDA's belief that a firm should register is not in itself justification to require registration.

FDA's conclusion regarding the registration of certain types of nuclear piarrnacies result from a.reasoned applicati~n of section 510 of 4t the act to the services which those establishments actually provide. The purpose of the guideline is to give guidance to nuclear pharmacies as to when one should register. Some situations regarding the manufacture of radioactive drugs present complex questions. These guidelines are not requirements, but rather an assurance that a person following the guideline will be follCMing procedures acceptable to FDA. Manufacturers are encouraged under FDA guideline procedures to bring to the agency's at!:E:ntion in advancE: situations in whi'd1 a guideline: rra:r: not be:

followE:d. FDA will attE:_mpt to rE:SolvE: in advanCE: disagre:E:rents bE:twE:E:n

• • • nucle:ar plarracie:s and FDA ovE:r whether registration is required.

11. CnE: OJITtn::nt stated that radiolabE:ling of a kit, as in e:xarnple:*

c. 2, is not donE: according to the dirE:ctions of a ph::rsician. Inste:ad a physician ide:ntifie:s t.'1e: e:nd product and the: pharrracist pn::pare:s the:

prE:scription for t.1at use.-

The: agency agre:e:s t.'fiat a pre:scription_ for a radioactive: drug d~s not nor~ally contain instructions for radiolabe:ling a kit. The: intE:nt of this e:xar.1ple: was to rove:r* those: instanCE:s where: a prescription did contain sud1 inforrration and to distinguish it from example C.*1, which OJVE:rs t.1osE: situations whE:rE: the: prE:scription does not a:mtain in:orr.a :.ion for t.1e: labe:l ing of a kit and the: nucle:ar pnarrracist pre:pare:s t:1E:; p;oa~ct as sE:t forth in thE: rranufacture:r 's instructions accompanying

~1E: rE:agent kit. Ha..1E:ve:r, sincE: only rarE:ly would a prE:scription contain ir.st=uc':ions for radio labE:ling a kit, this E:xarnple: has be:E:n c-le:tE:d from

12. SE::ve:ral co~nts statE:d that thE: guidE:liJ)E: should be: intE:grate:d wit:; t.:iE: :~:..iclE:ar ~e:-gulatory CoiillTlission (NRC) to limit rE:gulatory concerns to :2c and drug-*r.anufactur-ing concerns to FDA .

• ?;s prE:Viously state:d, the: purpose: of the: guidE:linE: is to give:

8L:ic~ce:- to nuclE:ar p:1aroocie:s so that ~e:y can d:::te::rmine: if the:y should re:giste:~ as drug e:stablishme::nts undE:r section 510 of the Fe:de:ral Food, Drug, and Cos1T1::tic Ac!:.. ThE: dE:te:rmination of whe:the::r or not a nucle:ar p,arr.acy should reg.iste::r is entire:ly *within FDA 's jurisdiction; the:re: is no ove:r lap wit.1 NRC' s_ are:a of jurisdiction. ThHe:fore:, the: age:ncy doe:s -

• *not se:e: any ne:e:d to intE:grate: NRC's are:a of juris_diction over nucle:ar p,arrreciE:s into the: guide:line:. The: agency has, hcwe:ve:r, supplie:d a copy of the: draft guide:line: to the: NRC for rE:vie:w and cornrne:nt and will rontinue: to work with NRC to avoid are:as of duplicati~n and

__inconsiste:ncie:s be:twe:e:n the: two agE:ncy's policie:s.

13. One: COITm::nt rE:co~nd2d that the: guidE:1 inE: includ2 nalTf::s of age:ncy pe:r sonne:1 to be: contacte:d whe:n nucl e:ar r;harrrecists have: a que:stion o::>nce:rning thE:ir OpE::rations.

AgE:ncy re:gulations on guide:line:s (21 CFR 10.90) re:quire: a guideline:

to contain the: name: of t1e: pe:rson re:sponsible: for rreintaining the:

gJ.icie:l ine:. This pe:r son is nalTf::d as the: "con tact pe:r son." in the: notice of availability ana this per son should *be: contacte:a if quE:stions arise: as a re:sult of thE: guide:line:. If a contact pe:rson cannot answe:r a que:stion he:

o: she: will re:fe:r ~1e: irquire:r to FDA E::!Tlploye:e:s knowle:dge:a.Dle: in t1e:

14. One: c-orrm::nt state:d that a require:ITf::nt th~t the: P3tie:nt 1 s nam2 appe:a: on a p_re:scription is in cons iste:nt with conte:mpor ary nucle:ar p.1arr.acy practicE: be:causE: :fXlYSicians oftE:n re:assign prE:scriptions to ot..1E:r patie:nts and is also inconsiste:nt with the: *guide:line: e:xample:s that p.,ysidans r.ay or&:r drug produ~s for the:ir a-.m USE:. One: rommE:nt statE:d t....,at a pre:scription is &.:fine:d as an orde:r for a particular patie:nt which would require: the: P3tie:nts nal'Tl2 to ap:pE:ar on the: prescription.

.., The agency advises that the act (section 503(b)(2)- (21 u.s.c .

353 (b) ( 2)) requires the label of a drug dispensed by pres er iption to contain the name of a p:i.tient when stated in the_* prescription. Even though the act does not require the p:itient's nal'1"e, it does imply that a prescription is written with a particular p:itient in mind. (See the resp:::inse to question 9). Further, rrany states require the p:1.tients full name and address on all prescriptions and even when not required by state law, the comrron accepted practice is for physicians to include the nal'1"e of the p:i.tient on a prescription. The agency recognizes, however, that there are certain differ*ences between traditional pharnacy and nuclear I_:harmacy. Thus, under the guideline a nuclear pharmacy may prepare a radioactive drug intended for administration to several p:i.tients in a multi-dose vial and dispense it provided the dispensing fharmacy engaging in such activities rraintains a hard copy of the prescription or p,.1ysician's order as required by section 503(b)(2} of the Federal Food, Drug, and Cosl'1"etic Act and the µ-iarrracy otherwise complies with all aspects of_accepted or tradition~l I_:harmacy practice. The guideline

- oontains a rrore complete discussion of this issu~ (pages 16-19).

15. Coe comment objected to the use of the term "diluting" in the guideline. .The roJT1ITent said this gave the impression that µ-iarrnacists only "dilute" and dispense when in fact when they dilute a product, they must be concerned with factors such as adjusting buffers, bacteriostatic agents and stabilizers. The word "preparing" was suggested as a subs ti tu te.

\i The agency believes that the use of the term "preparing" in place of "diluting" rray be inappropriate because it C'Oula imply that the nuclear p1arrrac'ist prepared the radioactive drug rather _than just performed some activities on a product prepared by a drug rranufacturer. Hwever, because "diluting" rray also not be appropriate, it has been decided for pjrposes of this guideline to define the term as including not only simple dilution, but also adjustment of such things as buffers, bacteriostatic agents and stabilizers.

l .,

APPENDIX. VI.

21*.cFR 361.1; Metabolic research regulations.

~ Ch. I (4-1-88 Edition) food and Drug Administration, HHS § 361.1

ler and ls used during oU: Indication. "For visualization of (l) The pharmacological dose is

diagnostic gallbladder biliary ducts during* cholecystogra- within the limits set forth in para-stography). phy." graph (b)(2l of this section;

(!I) The radiation dose Is within the ystokinetic active ingredi- PART 361-PRESCRIPTION DRUGS limits set forth in paragraph (bl(3) of

,\ FOR HUMAN USE GENERALLY this section;

redient of the product RECOGNIZED AS SAFE AND EF- (iii) The radiation exposure is Justi-

. aqueous emulsion of fied by the quality of the study being FECTIVE AND NOT MISBRANDED:

undertaken and the' importance of the DRUGS USED IN RESEARCH information It seeks to.obtain; 1g of cholecystokinetic <lvl The study meets the other re-AUTHORITY: Secs. 505, 70l(n.i, 52 , Stat.

1052-1053, as amended, 1055 <21 U.S.C. 355, quirements set forth in paragraph (d)

'of identity. The label- J71Ca)); the Public Hen.Ith Ser\'lce Act Cst'C. of this section regarding qualifications i.ict contains the estab- 151, 58 Stat. 702. n.s n.mendl'd <42 U.S.C. of the Investigator, proper llcensure

the drug, if any, and 2tl2)). for handllng radioactive materials, se-iroduct as a "gallblad- lection and consent of research sub-gent." I 361.1 Radioactive drug-H for certain re- jects, quallty of radioactive drugs lS. The labeling of the , search uses. . used, research protocol design, report-

• mder the heading "In- Ca) Radioactive drugs (as defined in ing of adverse reactions, and approval f ollowing: "For the I 310,3(n) of this chapter) are general- by an appropriate Institutional

he gallbladder during ly recognized as safe and effective Review Committee

and iadder studies." Other when administered, under the concll- Cvl The use of the radioactive drug

nonmlsleading state- Uons set forth In paragraph <bl of this In human subjects has the approval of 8}Y the indications aection, to human research subjects the Radioactive Drug Research Com-

'.aaJen established and during the course of a research project ml ttee.

ragraph (b), may also Intended to obtain basic Information <2> Limit on phannacological dose.

\vided in § 330.1Cc)(2), regarding the metabolism (including The amount of active ingredient or rovlsions of section 502 kinetics, distribution. and localization) combination of active ingredients to be ng to misbranding and of a radioactively labeled drug or re- administered shall be known not to in section 30l(d) of the rarding human physiology, pathophy- cause any clinically detectable phar-

'introduction or dellv- lJology, or biochemistry, but not In- macological effect in human beings. If iction into interstate the same active ingredients <exclusive a.pproved new drugs in tended for immediate therapeutic, di- of the radionuclide) are to be adminis-

on 505(a) of the act. agnostic, or slinllar purposes or to de- tered simultaneously, e.g., under. a tReservedl termine the safety and effectiveness or "Notice of Claimed Investlgatlonal Ex-l The labeling of the Ute drug in humans for such purposes emption !or a New Drug" or for a s the following state- <Le., to carry out a clinical trial). Cer-tain basic research studies, e.g., studies therapeutic use in accordance with la-

' heading "Directions": .bellng for a drug approved under Part

when* instructed by a . to determine whether a drug localizes 314 of this chapter, the total amount

. In a particular organ or fluid space of active ingredients including the ra-

.l before using."  :')*, and to describe the kinetics or that lo- dlonucllde shall be known not to te is ao* milliliters 20 11.'~,. callzation, may have eventual thera- exceed* the dose limitations applicable Hagnostic gallbladder * ,'. ':' peutic or diagnostic Implications, but to the separate administration of the ted by a doctor. * , * * . ':** the initial studies are considered to be active Ingredients excluding the radlo-

. "physician" may _be '-" t.sic research within the meaning of nucllde.

~word "doctor" in* this section. ' (3) Limit on radiation dose. The

• .-tatements in tpis

• Cb) The conditions under which use amount or radioactive material to be ol radioactive drugs !or research arc administered shall be such that the C'OnSidered safe and effective arc: subject receives the smallest radiation

e 10, 1983, as amended at Approval by Radioactive Drug

1, 1986; 52 FR 7830, Mar.

(1) dose with which it is practical to per-k3earch Committee. A Radioactive form the study without jeopardizing

Drug Research Committee, composed the benefits to be obtained from the ional labeling. and approved by the Food and Drug study.

rovided to health pro- Administration in accordance with (i) Under no circumstances may the

'. not to the general , '*._:.-. paragraph (c) of this section, has de~ radiation dose to an : adult research

\tain the following in*  :!ir;:;,.. , knn.lned, In accordance with the subject from a single study or cumula-

~*~. f Jroducts containing a  :~21\*.:' ll&lldards set or~h In paragraph Cdl of tively from a number of studies. con-

• ous emulsion of com ,.,,::>* .. Lb1s sectiqn, that. ducted within 1 year be generally rec-

~~

~~-:' '

201

J_

I I 1,

§ 361.1 21 CFR Ch. I ( 4-1-88 Edition) hod and Drug ./>.* :

ognlzed as 'safe If

• such dose exceeds pertinent to the field of nuclear medi- ace. and, for c:s:*

the following: cine (e.g., radiology, internal medicine, during the preced; clinical pathology, hematology, endo- of information pt Whole body, active blood-forming crinology, radiation therapy, radiation lowing format:

organs, lens of the eye, and gonads: physics, radiation biophysics, health REPORT ON RES£Al<C Rems physics, and radiopharmacy). Member- D ship shall be sufficiently diverse to permit expert review of the technical I. Title of the resc:i Single dose.......*.*..*.......*......*.......:.*...*.................... 3 Annual end total dose commitment. ......*............. 5 and scientific aspects of proposals sub- 2. Brief description Other organs: mitted to the committee. The addition n&earch project.

Single dose .*................*.*..............*.....*.*.........*....*... 5 of consultants in other pertinent medi- 3, Name of the lnve Annual and total dose commitment ..................... 15 4. Pharmacologlc!ll cal disciplines is encouraged. A Radio-active Drug Research Committee shall L Active Jngredlcnt (ii) For a research subject under 18 be either associated with a medical in- b. Maximum am<

years of. age at his last birthday, the stitution operated for care of patients aabject. .

and with sufficient scientific expertise 6. Name _of-- the .r, radiation dose shall not exceed 10 per- duding.any presenl, cent of that set forth in paragraph to allow for selection of committee nants or.impur,ltles.

Cb)C3)(1) of this section. members from its faculty, or with a 6. Radiation* abso (iii) All radioactive material included committee established by a State au- maximum. dose com in the drug either as essential material thority to provide advice on radiation body and each _org or as a significant contaminant or im- health matters. Joint committees in- 361.1Cb)C3)(1) _that. ,w purity shall be included when deter- volving more than one medical institu- aentative subject an mining the total radiation doses and tion which have been established lri erences that were

• dose commitments. Radiation doses order to achieve a high level and diver- maximum dose co from x-ray procedures that are part of sity of experience will be acceptable. shall Include the do the research study (i.e., would not The Director of the Center for Drugs the administered ra have occurred but for the study) shall and Biologics may modify any of the ray procedures asso also be included. The possibility of fol- foregoing requirements In a particular the study elicits da lowup studies shall be considered for situation where alternative factors cretlon of. the radio inclusion in "the dose calculations. provide substantially the same compo- the.estimation of d (iv) Numerical definitions of dose sition and association. the mean value an (2) Function. Each Radioactive Drug each subject provid shall be based on an absorbed fraction ca> Age, sex, and a method of radiation absorbed dose cal- Research Committee shall select a Cb> Total actlvity-culation, such as the system set forth chairman, who shall sign all applica- mlnlstered:for each.

by the Medical Internal Radiation tions, minutes, and reports of the com-

• the study. Report.

Dose* Committee of the Society of Nu- mittee. Each committee shall meet at used In conJunctlo~

clear Medicine, or the system set forth least once each quarter in which re- (C) If the subject by, the International Commission on search activity has been authorized or radioactive drug *res Radiological Protection. conducted. A quorum consisting of name of the radloa Cc> A Radioactive Drug Research more than 50 percent of the member- other studies, the Qommittee, in order to comply with ship must be present with appropriate and the total actlv paragraph Cb)Cl) of this section, shall representation of the required fields administered. If an be composed, shall function, and shall of specialization. Minutes shallibe kept used, identify the obtain and maintain approval of the and shall include the numerical results include an estlma Food and Drug Administration in con- of votes on protocols involving use in atlon doses. *'

formity with the following: human subjects. No member shall vote Cd) If more than>

Cl) Membership. A Radioactive Drug on a protocol in which he is an investi- radioactive drug pe Research Committee shall consist of gator. diation dose and (3) Reports. Each Radioactive Drug pressed as whol_e. b_

at least five individuals. Each commit- organs,. lens of th tee shall include the following three Research Committee shall submit an organ doses from t .

individuals: m A physician recognized annual report on or before January 31 elides. ,, , . ,.

as a specialist in nuclear medicine, (ii) of each year to the Food and Drug Ad- 7. A claim of conf a person qualified by training and ex- ministration, Center for Drugs and perience to formulate radioactive Biologics, HFN-150, 5600 Fishers NoTE: Contents o drugs, and Clii) a person with special Lane, Rockville, MD 20857. The for public dlsclosur competence in radiation safety and ra- annual report shall include the riames requested by the

• diation dosimetry. The remainder of and qualifications of the members of, quately shown bY.:*.

report constitutes,;

the committee shall consist of individ- and of any consultants used by, the uals qualified in various disciplines Radioactive Drug Research Commit-202

I

.J Edition) food and Drug Admlnllf,ratlon, HHS § 361.1

a.r medl- tee, and, for each study conducted dcntfal commercial Information as defined i ,* *nedlclne, during the preceding year, a summary In 21 CFR 20.61.

'Y,. endo- of lnformat'lon presented In the fol-rndlatlon lowtng format: Investigator

,. health

• -1:ember- Rl:l>ORT ON RESEARCH Us,: or RADIOACTIVE

.verse to Dauo

• Chairman, Radioactive Drug echnlcal l, Title of the research project. Research Committee sals sub- 2; Brief description of the purpose of the addition mearch project. At any time a proposal Is approved ntmedl- a. Name of the Investigator responsible. which Involves exposure either of

'\ Radlo- C. Pharmacological dose: more than 30 research subjects, or of

.ee shall L Active Ingredients. any research subject under 18 years of dical In- b. Maximum amount admlnlster!'d per age, the committee shall immediately patients .ubJect. submit to the Food and Drug Adminis-

-' * *::xpertlse 5. Name of the radlonuclidcCsJ used, In- tration a special summary of Informa-rnmmlttee duding any present, a.~ siKnificant contnml- tion In the format shown In this para-

'.:'. c1r with a nants or impurities. graph. Contents of these reports are State au- 6. Radiation nb11orbed dose. Pro\*lclr 1hr avnllnblc for public disclosure, unless

,.* radiation mAXlmum dose commltcmrnt to tile wholr confidentiality Is reQuested by the In-llody and each orKan spcclflNI In 21 CFR vestigator and It Is adeQuately shown c :: . :1 i Ltees In- Ul.l(b)(3)(1) thnt was received by a rcprc*

,-::1 lnstltu- by the Investigator that the report 1Pntatlve subject 1md the calculations or rr.f* constitutes a trade secret or confiden-

. :ished In trences that were used to estimate thcsf'

,- :id diver- lll&Xlmum dose commitments. The report tial commercial Information as defined

. eptable. lhall Include the dose contribution of both In § 20.61 of this chapter.

Jr Drugs Ule administered radlonuclldc(sJ and any X- (4) Approval. Each Radioactive Drug v of the ,ay procedures associated with the study. If Research Committee shall be specifi-

• .rtlcular Use study elicits data on the uptake or ex- cally approved by the Center for factors cretion of the radioactive drug pertinent to Drugs and Biologics of the Food and

, compo- Ille estimation of dose commitment, report Drug Administration. Applications Ille mean value and range of values. For shall be submitted to the Food and ve Drug ach subject provide:

• Drug Administration, Center for elect a Ca) Age, sex, and approximate weight. Drugs and Biologics, HFN-150, 5600 n.ppllca- * (bl Total activity of elj.Ch radionuclide ad* Fishers Lane, Rockville, MD, 20857,

• 1e com- a!nl.stered for each radioactive drug used In and shall contain the names and quali-11\e study. Report each X-ray procedure fications of the members of the com-meet at ~ In conjunction with the study.

,:l1ich re- mittee, and a statement that the com-

!cl It the subject has partlcipafrd In other mittee agrees to comply with the re-1 ,, : ~liorized or PM!foactlve drug research studies, report tlw c"rnsisting of 11&me of the radioactive drug used In tlws1* quirements set forth In this section.

if I.lie member- ocher studies, the dill!' of admfnlstrnllon. Approval shall be based upon an as-li.ii ,t;Jpropriate Ind the total activity of each radlon11clld1* sessment of the qualifications of the rr:q,:ired fields edmlnlstered. If nny *x-ray procr.durrs wcr1* members of 'the committee, and the as-

,:; .,: i: ;,11 be kept -a, Identify the X-rny proc1:dureCs> nnd i;4rance that all necessary fields of ex-

• " :* ica.I results ecJude an estimate of the absorbed rndl- pertise are covered. Approval of a com-lUon doses. mittee may be withdrawn at any time

- .. ,1g use in for failure of the committee to comply

-., .all vote Cd) If more than one administration or n

-, investl- .-dioactlve drug per subject, cumulative ra- with any of the requirements of this

,-Uon dose and dose commitment, ex- section. Approval of a committee shall e Drug .,.,_ed as whole body, active blood-forming remain effective unless and until the

• rnit an -.ans, lens of the eye, gonads, and other FDA withdraws suph ' approval.

lrS&l1 doses from the administered radionu- Changes In membership and appllca-iary 31

• ugAd- cDdes. I tlons for new members shall be sub-T. A claim of confidentiality, ff any. mitted to the Food and Drug Adminis-

• s* and

,~ishers .N'on:: Contents of this report are available tration as soon as, or before, vacancies The

• public disclosure unless confidentiality Is occur on the committee.*

riames 19tauested by the Investigator and It Is ade- (5) Monitoring. The Food and Drug

)CfS Of, ... lely shown by the Investigator that the Administration. shall conduct periodic*

flP)rt constitutes a trade secret or conff- reviews of approved committees. Moni-

--,.:, :Jy, the

'l.;*cl1 Commit- toring of the 'activities of the commit-'

203

'1 I

I ,

i I I,

§ 361.1 21 CFR Ch. I ( 4-1-88 Edition) hod and Drug Admlnl tee shall be conducted through review sion or Agreement State to possess permitted unless the R of its annual report, through review of and use the specific radionuclides for Research Committee c minutes and full protocols for certain research use or be a listed investigator Judgment, that sclent studies, and through on-site inspec- under a broad license, or in the case of and benefit is likely

. tlons.

• non-reactor-produced Isotopes, be li- Ulat study. Therefore:

(d) In making the determination re- censed by other appropriate State or lhall be based: uporf a l quired in paragraph (b)(l) of this sec- local authorities, when required by derived from il.ppropri tfon, a Radioactive Drug Research State or local law, to possess and use 1n or published literat Committee shall consider the follow- the specific radionuclldes for research of sound design such t ing requirements and assure that each .use. or scientific value may is met: (5) Human research subjects. Each dlatlon dose shall be (1) Radiation dose to subjects. To investigator shall select appropriate and no greater tha assure that the radiation dose to re- human subjects and shall obtain the obtain valid measure search subjects is as low as practicable review and approval of an -institutional jected number of subje to perform the study and meet the cri- *review committee that conforms to the nclent but no* greate_r teria of § 361.l(b)(3), the Radioactive requirements of Part 56 of this chap- for the purp*ose _of **

Drug Research Committee shall re- ter, and shall obtain the consent of number of subjects* s quire that: the subjects or their legal representa- the fact that* the stud (i) The investigator provide absorbed tives In accordance with Part 50 of this obtain basic research dose calculations based on biologic dis- chapter. The research subjects shall rerred to in paragrap tribution data availaple from pub- be at least 18 years of age and legally lion and not intende lished literature or from other valid competent. Exceptions are permitted therapeutic, dlagnostl studies.

• only In those special situations when it poses or to determi~e (ii) The investigator provide for an can be demonstrated to the committee effectiveness of the* d acceptable method of radioassay of that the study presents a unique op- ror such purposes Cl.e; the radioactive drug prior to its use to portunity to gain information not cur- clinical trial).

assure that the dose calculations actu- rently available, requires the use of re- (8) Adverse reac_tiom ally reflect the administered dose. search subjects less than 18 years of tor shall immediatel:i; (iii) The radioactive drug chosen for age, and Is without significant risk to Radioactive Drug Re:

the study has that combination of the subject. Studies involving minors tee all adverse effects half-life, types of radiations, radiation shall be supported with review by the use of the radioa energy, metabolism, chemical proper- qualified pediatric consultants to the research study. All a ties, etc., which results in the lowest Radioactive Drug Research Commit- probably attributable dose to the whole body or specific tee. Each female research subject of radioactive drug in th organs with which it is possible to childbearing potential shall state In shall be immediately obtain the necessary information. writing that she is not pregnant, or, on Radioactive Drug R (iv) The investigator utilize adequate the basis of a pregnancy test be. con- tee to tl;le Food and.

and appropriate instrumentation for firmed as not pregnant, before she tton, Center for _Dru the detection and measurement of the may participate In any study. HFN-150, 5600 Fish specific radionuclide. C6) Quality of radioactive drug. The ville, MD 20857 *. .

C2) Phannacolos,ical dosage. To de- radioactive *drug used in the research (9)

• Approval by termine that the amount of active in- study shall meet appropriate chemical, review board. The i gredients to be administered does not pharmaceutical, radiochemical, and ra- obtain the review anc exceed the limitations set forth in dlonuclidic standards of identity, institutional* re.view paragraph (b)(2) of this section, the strength, quality, and purity as needed forms to the requirer committee shall require that the inves- for safety and be of such uniform and* of this chapter. ..

tigator provide pharmacological dose reproducible quality as to give signifi- <e> The results of calculations based on data available cance to the research study conducted. ducted pursuant to t from published literature or from The Radioactive Drug Research Com- of the evaluation of other valid human studies. mittee shall determine that radioac~ to § 312.1 of this ~h (3) Qualifications of investigators. tlve materials for parenteral use are eluded

• in the sub Each investigator shall be qualified by prepared In sterile and pyrogen-free under § 312.1 of this training and experience to conduct the form. (f) A: radioactive proposed research studies. (7) Research protocoL No matter packaged, distribute (4) License *to handle: radioactive how small the amount of radioactivity, intended

• for use in*

materials. The responsible investiga- no study Involving administration of a the 'requirements of

. tor or institutions shall, in the case of radioactive drug, as defined in be exempt *from se, reactor-produced isotopes, be licensed § 310.3(n) of this chapter, to research the act and § § 201.5 B

.by the Nuclear ;Regulatory Commis- subjects under this section, shall_ be :chapter if -the 1;>acka@

204

' ..J.

i '

'I, I

I.

'I I

..,I\!.

h, I ( 4-1-88 .E~ltlon). '"d and Dri,,g Admlnl1tratlon, HHS § 361.1 nt State to possess permitted unless the Radioactive Drug bellng are in compliance with Federal, ific radionuclides for Research Committee concludes, in its State, and local law regarding radioac-

! a listed investigator Judgment, that scientific knowledge tive materials and If the label of the

nse, or in the case of and benefit is likely to result from immediate container and shielded con-teed isotopes, be li* I.hat study. Therefore, the protocol tainer, If any, either separate from or appropriate State or lhall be based upon a sound rationale as part of any label and labeling re-when required by derived from appropriate animal stud- quired for radioactive materials by the

'I, to possess and use ies or published literature and shall be Nuclear Regulatory Commission or by nuclldes for research of sound design such that information State or local radiological health au-of scientific value may result. The ra- thorities bear the following:

earch subjects. Each diation* dose shall be both sufficient CU The statement "Caution: Federal l select appropriate and no. greater than necessary to law prohibits dispensing without pre-md shall obtain the obtain valid measurement. The pro- scription";

,al of an institutional jected number of subjects shall be suf- (2) The statement "To be adminis-that conforms to the l'ldent but no greater than necessary tered In compliance with the require-

>art 56 of this chap- lor the purpose of the study. The ments of Federal regulations regard-1tain the consent of lltllllber of subjects shall also reflect Ing radioactive drugs for research use 1elr legal representa- lhe fact that the study is intended to (21 CFR 361.ll";

e with Part 50 of this obtain basic research information re- (3) The established name of the

eil.rch* subjects shall ferred to In paragraph Ca) of this sec- drug, If any;

,.rs of age and legally . ***.\.:'.,'. tlon and not Intended for Immediate (4) The established name and quan-ns are permitted therapeutic, diagnostic or similar pur- tity of each active Ingredient; ituatlons when.it to the committee resents a unique op-information not cur-

• equlres the use of re-t.*,1.*.1.1.,:_f e~~w..~r~~~'ff~;

dJnlcal trial).

1* (8)

Adverse reactions. The investlga-(5) The name and half-life of the ra-dionuclide, total quantity of radioac-tivity In the drug product's immediate container, and amount of radioactivity per unit volume or unit mass at a des-ess, .than 18 years of lor shall immediately report to the ignated referenced time; ut significant risk to Radioactive Drug Research Commit- (6) The route of administration, if It lies involving minora tee all adverse effects associated with is for the other than oral use; ted with review by lhe use of the radioactive drug in the (7) The net quantity of contents; c consultants to the raearch study. All adverse reactions (8) An Identifying lot or control .

r Research Commit- probably attributable to the use of the number from which It Is possible to de-research subject of radioactive drug In the research study termine the complete manufacturing mtial shall state in

, not pregnant, or, on 1hall be immediately reported by the Radioactive Drug Research Commit-history of the package of the drug; (9) The name and address of the I

egnancy test be con- tee to t.lJ,e Food and Drug Administra- manufacturer, packer, or distributor;

• regnant, before she Uon, Center for Drugs and Biologics, ( 10) The expiration date, If any; 1 any study. BPN-150, 5600 Fishers Lane, Rock- c11) If the drug Is Intended for par-adioactive drug. The .We, MD 20857. enteral use, a statement as to whether used in the research * * (9) Approval by an institutional the contents are sterile:

Lppropriate chemical,* lftrlew board. The Investigator shall (12) If the drug Is for other than a.diochemical, and ra- lbtaln the review and approval of an oral use, the names of all inactive In-dards of identity, lllstltutional review board that con- gredients, except that:

purity as needed 1,Dnns to the requirements of Part 56 (I) Trace amounts of harmless sub-uch uniform and et this chapter. stances added solely for individual

. y.as to give slgnifl* * <e> The results of any research con- product Identification need not be

.rch study conducted. ~ d pursuant to this section as part named.

Drug Research Com* et the evaluation of a drug pursuant CID If the drug Is Intended for paren-

!rmlne. that radloac- IO I 312.1 of this chapter shall be In- teral use, the quantity or proportion r parenteral use are duded in the submissions required of all Inactive Ingredients, except that lie and pyrogen-free -,<<Ser § 312.1 of this chapter. ingredients* added to adjust pH or to U> A

• radioactive drug prepared, make the drug Isotonic may be de-1rotocol. No matter ,-cJtaged, distributed, and primarily clared by name and a statement of aunt of radioactivity, *~nded for use In accordance with their effect: if the vehicle is water for

~ administration of

• 11W requirements of this section shall injection, it need not be named. Pro-

, as defined In .. exempt from section 502( !)( ll of 1,ided, however, That in the case of

• ~hapter, to research \be act and§§ 201.5 and 201.100 of this containers too small or otherwise

iis section, shall bt ~pter if the packaging, label. and la- unable to accommodate a label with 205

§ 369.1 food and Drug Admlni 21 CFR Ch. I (4-1-88 Edition) sufficient space to bear all such infor- Lhe drugs named in § Subpart A-Definitions and chapter (cross-re'feren mation, the information required by Interpretations paragraph Cf) Cl) and Cl2) of this sec- of this part) are includi of this part, . the inc tion may be placed on the shielded § 369.1 Purpose of issuance. drUgS in §§ 369.20, 369 container only. way affects the requlr The warning and caution statements

[40 FR 3130.8, July 25, 1975, as amended at suggested in Subparts B and C of this pl!ance with § 310.201 40 FR 44543, Sept. 29, 19'15; 42 FR 15674, part, for inclusion in the label or label- \er, or the provisions Mar. 22, 1977; 43 FR 14646, Apr. 7, 1978; 46 ing of drugs and devices subject to sec- application pursuant FR 8955, Jan. 27, 1981; 49 FR 44460, Nov. 7, tion 502(d) and (f)(2) and other rele- of the act.

1984; 50 FR 8996, Mar. 6, 1985] vant provisions of the Federal Food, Drug, and Cosmetic Act are issued for 13 69.4 Warnings sugge PART 369-INTERPRETATIVE STATE- the purpose of assisting industry in formal or inform MENTS RE WARNINGS ON preparing proper labeling for these ar- policy.

DRUGS AND DEVICES FOR ticles for over-the-counter sale and in The warning and ca OVER-THE-COUNTER SALE meeting the legal requirements of the included in Subpart act that the label or labeling of drugs no way affect any wa Subpart A-Deflnltians and Interpretations and devices bear adequate warnings, in suggested for such d .

such manner and form :as are neces- anY statement of pollc Sec. sary for the protection of users. Only tion in Subchapter C Q 369.1 Purpose of Issuance. section 502(d) of the act requires use of the specific language included in (39 FR 11745, Mar. 29, H 36.9.2 Definitions. . . 40 FR 13496, Mar. 27, 197\

369.3 Warnings required on drugs exempt- these suggested warning and caution ed from prescription-dispensing require- statements. These suggested warning A369.5 Warnings reqii(J ments of section 503(b)Cl)(C). or caution statements are illustrative tended for over-the-ci 369.4 Warnings suggested for drugs by of those that may be necessary or de-formal or Informal. statements of policy. sirable. It is the responsibJlity of the Waming_iand. cautlo1 369.5 Warnings required on Insulin Intend- manufacturer, packer, shipper, or dis- insulin products spld ,c ed for over-the-counter sale. tributor in interstate commerce to see must comply with the 369.6 Warnings required o*n certifiable that such statements are adequate for provisions of th_e 9:c~

antibiotics exempted from prescription- compliance with the provisions of the this chapter. * **

dispensing requirements.

369.7 Warnings required by offlclal com- law. Omission of any article from this

.. pendla. suggested list does not relieve drugs ll 369.6 Warnings requl and devices subject to provisions of antibiotics exempted 369.8 Warning statements In relation to dispensing require~

conditions for use. the act from bearing adequate warn-369.9 General warnings re accidental Inges- ing or caution statements where such certain certifiable*

tion by children. statements are necessary or desirable are exempte.~. from 369.10 Conspicuousness of warning state- for the protection of the user. pensing *requll'.ement ments. 507 of the act, but a

§ 369.2 Definitions. specific labeling requ Subpart 8-Warnlng and Caution Statements <al As used in this part, the term ing warning or cauti for Drugs "act" means the Federal Food, Drug, the applicable sectio 369.20 Drugs; recommended warning and and Cosmetic Act. regUlations.

caution statements. Cb) The terms "drugs" and "devices" EFFEC'IIVE DATE Non 369.21 Drugs; warning and caution state- are defined in section 201(g) and (k) of removed at 52 FR 4732 ments required by regulations. the act. !ectlve pecern~_er 12, 19 369.22 Drugs; warning and caution state- <c> Official compendia are defined In ments specifically required by law. section 20l(j) of the act. 11 369 _7 . w~;nlngs requ AUTHORITY: Secs. 502, 503, 506, 507, 701, 52 pendla;

§ 369.3 Warnings required on drugs ex-Stat. 1050-1052 as amended, 1055-1056 as empted from prescription-dispensing AnY drug include amended, 55 Stat. 851, 59 Stat. 463 as compendia defined amended <21 U.S.C. 352, 353, 356, 357, 371>; requirements of section 503(b)(l)(C).

bear such warning 21 CFR 5.10 and 5.11. " Drugs exempted from prescription- ment as may be req SOURCE: 39 FR 11745, Mar. 29, 1974, unless dispensing requirements under section pendia, and no stateIJ otherwise noted. 503(b)(l)(Cl of the act are subject to or Subpart C of th1 the labeling requirements prescribed to alter, modify, o in § 310.20l(a) of this chapter. Al- sion of any such though, for convenience, warning and by such compendia.

caution statements for a number of 206

APPENDIX. VII.

Pack~ge insert departu~es for non-radio~ctive drugs.

J,

UNIVERSITY OF CALIFORNIA, LOS ANGELES UCLA BERKELEY ' DAVIS

• 11\VINE

• I.OS ANCEi.ES

• IIIYERSIDE

• SAN DIEGO

• SAN FllANCISCO SANTA llAIIBAIIA

• SANTA CRUZ UCLA SCHOOL OF MEDICINE HARBOR - UCLA MEDICAL CENTER DEPARTMENT OF RADIOLOGY 1000 CARSON STREET Harold P. Denton, D:i,rector TORRANCE, CALIFORNIA 90509 Office of Governmental and Public Affairs May 3, 1990 U.S. Nuclear Regulatory Commission 1].555 Rockville Pike Rockville, MD 20852

Dear Mr. Denton:

It was a pleasure to meet you at the CalRad Forum Meeting in San*Diego. After our discussion about radiopharmaceutical package inserts, it occurred to me that you were possibly unaware that hospital pharmacists commonly deviate from

-package insert reconstitution instructions for ordinary, non-radioactive drugs.

I thought it might be helpful to itemize these types of deviations so that you can compare them with the ones Dr. Hoogland of Syncor described in his letter to Dr. Temple of FDA. The types of deviations have basic similarities. They are patient-specific, scientifically supportable, described in the professional literature and/or considered the appropriate "standard of practice". The phrase "standard of practice" is very important, as it encompasses the basis upon which peer-reviewed professional behavior is judged in medicine and pharmacy. There are few prescriptive regulations in our fields. There is instead wide pro-fessional freedom tempered by total professional responsibility and account-ability. This is necessitated by the infinitely variable nature of people and their diseases, as opposed to the limited and definable variability of machines, the regulatory framework for which may therefore be encompassed by prescriptive regulation.

There are no regulations prohibi.ting deviations from package insert reconsti-tution instructions for non-radioactive drugs, and no reporting or recordkeeping requirements for such~deviations. The package insert is informational only, analogous to an instruction manual fo1/2 an item of equipment. The informational intent has been r1:;peatedly stated by :l!'DA(FR43:11211, 17 Mar 78; FDA Drug Bulletin 12(1).:4-5, Apr 1982; JAMA 253:632, 1985; J.AMJ\252:1054-1055, 1984; Med Clin_

North Am 58:1151-1159, 1974; .AFP p269, Sept., 1986.); enclosed are several of the cited references, which were also submitted as Addendum to the ACNP/SNN\Petition to change 10 CFR Part 35.

The information that follows was obtained from one of our hospital pharmacists, Dr. Nelson Der. Dr: Der received his Pharm. D. from U.C. San Francisco and his M.S. in Radiopharmacy from U.S.C. He then became a Clinical Pharmacist, and directed the Pharmacy Service at the Los Angeles County-U.S.C. Medical Center Intensive Care Unit for a number of years before coming to Harbor-UCLA.

CATEGORIES AND EXAMPLES OF PACKAGE INSERT DEVIATIONS FROM RE-CONSTITUTION INSTRUCTIONS FOR NON-RADIOACTIVE DRUGS

i.. -

1. One of the commone.st deviations is to reconstitute lyopnilized drugs so that they are more concentrated than stated in the package insert. This is necessary when patients are fluid restricted, as in cases of renal insuffi,ciency and renal failure.

2. Many diluents for reconstitution specify solutions containing sodium benzoate as a preservative. This is often,specifically omitted for neonates under the age of 1 month, because sodium benzoate may cause seizures in this patient group.

3. Reconstitution instructions specifying isotonic NaCl solution are .often ,changed to 5% glucose in water for patients in conges-tive heart fa'ilure who are sodium restricted.

4. Drugs calling for phosphate buffer are often made up substituting citrate buffer in patients in renal failure because of phosphate overload in these patients.

5. Water is often substituted for isotonic saline in order to reduce volume and maintain tonicity in fluid restricted patients.

6. There are no package insert instructions for reconstitution of most drugs for continuous infusion, as opposed to intravenous "piggyback" administration. This is decided by the hospital pharmacist.

7. Certain drugs, such as dilantin,are poorly soluble in water and there-fore are dissolved in large volumes for intravenous administration.

If the patient is fluid restricted, the non-polar drug is made up in a small volume of ethanol and water instead.

8. -Drugs which irritate the lining (endothelium) of veins may cause an inflammation at the site of intravenous administration (phlebitis).

In this situation, cortisone (an antiinflammatory agent) may be mixed with the offending drug, such as amphotericin (an antifungal anti-biotic) or hyperalimentation solutions to decrease the incidence of phlebitis. j

9. Dr. Der estimated that deviations from package insert reconstitution instructions for Medical Intensive Care Unit patients occur with a frequency of about 25%.

As an aside, it is important to note that I could not have made up this list myself. My responsibility as a physician has been to decide which drug and dose to administer. The reconstitution chemistry is the pharmacist's domain and professional responsibility. In cases of altered biodistribution, kinetics, and metabolism, the pharmacist is often consulted for drug dose schedule as well. The physician-pharmacist relationship is a complementary one, and appropriately so. It is essential that this partnership be under-stood by NRC as it considers revisions to 10 CFR Part 35.

Yo~ also asked about the difference between a nuclear pharmacy and a man-uf?c turer. This. is very.* clearly explained in an FDA document published in M~y, 1984. It is entitled., "Nuclear Pharmacy Guideline: Critefia for Determining When to Register as a Drug Establishment." This document was included as Addendum V. of the Petition, and is still in effect according to a letter sent by Paula Botstein,. M.D. to Richard E. *cunningham of NRC, dated 14 Feb. 89. This letter is included as Addendum XV. v. in the Petition. I am also enclosing three pages of the Food, Drug, and Cosmetic Act which is the statutory basis for the Nuclear Pharmacy Guideline, As you can see, the State~ determine that which constitutes the Practice of Pharmacy.

We are most grateful for your attention and consideration. Please do not h.~sitate to request any additional clarification or information that you may find necessary or desirable. Thank you for your interest in our fields of Nuclear Medicine and Nuclear Pharmacy.

Sincerely, Carol S. Marcus, Ph.D., M.D.

Director, Nuclear Medicine Outpt. Clinic Bldg. A-13 and Assoc. Prof. of Radiological Sciences, UCLA CSM:dt Enc:

cc: Richard Cunningham I Robert Temple, M.D *

. Eric Jones, M.D.

Valerie Fedio, ACNP/SNM

D CKET NUMBER t'ROPOSED RULE Pft 30 + .35

{ j 'SF~ c3"-/ 5/ 3)

ITT)~~~

National Association of Boards of Pharcg;.\,~t-,....

O'Hare Corporate Center

• 1300 Higgins Road

• Park Ridge, IL 60068

• 708/698-6227 '\,

November 8, 1990 Frederick J. Shon

• Deputy Chief Administrative Judge Atomic Safety & Licensing Board Panel USNRC Washington, DC 20555

Dear Mr. Shon:

I am contacting you as the Executive Director of the National Association of Board of Pharmacy (NABP), the association that represents the state boards of pharmacy in the United States, the District of Columbia, Puerto Rico, the Virgin Islands, eight Canadian provinces and the State of Victoria, Australia.

NABP affirms its support of the Nuclear Regulatory Commission's (NRC) decision to withdraw its previous regulation and recognize that pharmacists, in the

• course of pharmacy practice, i.e. preparing and dispensing radiopharmaceuticals, are legally able to depart from the package insert pursuant to a valid prescription. The decision of the NRC in this regard recognizes the professional judgement of the pharmacist in preparing pharmaceuticals, rloes n0t irnpingP- on ~tates' authority to regulate the practice of pharmacy, and does not conflict with Food and Drug Administration (FDA) policies for the compounding and dispensing of radiopharmaceuticals.

It has been the position of NABP and its members that cooperative federal and state regulation is the key to successfully protecting the public health. The NRC plays a critical role in regulating radiopharmaceuticals. However, it should not be the agency solely responsible for this regulation and engage in activities that conflict with the states' authority to regulate pharmacy practice.

-JAN 2 8 1991

.. ,101nl.;aged by card""' , ;,, . ........,-

I*. NUCLEAR REGULATORY COM~~I DOCKETING & SERVICE SECT)

OFFICE OF THE SECRETA v OF THE COMMISSIO Document Stati;;tics

!mark Date II q 'Jo ( A.SL/3P)

,1: Received _ _ /__

• 1 Copies Reproduced -=--

' cial Distribution RIDS iI PDR) ~

November 8, 1990 Page 2 We strongly disagree with a minority of individuals that continue to assert state boards of pharmacy are not regulating the preparation and dispensing of radiopharmaceuticals. Such contentions are false and dangerous. The state boards of pharmacy are regulating the practice of nuclear pharmacy and recognize the

• uniqueness of this practice.

I am hopeful that you will continue to support the cooperative federal and state regulation of radiopharmaceuticals as it currently exists and discourage any movement by the NRC to assume total responsibility for this area of patient care and the practice of pharmacy. Thank you for your consideration.

Respectfully Yours, NATIONAL ASSOCIATION OF FPHARMACY C. A. Catizone, M.S., R.Ph.

Executive Director CC/ps

. (

UNITED STATES NUCLEAR REGULATORY COMMISSION ATOMIC SAFETY AND LICENSING BOARD PANEL WASHINGTON . D.C. 20555 November 14, 1990 MEMORANDUM TO: S. Chilk FROM: Frederick J. Sho

SUBJECT:

COMMENT ON INTERIM RULE 55 FR 34513 I have received the enclosed letter, apparently a comment on the subject rule, and I am forwarding it for appropriate action by your Docketing and Service Branch.

UNITED STATES NUCLEAR REGULATORY COMMISSION ATOMIC SAFETY AND LICENSING BOARD PANEL WASHINGTON, D.C. 20555 November 14, 1990 Mr. C. A. catizone, M.S., R.Ph., Executive Director National Association of Boards of Pharmacy O'Hare Corporate Center 1300 Higgins Road, Suite 103 Park Ridge, IL 60068

Dear Mr. Catizone:

Thank you for your letter of November 8 commenting on a recent Commission action. In my present position I have no role in that particular rulemaking, and, indeed, I think it unlikely that the Commission will opt to involve the Licensing Board Panel in the development of a rule concerning pharmaceuticals (although that course of action would probably be open to the Commission if it so chose).

Accordingly, I have treated your letter as a comment in response to the Federal Register Notice of August 23, 1990 (55 Fed. Reg. 34513), and forwarded it to the Secretary of the Commission, Mr. Samuel Chilk.

The Federal Register Notice responded to two of many points made in a Petition for Rulemaking submitted by the American College of Nuclear Physicians and the Society of Nuclear Medicine in June of 1989. The notice announced an "interim final rule" ("interim" in that it is effective for a limited period, "final" in that it is effective from the date of publication). Of the matters mentioned in your letter, the rule focusses chiefly on permission to depart from the manufacturer's package insert in accord with a valid prescription. Other aspects of the petition concerning compounding and dispensing are still pending, I understand.

I have been in contact with our Dr. Anthony Tse, whom I believe you know, and he tells me that progress is being made on the other aspects of the ACNP/SNM petition, and that further responses to the matters contained in that petition should be forthcoming shortly.

cc: A. Tse S. ChilkV"'"

DOCKET NUMBER pn 3 ~ 35 PROPOSED P.Ulf n - ~)

( 5'5 Fe 34513;

[iuCKE iTe USNHC New Scotland Avenue, Albany, New York 12208

• 90 OCT -9 A9 :28 ALBANY MEDICAL CENTER October 3, 1990 Secretary of the Commission U.S. Nuclear Regulatory Commission Washington, DC 20555

Dear Mr. Secretary:

The Nuclear Regulatory Commission interim final rule entitled "Authorization to Prepare Radiopharmaceutical Reagent Kits and Elute Radiopharmaceutical Generators; Uses or Radiopharmaceuticals for Therapy" continues to disenfranchise nuclear pharmacists from the NRC recognized pool of skilled healthcare providers.

Nuclear pharmacists are not permitted to compound radioactive drugs except by following the manufacturer's instructions or in cases in which an authorized user physician directs a specific departure, a precise description of the departure, and a brief description of why the departure from the manufacturer's instructions would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition.

The author(s) of the new regulation erroneously assumes (1) that the package insert direction for compounding cannot be improved upon by the pharmacist, (2) that the manufacturer will file an amended new drug application whenever improved compounding procedures are developed and (3) that the "authorized user physician" is the expert in the compounding of radioactive drugs. The nuclear pharmacist, relative to his role in compounding dtugs, assumes a technical role.

The new regulations, as they define the pharmacist's role in the compounding of radioactive drugs, equates the physician-pharmacist relationship with the physician-technologist relationship. In the physician-pharmacist relationship the pharmacist is the professional responsible for the appropriate use of radioactive drugs and services to achieve optimal therapeutic (diagnostic) outcome. In the physician-technologist relationship the responsibility for pharmacy practice lies with the physician.

Consider the case in which a nuclear physician wishes prescribe for his patient 10 mCi Tc-99m autologous leukocytes for a nuclear imaging study. There is no package insert which describes the compounding procedure for this drug. There are package inserts for some of the radioactive and nonradioactive drug components. How wi11 the physician write the prescription? The regulatory requirement is that the instructions must be precise. The nuclear physician must be intimately familiar with the compounding procedure and must flawlessly transmit the compounding procedure, to the nuclear pharmacist. The physician must also transmit a brief statement of why the departure from the manufacturer's instructions would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition.

Acknowledg d by rd 11 .

ffB O1 1991 f/'t .,,........... , ..........,

IJ.S NUCLEAR RF-'3ULATOR OMMISSIO

')(') :Kr-Tff,j(' ,o '* _p ,'ICE SECTIO

• r::= OF Tl-i[* SECRETARY c-- THE ,() Ml'=;SIO l D c1 11 er tatis:ics

• 'ostmar Date _ 'l-'0+= 3+-'-9.,;;.b_ _ _ __

op1es R.::ce111 a I ___

Add'I Co~ aL Reproduced 3 __ _

• pec,a, D1stnout1on RIPS~DR 1 _'J'sL

The regulations should permit physicians to prescribe the radioactive drugs they need for their patients, and allow pharmacists to compound those drugs in accordance with the directions from the prescriber and the state of the art.

Example: A nuclear physician should be able to present the following prescription to a nuclear pharmacist:

Dr. Sam Jones Anyhospital Anywhere, USA 00000 Mr. John J. Patient Age: 63 years Room 402, Anyhospital Anywhere, USA Rx:

10 mCi Tc-99m Autologous Leukocytes Injection Mix and make, according to the art.

Sig: Administer intravenously for scintigraphic evaluation of inflammatory process.

Physician Signature:

This apparently valid prescription would not meet the NRC's requirements for a valid prescription. In the prescription displayed above,the physician relies upon the pharmacist to compound a drug that meets the requirements set forth in the prescription.

The radiation protection for the patient should be regulated in the licensure of the physician and the pharmacist to practice their respective professions.

Please amend the regulations in order to allow the pharmacist to serve a professional role rather than a technical role with respect to compounding radioactive drugs. The nuclar pharmacist is the best trained health care provider to assume that role. Thank you for your consideration of this matter.

Yours truly, 0-r-f ni ~

Raymond N. Dansereau, Ph.D.

Nuclear Pharmacist

DOCKET NUMBER PR 3tJ Y-- 3;ff (t)

The University of Iowa PROPOSED RULE Iowa City, Iowa 52242 ( 5'JFt;_, 3 l./5/ 3j The University of Iowa Hospitals and Clinics Department of Radiology 319/356-2188 If no answer, 356-1616 DOCKE T[()

USNRC

• 90 OCT -1 P4 :OS

- I 1847

,:,p:,c:;: OF SECRE : AR','

GOCl'Cr-TING & c:;:-i,VI Cf Septembe~R2'J1~Hl 990 Secretary of the Commission U.S. Nuclear Regulatory Commission Washington, D.C. 20555 ATTN: Docketing and Service Branch RE: 10 CFR Parts 30 and 35 Authorization To Prepare Radiopharmaceutical Reagent Kits and Elute Radiopharmaceutical Generators; Use of Radiopharmaceuticals for Therapy

Dear Sirs:

I was pleased to read this final interim rule published in the Federal Register on Thursday, August 23, 1990 [FR55(164):35513-35518].

I am overjoyed that the Commission agrees with my comments and those of many others that previous regulations governing the preparation of radiopharma-ceuticals and the indications and the method of administration for the therapeutic use of radiopharmaceuticals were overly restrictive and would not permit proper patient care to be provided to some patients. The current interim rule referred to above is a welcome step in the right direction. Though the Commission is to be corrunended on its prompt action in this regard, the interim rule is not beyond reproach.

While I concede that some documentation is important whenever departures from manufacturer's instructions occur, I feel strongly that the record-keeping requirements in the interim rule are unnecessarily excessive. My specific comments are as follows:

1. When a departure is made pursuant to a medical decision for a specific patient, the requirement for such a departure is inherent in the prescription or medical order. For example, if Tc-99m macroaggregated albumin with high specific activity and low particle concentration is required to safely perform a lung scan in a patient who has pulmonary hypertension, the authorized physician will prescribe or order the radiopharmaceutical dosage in terms of both radioactivity and number of particles (e.g., 4 mCi = 100,000 particles). It is then incumbent on the pharmacist to use his/her professional judgement and expertise in the actual preparation of this radiopharmaceutical. Departures, if needed, would be documented in the pharmacy's compounding records. Additionally, standards of practice and associated legal obligations (i.e., anti-malpractice)

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Secretary of the Commission US Nuclear Regulatory Commission Page 2 September 27, 1990 I. (Cont'd) dictate that appropriate quality control testing be performed to verify that the departure(s) do not adversely affect the quality of the finished product. These quality control results would similarly be recorded in the pharmacy's records.

2. When a departure is made on a more global basis, such as the addition of an antioxidant to a relatively unstable radiopharmaceutical, the rationale for such a departure should be known to result in a final product with quality equal to or better than the final product prepared according to the manufacturer's instructions. Such knowledge may either come from personal experience (including in-house quality control testing) and/or from data published in the scientific literature. In this situation, the pharmacist must be prepared to defend his/her departure (i.e., maintain records of quality control tests or literature citations) if challenged in a court of law.

3. When a departure is made regarding package insert instructions for a medical indication or method of administration, the departure should have a rational basis. Such a medical decision is usually based on personal experience and/or data in the medical literature. In this situation, the physician must be prepared to defend his/her departure if challenged in a court of law.

4. The interim rule's requirement for maintaining records of departures for 5 years is inconsistent with other regulations. For example, state laws govern the maintenance of prescriptions -- typically for a period of 2 years. Furthermore, 10 CFR 35.53(c) requires that radiopharmaceutical dosage dispensing records be maintained for 2 years.

In summary, I wholeheartedly support the Commission's decision to allow a licensee to depart from the manufacturer's instructions for eluting generators and preparing radiopharmaceutical kits, and to depart from package insert instructions regarding indications or method of administration. However, I disagree with the record-keeping requirements in these circumstances. I believe the record-keeping requirements to be excessive, burdensome, at times redundant with other record-keeping requirements, inconsistent with other regulations regarding duration of keeping records, and simply unnecessary and possibly even counter-productive. The requirement for a written directive by an authorized user physician that directs a specific departure for a particular patient is unnecessary; it is inherent in the prescription or medical order. It is the professional responsibility of the pharmacist to use his/her professional judgement and expertise to prepare a final product that both meets the requirements of the specific prescription and achieves the same quality as a product prepared according to the manufacturer's instructions. The requirement for a written directive by an authorized user physician that directs a specific

Secretary of the Commission US Nuclear Regulatory Commission Page 3 September 27, 1990 departure for a radiopharmaceutical is inappropriate -- this decision is also the responsibility of the pharmacist who prepares the radiopharmaceutical. Such decisions may be the result of in-house quality control testing and/or knowledge obtained from the professional scientific literature. Although records may be maintained by the pharmacist, the requirement to do so is unfounded. The requirement for recording the specific nature of the departure and a precise description of the departure is unnecessary -- such information, although not necessarily in a descriptive format, is already contained in the radiopharmacy preparation records. The requirement for recording a brief statement of the reasons why the departure from the manufacturer's instructions for preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition is unnecessary. Physicians routinely act in the best interests of their patients, providing care with the greatest benefits and lowest risks.

These medical decisions are usually not black or white (wrong vs. right) but rather are relative shades of gray requiring professional judgement. Recording reasons for departure decisions may be important for peer-review of medical practice, but is simply not relevant to Commission activities.

The requirements for maintenance of departure records for 5 years is inconsistent with other requirements for record-keeping. The requirement for keeping a record of the number of patient administrations under the departure offers no benefits and is probably counter-productive. What is the Commission going to do with these data? Simply compiling the total number of departures yields absolutely meaningless numbers. Since the Commission does not have the medical expertise to evaluate the appropriateness of each departure, the total number of departures is irrelevant -- although one physician may have more departures than average, each departure may be appropriate; conversely, a physician who has fewer departures than average may not be providing optimal care in that more departures should be ordered.

In conclusion, I recommend that the Commission continue to allow licensees to depart from manufacturer's instructions for eluting generators and preparing reagent kits and package insert instructions regarding indications or method of administration. However, I recommend that the record-keeping requirements in the interim rule be abolished. These record-keeping requirements basically address documenting the reasons for the medical decision for departure, a professional judgement which the Commission is unable to evaluate. Records of actual departures are already being maintained within prescription/medical order records and within radiopharmaceutical preparation/dispensing records. The total number of departures is irrelevant and, if interpreted out of context, may be counter-productive.

Secretary of the Commission US Nuclear Regulatory Commission Page 4 September 27, 1990 Thank you in advance for your consideration of these comments.

Sinc*n::fJ A Ja~sA. Ponto, MS, RPh

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• Nuclear Pharmacist and linical Associate Professor Division of Nuclear Medicine University of Iowa Hospitals & Clinics Iowa City, IA 52242 JAP/pv

BAKER DOCKET NUMBER PR 3tJ .,_,35 4

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& PROPOSED RULE ~ l 3 951 HOSTETLER ( 55  ;=£ ~

COUNSELLORS Kr LAW WASHINGTON SQUARE, SUITE 1100

• 1050 CONNECTICUT AVENUE, N.W.

• WASHINGTON, D.C. 20036

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(202) 86 1 -1 726 DOCKETED September 20, 1990 SEP 2 4: \990 oocKE'TING&

RVICE BRANC By Hand Mr. Samuel J. Chilk Secretary of the Commission Attention: Docketing and Service Branch U.S. Nuclear Regulatory Commission 11555 Rockville Pike Rockvi l le, MD 20852 Re: RIN 3150-AD43

Dear Mr. Chilk:

There is enclosed for filing a Petition for Reconsideration and for Stay of Action in connection with the Interim F i nal Rule published by the Commission in the Federal Register of August 23, 1990.

So that my client may preserve its right to seek j udicial review, please note our request, detail.e d on page 1 of the Petition, for a reply before October 22, 1990.

an Attorne f or sync or Intern tional Corp oration AJL/mt enclosure CLEVEUND. Omo CoWMBUS. Omo DENVER, CowRAIJO H OUSTON, 'fExAs l.oNG Bl!ACH, CALIFORNIA Los ANGELES, CAIJFOIINIA ORLANoo, Fw=

(216) 621-0200 (614) 228-1541 (30 3) 8 61-0600 (713) 236-0020 (213) 432-2827 (213) 624-2400 (407) 649-4000

J DOCKETED BEFORE THE UNITED STATES SEP 24 1 NUCLEAR REGUI.ATORY COMMISSION

)

Interim Final Rule; Authorization)

To Prepare Radiopharmaceutical )

Reagent Kits and Elute )

Radiopharmaceutical Generators; ) RIN 3150-AD43 Use of Radiopharmaceuticals for )

Therapy; 55 Fed. Reg. 34513 )

(August 23, 1990) )

)

PETITION FOR RECONSIDERATION AND FOR STAY OF ACTION Alvin J. Lorman Ann K. Pollock Baker & Hostetler 1050 Connecticut Avenue, N.W.

Washington, D.C. 20036

{202) 861-1500 Attorneys for SYNCOR INTERNATIONAL CORPORATION September 20, 1990

TABLE OF CONTENTS I. ACTION REQUESTED . . 1 II.

SUMMARY

OF PETITION 2 III. STATEMENT OF FACTS . . 3 IV. STATEMENT OF GROUNDS. 10 A. THE INTERIM FINAL RULE WAS PROMULGATED IN VIOLATION OF THE ATOMIC ENERGY ACT, THE ADMINISTRATIVE PROCEDURE ACT AND NRC'S IMPLEMENTING REGULATIONS . . 10

1. NRC illegally failed to publish a notice of proposed rulemaking and to afford interested persons an opportunity to comment * . . . . . . 10

2. NRC failed to make its views on the Interim Final Rule known, thereby denying the public an opportunity for meaningful comment . . . . . 20

3. NRC failed to disclose on the record the factual basis for the rule and the methodology used in reasoning from the data to the rule . . 20

4. NRC failed to provlde a record of ex parte communications which were considered and formed part of the basis of the Interim Final Rule. . .............. o 21

5. NRC failed to provide the required 30 day comment period before making the Interim Final Rule effective . . . . . . . . . . * . . . . . 23 B. THE RECORD-KEEPING REQUIREMENTS OF THE INTERIM FINAL RULE WILL HAVE A DIRECT AND NEGATIVE IMPACT ON NUCLEAR PHARMACIES. . . . . * . . . . . . . 25

v. CONCLUSION. 31

- i -

BEFORE THE UNITED STATES NUCLEAR REGULATORY COMMISSION

)

Interim Final Rule; Authorization)

To Prepare Radiopharmaceutical )

Reagent Kits and Elute )

Radiopharmaceutical Generators; ) RIN 3150-AD43 Use of Radiopharmaceuticals for )

Therapy; 55 Fed. Reg. 34513 )

(August 23, 1990) )

)

PETITION FOR RECONSIDERATION AND FOR STAY OF ACTION I. ACTION REQUESTED Syncor International Corporation ("Syncor") submits this Petition for Reconsideration and for Stay of Action ("the Petition") under the Administrative Procedure Act ("APA"), 5 u.s.c.

§ 553, and the implementing regulations of the Nuclear Regulatory Commission ("NRC"), 10 C.F.R. §§ 2.800 et seq. Syncor requests that NRC stay the effective date of the record-keeping requirements imposed upon nuclear pharmacies by the Interim Final Rule it published and made effective on August 23, 1990, 55 Fed. Reg. 34513. syncor also requests that those record-keeping requirements be withdrawn as unduly burdensome. The Interim Final Rule amended NRC regulations and Syncor's license concerning the preparation and use of radiopharmaceuticals. Because the time for filing a petition for review of this final agency action expires on October 22, 1990, 42 u.s.c. § 2239 (1988), syncor further requests that the NRC respond to this Petition before that date.

II.

SUMMARY

OF PETITION This Petition, submitted on behalf of Syncor International Corporation, a company operating 84 nuclear pharmacies across the United States, challenges the legality of the record-keeping requirements imposed upon nuclear pharmacies as part of an Interim Final Rule published and made effective by the Commission on August 23, 1990. That Rule, which amended Syncor' s license and the regulations governing the use of radiopharmaceuticals for diagnostic and therapeutic purposes, was promulgated in violation of important procedural requirements mandated both by the Ad-ministrative Procedure Act and the Atomic Energy Act:

o The Interim Final Rule was not preceded by a proposal and an opportunity for public comment. Instead, the NRC appears to rely upon its publication of a notice in the Federal Register noting that third parties had petitioned the NRC to* engage in rulemaking. The NRC at no time gave its views on that petition nor even stated that it would engage in the rulemaking requested.

0 The NRC apparently has relied upon ex parte communications with some, but not all, interested parties in deciding upon the terms of the Interim Final Rule.

o The NRC made the Rule effective immediately, instead of affording the public the 30 day notice required by the APA and the NRC's own rules. The NRC's argument that good cause exists for this truncation is wrong.

o The NRC has not established the post-adoption comment period required by its own rules, even if, hypothetic-ally, the Rule were legally promulgated with immediate effectiveness.

In addition to these procedural defects, the record-keeping requirements that would be imposed upon commercial nuclear pharmacies under the terms of the Interim Final Rule are burdensome, expensive, and unnecessary. Observance of these rules would clearly increase the cost to the public of radiopharma-ceuticals and might well result in interference in the doctor-patient relationship, yet provide no particular benefit to the public.

For the above-stated reasons and as more fully discussed below, Syncor requests that the record-keeping requirements of the Interim Final Rule be stayed and that the Commission reconsider those requirements, and, upon reconsideration, revoke them.

III. STATEMENT OF FACTS on August 23, 1990, NRC issued an Interim Final Rule, 55 Fed.

Reg 34513 (Aug. 23, 1990), which amended Syncor' s license and existing regulations contained in 10 C.F.R. §§ 30.34, 35.200, and 35.300 governing the preparation and use of radiopharmaceuticals.

Not only did the NRC not provide a period for public comment on a proposed rule, but it also put the final rule into effect immediately.

syncor is a public company which operates 84 nuclear pharmacies across the country. Syncor nuclear pharmacies procure, prepare, and dispense radiopharmaceuticals used for the diagnosis and therapeutic treatment of human disease. Each year, Syncor nuclear pharmacies dispense approximately four million diagnostic doses and approximately 40 percent of all therapy doses of radiopharmaceuticals.

Some Syncor nuclear pharmacies are licensed by the NRC as byproduct material licensees pursuant to 10 C.F.R. Parts 30 and 32.

The remaining Syncor nuclear pharmacies are licensed as radioactive material licensees by Agreement States . 1 10 C.F.R. § 8.4(j)

(1990). All Syncor nuclear pharmacies, therefore, are affected by the Interim Final Rule.

The existing regulations amended by the Interim Final Rule became effective on April 1, 1987. These regulations, among others, were promulgated pursuant to notice and comment rulemaking.

50 Fed. Reg. 30616 (July 26, 1985); 51 Fed. Reg. 36932 (Oct. 16, 1986). NRC also allowed NRC licensees almost six months between l

An Agreement State is any state which the NRC has entered into an agreement with under Section 274(b) of the Atomic Energy Act, as amended, 42 u.s.c. § 2021(b) (1988). The agreement gives the state limited authority to license and inspect certain nuclear facilities and requires the state to assert its best efforts to assure that its regulatory program for protection against radiation hazards will be consistent with the NRC's program.

J) ,,.

publication of the final rule and the effective date to prepare for compliance with these and other regulations.

Prior to the change effected by the Interim Final Rule, the regulations and Syncor*s license restricted hospitals and physicians to the use of radiopharmaceuticals approved by the Food and Drug Administration ("FDA") under a Notice of Claimed Investigational Exemption for a New Drug ("IND") or an approved New Drug Application ( "NDA") . 2 As to radiopharmaceuticals used for therapy, the regulations required hospitals and physicians to prescribe and administer the FDA-approved drug according to the package insert. The regulations and license conditions also 2

10 C.F.R. §§ 35.200 and 35.200 read as follows:

§ 35.200 Use of radiopharmaceuticals. generators.

and reagent kits for imaging and localization studies.

(a) A licensee may use any byproduct material in a diagnostic radiopharmaceutical or any generator or reagent kit for preparation and diagnostic use of a radiopharmaceutical containing byproduct material for which the Food and Drug Administration has accepted a "Notice of Claimed Investigational Exemption for a New Drug" (IND) or approved a "New Drug Application" (NDA).

(b) A licensee shall elute generators and. prepare reagent kits in accordance with the manufacturer's instructions.

§ 35.300 Use of radiopharmaceuticals for therapy.

A licensee may use any byproduct material in a radiopharmaceutical and for a therapeutic use for which the Food and Drug Administration has accepted a "Notice of Claimed Investigational Exemption for a New Drug" (IND), or approved a "New Drug Application" (NDA). The licensee shall comply with the package insert instructions regarding indications and method of administration.

restricted nuclear pharmacies, such as those operated by Syncor, from preparing radiopharmaceuticals not approved by FDA under an IND or an NOA. 3 Finally, the regulations prohibited. nuclear pharmacies from preparing FDA-approved radiopharmaceuticals in a manner different than the manufacturer's instructions.

on December 2, 1988, NRC sent an internal memorandum to its Regional Division of Radiation Safety and Safeguards Directors.

See Exhibit 1. NRC noted that questions had been raised as to whether non-IND and non-NDA radiopharmaceuticals may be used in human applications. The memorandum then stated that:

[NRCJ is reexamining the issues raised in the regulations and policy statements in this regard and hopes to resolve them shortly.

Pending completion of this reexamination, all proposed enforcement actions on this matter, including those involving violations assessed at Severity Levels IV and V, should be referred to this Division with a copy to the Office of Enforcement before issuance in order to ensure consistent and appropriate disposition. Among the actions [NRCJ is considering are exemptions and the advisability of amending the regulations.

e See Exhibit 1. Relatively infrequent enforcement actions have been instituted alleging that non-IND or non-NDA radiopharmaceuticals have been prepared or used in violation of the regulations.

On June 5, 1989, the American College of Nuclear Physicians

( "ACNP") and the Society of Nuclear Medicine ( "SNM") filed a 3

Although the restriction was not specified in 10 C.F.R.

§ 30.34, nuclear pharmacies were bound by these requirements by virtue of similar license conditions placed in their licenses by NRC *.

Petition for Rulemaking requesting that NRC amend its regulations governing the preparation and use of radiopharmaceuticals. See Exhibit 2. ACNP and SNM are associations which represent nuclear physicians, technologists, and pharmacists. Syncor is not a voting member of either association. ACNP/SNM "requested action because under current NRC regulations, they cannot appropriately practice their professions. 11 Petition at p. 1, Exh. 2. The ACNP/SNM Petition explained that, "the delivery of quality patient care often requires that a physician modify an existing clinical procedure, create a new clinical procedure, or use an existing product for an application not described in the package insert."

Petition at p. 4, Exh. 2. ACNP/SNM argued that the NRC regulations prohibited activities permitted by FDA and state law and that the NRC regulations also conflicted with the Hippocratic Oath and the spirit of the Atomic Energy Act.

ACNP/SNM generally requested that the NRC regulations be amended to "allow nuclear physicians and nuclear pharmacists to reconstitute non-radioactive kits differently from the method recommended by the manufacturer; allow nuclear physicians and nuclear pharmacists to prepare radiopharmaceuticals whose manufacture and distribution are purposefully not regulated by FDA; and permit nuclear physici~ns to determine appropriate diagnostic and ther~peutic applications of radiopharmaceuticals, as is their professional obligation." Petition at p.

• 4; Exh. 2. ACNP/SNM also submitted a proposed regulatory text. As to nuclear pharmacies, ACNP/SNM requested appropriate changes to the byproduct material license issued to a nuclear pharmacy. Specifically, the ACNP/SNM Petition stated:

The NRC must amend these licenses to allow free-standing radiopharmacies licensed under 10 C.F.R. 32.72 and 10 C.F.R 32.73 to also compound radiopharmaceuticals ... Those licenses will be amended by NRC, without charge to the licensee, to: remove the requirement to reconstitute radiopharma-ceuticals in accordance with the manufacturer's instructions, and allow the compounding of radiopharmaceuticals under the practice of pharmacy regulations in accordance with requirements of the Food and Drug Administration and applicable State requirements.

Petition at p. 12; Exh. 2.

On September 15, 1989, NRC published in the Federal Register a Notice of Receipt of the ACNP / SNM Petition for Rulemaking (hereinafter "Notice of Receipt") and requested public comment on the ACNP/SNM Petition. 54 Fed. Reg. 38239 (Sept. 15, 1989). This Notice of Receipt contained the following: (1) a description of the identity of the petitioners, ( 2) an explanation of the petitioners' interest in the requested action, (3) a statement of background explaining FDA regulation as described by the petitioners, (4) the petitioners' proposed regulatory text, (5) a statement of the grounds cited by the petitioners, and (6) a statement of petitioners in support. Individual Syncor pharmacists submitted comments on the ACNP/SNM Petition, as did other interested parties.

The Notice of Receipt did not state or even suggest that NRC was considering amending its regulations. Nowhere in the Notice of Receipt did NRC reveal its views on the relief requested by the petition. The Notice of Receipt, despite its patent deficiencies, was the only document published by the NRC in the Federal Register before the publication of the Interim Final Rule.

The rule changes requested in the ACNP/SNM Petition vary greatly from the rule changes mandated by the Interim Final Rule.

The rules proposed by ACNP/SNM contained no record-keeping requirement whatsoever while the Interim Final Rule imposes substantial record-keeping requiremen;ts on nuclear pharmacies,

• hospitals, and physicians. NRC' s Interim Final Rule permits deviation from the manufacturer's elution and preparation instructions only if the nuclear pharmacy, "has a written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radiopharmaceutical . . . . 11 10 C.F.R. § 30.34. Deviations are not permitted to be made at all for radiopharmaceuticals for therapy nor can nuclear pharmacies compound non-IND or non-NDA radiopharmaceuticals under the Interim Final Rule.

IV. STATEMENT OF GROUNDS A. THE INTERIM FINAL RULE WAS PROMULGATED IN VIOLATION OF THE ATOMIC ENERGY ACT, THE ADMINISTRATIVE PROCEDURE ACT AND NRC'S IMPLEMENTING REGULATIONS.

1. NRC illegally failed to publish a notice of proposed rulemaking and to afford interested persons an opportunity to comment.

NRC' s organic statute, the Atomic Energy Act, provides in p~rtinent part, that In any proceeding under this chapter, for the

. . . amending of any license . . . , and in any proceeding for the issuance or modification of rules and regulations dealing with the activities of licensees .

• the Commission shall , grant a hearing upon the request of any person whose interest may be affected by the proceeding, and shall admit any such person as a party to such proceeding.

42 u.s.c. § 2239. The Interim Final Rule is ,a "proceeding" for the "amending of [a] license" and "for the issuance . . . of rule

. dealing with the activities of licensees . . . " within the meaning of the statute. By enacting the Interim Final Rule, NRC amended 10 C.F.R. § 30.34, "Terms and conditions of licenses,"

which, as the title of the regulation implies, contains the license conditions in commercial nuclear pharmacy licenses. Indeed, the actual text of the rule demonstrates that it amends individual licenses by stating:

. The actions authorized in paragraph (i) (1) of this section are permitted notwithstanding more restrictive language in license conditions unless those license conditions specifically reference§ 30.34(i).

10 C.F.R. § 30.34(i)(2).

The Interim Final Rule is also a "proceeding for the issuance of rules and regulations dealing with the activities of licensees" under the terms of the statute. Whether it is characterized as a license amendment or as a rulemaking, the Atomic Energy Act requires notice and comment for both types of proceedings. Union of Concerned Scientists v. NRC, 711 F.2d 370, 380 (D.C. Cir. 1983).

NRC, however, failed to provide interested parties the opportunity for notice and comment, thus violating the Atomic Energy Act.

Section 553 of the Administrative Procedure Act ("APA"),

5 u.s.c. § 553, also provides that, for all substantive rules, a notice of proposed rulemaking must be published in the Federal Register. Section 553 further provides that agencies must give interested persons an opportunity to participate in the rulemaking through submission of written data, views, or arguments. Id. The Atomic Energy Act states that "the provisions of [the Administrative Procedure Act] shall apply to all agency action taken under this chapter 11 42 U.S. c. § 2231. NRC' s implementing regulations similarly require that adoption of a rule be preceded by a proposal affording the opportunity for meaningful comment by the public. See 10 C.F.R. § 2.800 et seq.

The APA was designed to assure fairness and mature consideration of rules of general application. NLRB V. Wyman-Gordon Co., 394 U.S. 759 (1969). In enacting the APA, Congress intended to give the public an opportunity to participate in the rulemaking process. National Retired Teachers Ass' n v. United states Postal Service, 430 F. Supp. 141 (D.D.C. 1977), aff'd, 593 F.2d 1360 (O.C. Cir. 1979) .

. In this case, NRC contravened the requirements of both the APA and the Atomic Energy Act by publishing the Interim Final Rule without first publishing a proposal upon which the public could comment. The Interim Final Rule amends the regulations governing the medical use of byproduct material by byproduct material licensees and by medical use licensees. It is clearly a substantive rule imposing legal obligations, and thus, is final agency action. S e e , ~ , Pharmaceutical Manufacturers Ass'n v.

Finch, 307 F. Supp. 858 (D. Del. 1970) (regulations having an immediate and substantial impact on pharmaceutical companies' business required notice and comment before adoption). That it is characterized as an "Interim" Final Rule has no bearing upon the agency's legal duty to promulgate the rule pursuant to the requirements of notice and comment rulemaking. S e e , ~ , Union of Concerned Scientists v. NRC, 711 F.2d 370 (D.C. Cir. 1983).

NRC admitted in the preamble to the Interim Final Rule that it was 11

• omitting the notice of proposed rulemaking and the public procedures thereon . , 11 55 Fed. Reg. 34513, 345],.5 (Aug. 23, 1990), but asserted that good cause existed to do so.

The APA provides that a "good cause" exception is available to an agency, " [ e] xcept when notice or hearing is required by the statute." 5 U.S.C. § 553(b) (1990). The Atomic Energy Act is a statute which requires a hearing. Id. Accordingly, the notice and comment procedures required by the statute cannot be circumvented through the "good cause" exception to the APA.

Even if the Atomic Energy Act did not apply, NRC may not apply the "good cause" exception in this case. The APA permits a suspension of the requirement for notice and comment, "when the agency for good cause finds . . . that notice and public procedure thereon are impracticable, unnecessary, or contrary to the public

.interest. 11 5 U.S.C. § 553(b)(3)(B). In adopting a good cause exception in Section 553 of the APA, Congress indicated that the good cause exception, 11 is not an 'escape clause' which may be arbitrarily exercised but requires legitimate grounds supported in law and fact by the required finding." s. Rep. No.79-752, 79th Cong., 1st Sess. (1946). Furthermore, courts have uniformly held that exceptions to the requirement of notice and comment rulemaking should be narrowly construed and reluctantly countenanced. New Jersey Dept. of Environmental Protection v. EPA, 626 F.2d 1038 (O.C. Cir. 1980); Humana of South Carolina. Inc. v. Califano,

• 590 F.2d 1070 (O.C. Cir. 1978); Union of Concerned Scientists v.

NRC, 711 F.2d 370 (D.C. Cir. 1983); Sharon Steel Corp. v. EPA, 597 F.2d 377 (3d Cir. 1979); city of Waco v. EPA, 620 F.2d 84 (5th Cir.

1980). As the United States Court of Appeals for the District of Columbia has stated, "the exception is confined to emergency actions which are indeed rare." Union of Concerned Scientists v.

NRC, 711, supra, F.2d at 382 (citation omitted).

In this case, NRC found the notice and comment procedures to be "unnecessary and contrary to the public interest" because existing regulations "if left in place could have an adverse impact on public health and safety" and because "NRC has received and considered public comments" on a related petition for rulemaking.

55 Fed. Reg. 34513, 34515 (Aug. 23, 1990) . Neither of these reasons, however, constitute good cause for suspending the requirement of notice and comment rulemaking.

NRC argues that good cause exists to amend regulations without notice or comment to the public because existing regulations created by the Agency itself years ago may adversely impact public health and safety. In Union of Concerned Scientists v. NRC, 711 F.2d 370 (D.C. Cir. 1983), however, NRC published a rule without notice and comment which amended all operating licenses by suspending indefinitely the deadline by which nuclear facilities had to complete "environmental qualification" of their equipment.

NRC invoked the good cause exception stating among other things

• that it had to lift the deadline or licensees would have been placed in jeopardy of enforcement action. The court, however, vacated the rule because the agency had prosecutorial discretion to suspend the deadline without amending the rule. In the words of the Court,

[ T] he agency could have chosen to take no action or it could have issued, without notice and comment, a "statement of policy" regarding its intent not to enforce the deadline. See 5 u.s.c. § 553 (b) (A). Instead, it chose to amend all operating licenses to remove license conditions. While we are reluctant to vacate a rule when an agency could have achieved the same result by doing nothing, the very power to do nothing demonstrates conclusively that the Commission's concern for licensees' "jeopardy" does not rise to the level of an emergency situation falling within the scope of the "good cause" exception.

711 F.2d at 383.

Whether it is an NRC deadline or NRC restrictions, NRC has the prosecutorial discretion to remedy the situation without the drastic step of amending its regulations without the opportunity for notice and comment rulemaking. NRC could have issued a statement of policy regarding its intent not to hold its licensees to the restrictions in its regulations on compounding radiopharmaceuticals. Instead, the Agency improperly invoked the good cause exception.

NRC's use of the good cause exception is even more offensive in this case because of the fact that NRC has not enforced the requirements which it now alleges "may adversely affect the public health and safety because the delivery of proper patient care may require, in certain instances, that some radiopharmaceuticals be prepared and administered in a manner different from that stated in the FDA-approved instructions." 55 Fed. Reg. 34513, 34515 (Aug. 23, 1990). In fact, NRC has delayed enforcement of the restrictions in its regulations and has permitted byproduct material and medical use licensees to deviate from FDA-approved instructions in their medical judgment.

NRC's inaction is exemplified by an internal memorandum dated December 2, 1988 which was sent to NRC' s Regional Division of Radiation Safety and Safeguards Directors. See Exhibit~- NRC noted that questions had been raised as to whether non-IND and non-NOA radiopharmaceuticals may be used in human applications. The memorandum then stated that:

[NRCJ is reexamining the issues raised in the regulations and policy statements in this regard and hopes to resolve them shortly.

Pending completion of this reexamination, all proposed enforcement actions on this matter, including those involving violations assessed at Severity Levels IV and V, should be referred to this Division with a copy to the Office of Enforcement before issuance in order to ensure consistent and appropriate disposition. Among the actions [NRCJ is considering are exemptions and the advisability of amending the regulations.

see Exhibit 1. NRC may not suspend the requirements of notice and comment rulemaking and claim "emergency status" for an issue of its own making that it has been considering for years. The issue under consideration must be of a pressing and urgent nature. See,~,

- United States v. Davis, 482 F.2d 893, 903-04 n.26 (9th Cir. 1973)

(court upheld good cause issuance of an FAA rule requiring the placement of armed guards at final passenger screening areas because of the danger of sky-jackings).

Moreover, NRC's assertion that the situation as it existed prior to adoption of this rule may adversely affect the public health is conclusory and not supported by fact. The good cause exception may not be invoked arbitrarily without a factual basis.

NRC's determination that "continued application of the subject requirements, without exceptions, may adversely affect the public health and safety" is speculative, since in practice NRC did not compel compliance. The good cause exception, "is designed to provide agencies with a safety valve when delay would do real harm." United States v. Garner, 767 F.2d 104 (5th Cir. 1985);

United states Steel Corp. v. EPA, 595 F.2d 207, 214 (5th Cir.

1979). A mere recital of good cause to justify an exception to the APA's requirements is not sufficient. Mobil Oil Corp. v. DOE, 610

- F.2d 796 (Temp. Erner. ct. App. 1979), cert. denied, 446 U.S. 937 (1980). As the legislative history of the APA* indicates, the agency's basis for invoking the . good cause exception must be supported in law and fact. NRC' s contention that it may invoke the good cause exception because existing, unenforced regulations may adversely impact public health and safety is not supported either by law or. fact.

NRC also found that the notice and comment rulemaking

- procedures were "unnecessary" because "the NRC has received and considered public comments* on the petition for rulemaking. 11 55 Fed. Reg. 34513, 34515 (Aug. 23, 1990). NRC's determination is again not supported by law. The Notice of Receipt of the ACNP/SNM citizen petition and the acceptance of comments thereon do not substitute for notice and comment rulemaking procedures. Indeed, the NRC's own procedural regulations envision that publication of a notice of filing of a petition for rulemaking cannot substitute for a notice of proposed rulemaking:

Public comment may be requested by publication of a notice of the docketing of the petition in the FEDERAL REGISTER, or, in appropriate cases, may be invited for the first time upon publication in the FEDERAL REGISTER of a proposed rule developed in response to the petition.

10 C.F.R. § 2.802(e). As the NRC regulations suggest, petitions for rulemaking, if accepted, result in the publication of a notice of proposed rulemaking by NRC. Specifically, the regulations

state, No hearing will be held on the petition unless the Commission deems it advisable. If the Commission determines that sufficient reason exists, it will publish a notice of proposed rulemaking. In any other case, it will deny the petition and will notify the petitioner with a simple statement of the grounds of denial.

10 C.F.R. § 2.803. The NRC neither published a notice of proposed rulemaking nor denied the petition. There is no legal basis in NRC's own regulations for the course of conduct it chose in this case: simply publishing a final rule.

The great disparity between the rule proposed by the ACNP/SNM petition and the Interim Final Rule also means that interested parties were denied an opportunity for meaningful comment if they based their decisions on the Petition. Indeed, while individual Syncor pharmacists commented on the Petition, syncor as a corporation did not. It most certainly would have commented had it had any reason to suspect that the NRC would later claim that the Petition served as a proposed rule.

There are few cases in which courts have upheld agency determinations that notice and comment rulemaking procedures are "unnecessary" under the good cause exception in the APA. These cases indicate that notice and comment rulemaking procedures are only unnecessary where technical, administrative changes are involved or where duplicative agency proceedings have been held.

See, ~ , Appalachian Power Co. V. EPA, 477 F.2d 495 (4th Cir.

1973) (court held that notice and comment rulemaking on Clean Air Act implementing regulations would be duplicative and therefore "unnecessary" because proceedings on similar state provisions had already been held). The Attorney General's Manual on the Administrative Procedure Act states that the "unnecessary" concept covers the "issuance of a minor rule or amendment in which the public is not particularly interested." Attorney General's Manual on the Administrative Procedure Act, at 31 (1947). NRC cannot

- argue that this matter is one of no interest .to the public, particularly when the 12,000 members of ACNP/SNM requested rulemaking on the subject. Moreover, in view of the deficiencies of NRC' public notice on this issue, NRC may not contend that affording notice and comment procedures would be duplicative.

NRC*' s Notice of Receipt cannot substitute for a notice of proposed rulemaking because it failed to meet the requirements of a notice of proposed rulemaking in several important respects.

2. NRC failed to make its views on the Interim Final Rule known, thereby denying the public an opportunity for meaningful comment.

The mere publication of the Notice of Receipt cannot now be claimed to serve the purposes of a proposed rule because NRC's Notice of Receipt failed to disclose "the thinking that has animated the form of a proposed rule and the data upon which that rule is based." Home Box Office. Inc. v. FCC, 567 F.2d 9, 35 (D.C.

Cir.), cert. denied, 434 U.S. 829 (1977). The Home Box Office Court stated that the agency proposing the rule must "make its views known to the public in a concrete and focused form so as to make criticism or formulation of alternatives possible." Id. at 3 6. At no point, however, in the notice of receipt of the petition for rulemaking did NRC indicate what its views were on the requested relief. Nor in the Interim Final Rule did NRC gave any indication of why it did not adopt the rule suggested by the ACNP/SNM petition in its entirety. In rejecting rulemaking alternatives, an agency must explain why its other choice was more desirable. Independent United States Tanker Owners Comm. v. Dole, 809 F.2d 847 (D.C. Cir.), cert. denied, 484 U.S. 819 (1987).

3. NRC failed to disclose on the record the factual basis for the rule and the methodology used in reasoning from the data to the rule.

The APA requires federal agencies to disclose on the record the* factual basis for the rule and the methodology used in reasoning from the data to the proposals. See, ~ , Portland Cement Ass*n v. Ruckelshaus, 486 F.2d 375, 393 (D.C. cir. 1973),

cert. denied, 417 U.S. 921 (1974); National Crushed Stone Ass*n v.

EPA, 601 F.2d 111, 117 (4th Cir. 1979), rev'd on other grounds, 449 U.S. 64 (1980); Int'l Harvester v. Ruckelshaus, 478 F.2d 615, 631-32 (D.C.Cir. 1973). The preamble to the Interim Final Rule makes clear that NRC did not adhere to this fundamental and basic legal requirement. Indeed, the Interim Final Rule states, "Information submitted by the ACNP-SNM in the petition for rulemaking and obtained during subsequent discussions with licensees indicates that the requirements in§ 35.200(b) regarding preparation of radiopharmaceuticals and in § 35. 3 00 regarding indications and method of administration for therapy procedures are preventing authorized user physicians from providing certain nuclear medicine clinical procedures." 55 Fed. Reg. 34513, 34514 (Aug. 23, 1990) (emphasis added). If information obtain during "subsequent discussions" with licensees formed part of the basis of the Interim Final Rule, such information should have been included in the public record for all interested parties.

4. NRC failed to provide a record of ex parte communications which were considered and formed part of the basis of the Interim Final Rule.

Syncor has reason to believe that the record does not reflect the occurrence of certain ex parte communications 4 which resulted 4

An ex parte communication is defined in the APA as "an oral or written communication not on the public record with respect to which reasonable prior notice to all parties is not given, but it shall not include requests for status reports on any matter or proceeding covered by this subchapter. 11 5 U. s. c. § 551 ( 14) ( 1988)

• A similar definition is contained in the NRC regulations.

10 C.F.R. § 2.4 (1990).

in NRC's promulgation of the Interim Final Rule. Syncor believes that a series of ex parte communications between the NRC and ACNP / SNM and between the NRC and the FDA which are not on the record led to the publication of the Interim Final Rule. 5 These communications, if proved, would demonstrate that NRC has not disclosed the basis for its Interim Final Rule, in violation of the APA. Home Box Office. Inc. v. FCC, 567 F.2d 9 (D.C. Cir. 1977),

cert. denied, 434 U.S. 829 (1977). Interested parties, like Syncor (which is not an active member of the ACNP/SNM), are entitled to know what input the ACNP/SNM and the FDA had into the Interim Final Rule when that input forms the basis for the NRC's action as a 6

matter of basic fairness. It is NRC's burden under the APA to provide a record of all communications which were considered in the 5

Syncor has reasons to believe that the following scenario may have occurred. NRC negotiated the provisions of the Interim Final Rule with representatives of the ACNP/SNM in a series of meetings. After an agreement was reached, NRC representatives sought the opinion of FDA on the Interim Final Rule. Thereafter, communications between FDA and NRC representatives occurred, including but not limited to a letter from Dr. Carl Peck to NRC representatives dated May 18, 1990. The Interim Final Rule was then modified by NRC in accordance with communications from FDA.

6 Syncor recognizes that, since Home Box Office, the United States Court of Appeals for the District of Columbia has recognized that the doctrine of that case has not been applied to informal rulemaking of a general policymaking nature. Sierra Club v.

Castle, 657 F.2d 298, 402 (D.C. Cir. 1981). However, in this case, NRC has not fallowed the requirements of informal notice and comment rulemaking. Nor is this a matter involving general policymaking. Since, as to Syncor, this is a licensing proceeding, the Home Box Office rule applies. In any event, as a matter of basic fairness, NRC officials were obligated in this case to prepare memorandum for the record which accurately reflected these communications.

development of and formed part of the basis of this Interim Final Rule.

Moreover, to the extent that this proceeding purports to amend Syncor's license, NRC regulations require that initial decisions must be based on information upon which all parties had the opportunity to comment. Specifically, the regulations governing the conduct of byproduct material license proceedings state:

An initial decision must be in writing and must be based only upon information in the record or facts officially noticed. The

• 10 C.F.R.

record must include all information submitted in the proceeding with respect to which all parties have been given reasonable prior notice and an opportunity to comment.

§ 2.1251. In promulgating this procedural rule, the Commission stated that as a matter of due process, "the decision resulting from the adjudication should not be based upon information about which the parties have not had notice and a chance to provide their views." 52 Fed. Reg. 20089, 20091 (May 29, 1987) .

. 5. NRC failed to provide the required 30 day comment period: before making the Interim Final Rule effective.

The APA requires that a substantive rule be published not less than 30 days before its effective date. 5 u.s.c. § 553(d) (1988).

The APA also has a good cause exception to this requirement upon which the NRC again relies in this case for the same reasons it claimed it could not afford interested parties an opportunity for notice and comment. Courts have relied upon the same basic standards used to determine the existence of good cause in the context of the notice and comment requirements in determining whether an agency may properly forgo the 30 day waiting period before a rule's effective date. Sannon v. United States, 460 F.

Supp. 458, 468 n. 41 (S.D. Fla. 1978). Accordingly, because the NRC has not established that good cause for suspending notice and comment rulemaking exists, it has not established that it can also suspend the APA's requirement that a rule be published at least 30 days in advance of its effective date.

There is sound public policy behind the requirements that the public be given time in which to prepare to comply with new rules.

The record-keeping requirements that are imposed upon nuclear pharmacies like Syncor are burdensome, new, and untested. Yet, failure to follow those requirements has been a violation since the August 23d publication of the Interim Final Rule. There is simply no way that a computerized record-keeping system such as Syncor's can be revised drastically overnight and still perform reliably.

The Interim Final Rule states, "In view of the interim nature of this rulemaking, comments will be welcome at any time during the three year period." 55 Fed. Reg. 34513 (Aug. 23, 1990).

Opportunity to comment after promulgation of a regulation cannot substitute for notice and an opportunity to comment beforehand.

Mob'il Oil Corp. v. DOE, 610 F.2d 796 (Temp. Erner. ct. App. 1979),

cert. denied, 446 U.S. 937; United States Steel Corp. v. EPA, 649 F.2d 572 (8th Cir. 1981). Parties should be able to comment while rules are still in their "formative" stage, and not after minds have been made up. National Tour Brokers Ass'n v. United states, 591 F.2d 896, 901-902 (D.C. Cir. 1978); Sharon Steel corp.

v. EPA, 597 F.2d 377, 381 (3d Cir. 1979); National Ass*n of Farmworkers Organizations v. Marshall, 628 F.2d 604, 622 (D.c. Cir.

• 1980). Moreover, accepting comment for the life of the rule does not satisfy the requirement for a post-adoption comment period.

When a rule is adopted without notice and comment on the basis of the good cause exception, NRC's own regulations require that there be a 30-day post-enactment comment period, and that the Commission respond in the Federal Register to any comments filed. 10 C.F.R.

§ 2.804(e). Here, the NRC is accepting comment for three years, the intended life of the rule, which shows that the NRC has no intention of responding to comments or revising this rule during its lifetime.

B. THE RECORD-KEEPING REQUIREMENTS OF THE INTERIM FINAL RULE WILL HAVE A DIRECT AND NEGATIVE IMPACT ON NUCLEAR PHARMACIES.

The Interim Final Rule requires that nuclear pharmacies, as NRC byproduct material licensees, have a "written directive" from a physician in order to depart from the manufacturer's elution and preparation instructions for a particular patient, or patients, or for a radiopharmaceutical in the case of an imaging or localization study. 10 C.F.R. § 30.34(i) (1) (i), 55 Fed. Reg. 34513,- 34517 (Aug.

23, 1990) . The "written directive" is to include the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manufacturer's instructions for preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. Id. Despite the fact that the requirements of the rule are only effective for three years, the rule requires NRC licensees to keep the written directive and record of the number of prescriptions dispensed under the departure in an auditable form and available for inspection for 5 years. Id.

Syncor estimates that of the ten to twelve million imaging or localization studies performed each year, at least 10 to 20 percent involve deviations from the manufacturer's instructions.

Accordingly, Syncor believes the Interim Final Rule requires the industry to obtain at least 1 million to 2. 4 million "written directives" each year for the next three years and maintain at up to 7.2 million written directives for up to five years.

Because the Interim Final Rule states that a written directive may direct a departure not only for a particular patient but for patients or for a radiopharmaceutical, it is conceivable that a nuclear pharmacy could obtain a written directive from a physician covering more than one patient or covering the preparation of particular kinds of radiopharmaceuticals. However, the Interim Final Rule also requires that the nuclear pharmacy record the number of the prescription dispensed under the departure and keep this record in an auditable form. Therefore, the Interim Final

'!l

Rule requires some notation each time a radiopharmaceutical not prepared in accordance with the manufacturer' s instructions is dispensed.

Exceptions only to the timing of the record-keeping requirements are made by the Interim Final Rule. 7 If a delay in preparing the radiopharmaceutical in order to make a written directive would jeopardize the patient's heal th because of the emergency nature of the patient's medical condition, the nuclear pharmacy can have three working days in which to obtain the written directive. 10 C.F.R. § 30.34(i) (1) (ii). However, in this

' . ~ .

instance, the written directive must have a "notation regarding the 7

The preamble to the Interim Final Rule appears to suggest that commercial nuclear pharmacies can apply so their licenses will be amended to permit departures not covered by 10 C.F.R. § 30.34.

Specifically, the preamble states, "For situations not within the scope of the amended § 3 O. 3 4, a commercial nuclear pharmacy licensee may file an application to have its license amended to permit specific departures from the manufacturer's instructions for identified products." 55 Fed. Reg. 34513, 34516 (Aug. 23, 1990).

This suggestion, however, is in direct conflict with NRC' s procedural regulations. Under the informal adjudication procedures in material license proceedings, the regulations state:

Except as provided in paragraph (b) of this section, any regulation of the Commission issued in its program for the licensing and regulation of~

byproduct material may not be challenged in any adjudication subject to this subpart.

10 C.F.R. § 2.1239(a) (1990). Paragraph (b) states that the sole ground for a request for waiver or.exception must be that special circumstances exist so that application of the regulation to the subject matter of the proceeding would not serve the purposes for which the regulation was adopted. 10 C.F.R. § 2.1239(b).

Accordingly, Syncor does not perceive that it could obtain a license amendment which would reduce the record-keeping burdens imposed by the regulation.

emergency" as well as all of the other information required to be contained in a written directive. Id.

The sheer number of the records required by the Interim Final Rule will be costly for nuclear pharmacies to maintain. Moreover, syncor believes it will be extraordinarily expensive to obtain the records in a timely fashion. Today, a radiopharmaceutical, whether for therapeutic or diagnostic use, is ordinarily ordered by phone from a nuclear pharmacy which then dispenses the radiopharma-ceutical to the physician for administration to the patient under the physician's direction. In addition, it is not unusual for a_

physician to order a multi-dose quantity of a radiopharmaceutical to cover several unrelated, unidentified patients. For example, physicians will frequently schedule several patients to undergo the same diagnostic procedure and rather than use separate containers of the radiopharmaceutical for each patient, the physician will use a multi-dose container of the drug to administer to all patients.

By enacting the Interim Final Rule, NRC restricts phone orders for at least 10 to 20 percent of the radiopharmaceuticals dispensed by nuclear pharmacies. The Interim Final Rule will require the nuclear pharmacy to have the written directive on hand before compounding and dispensing the radiopharmaceutical to the hospital or physician. Syncor believes that this record-keeping burden could, therefore, double its operating costs.

The current practice of nuclear pharmacies in filling prescriptions received orally is sanctioned by state pharmacy and nuclear pharmacy laws and regulations. Moreover, FDA has evaluated this practice and has concluded it is acceptable as long as it is consistent with state pharmacy laws. See* FDA Nuclear Pharmacy Guideline: Criteria for Determining When to Register as a Drug Establishment (May 1984) , at 17-19. By the adoption. of the Interim Final Rule, NRC has worked a fundamental change in the practice of nuclear pharmacy as it currently exists.

The most troublesome aspect of the record-keeping requirement imposed by the Interim Final Rule is the possibility that nuclear pharmacies may be required. to "second guess" nuclear physicians when they prescribe radiopharmaceuticals for patients which are to be compounded in a fashion not described in the manufacturer's instructions or prescribe non-IND and non-NDA radiopharmaceuticals.

Generally, courts have held that pharmacists are required to exercise a high degree of care which a very prudent and cautious person would exercise under the same or similar circumstances.

Speer v. United States, 512 F. Supp. 670 (N.D. Tex. 1981), aff'd, 675 F.2d 100 (5th Cir. 1982). Because nuclear pharmacies are now required to have a written directive not only specifying the departure from the manufacturer's instruction but a statement of reasons for the departure, nuclear pharmacies may be required to assume an independent duty to warn patients and a duty to consult with physicians concerning the departure. syncor believes this would be an unwarranted intrusion into the doctor-patient relationship.

Some illustrations will demonstrate the problem created by the Interim Final Rule. First, assume a physician prepares a "written directive" for the nuclear pharmacy and the "written directive" states that the reason for the departure is that the radiopharmaceutical is cheaper. Is syncor obliged to consult the physician or not fill the prescription because the reason stated does not explain why the departure would obtain medical results not otherwise attainable or would reduce medical risk? What if the fact that the radiopharmaceutical is cheaper is described as a reason in addition to the physician's belief that the departure would obtain medical results not otherwise attainable and the patient receiving the radiopharmaceutical is harmed. Does the patient have a cause of action against the nuclear pharmacy for dispensing the radiopharmaceutical? What if a radiopharmaceutical is dispensed in an emergency and the physician fails to send the nuclear pharmacy a "written directive" that presents a reason for the departure from the manufacturer's instructions? Does the nuclear pharmacy have a duty to warn the patient? Syncor believes the Interim Final Rule will increase its professional liability risks because it may place nuclear pharmacies in an unwanted oversight position in these and other situations.

Syncor believes that the NRC' s record-keeping requirements are unnecessary. But even if they are thought to be necessary, syncor believes that the record-keeping burden of deviating from the manufacturer's directions should not be placed on the pharmacy, whose sole function is to fill the prescription. While requiring a pharmacy to keep these records may make it easier for NRC to audit compliance, it is the prescription that is being audited, not the filling of it. Although pharmacies are pervasively regulated in the public interest, a requirement that a physician's prescription detail the intended use of the product ordered is simply unheard of. Accordingly, nuclear pharmacies should not bear the burden of keeping records so that NRC can easily monitor the compliance of others.

V. CONCLUSION For the reasons and supporting authorities set forth above, the Commission is respectfully requested to stay the effectiveness of the pharmacy record-keeping requirements of the Interim Final Rule on the use and preparation of radiopharmaceuticals by byproduct material and medical use licensees. The Commission is also urged to reconsider those provisions, and, upon reconsideration, to revoke them.

Respectfully submitted, Baker & Hostetler 1050 Connecticut Avenue, N.W.

Washington, D.C. 20036 (202) 861-1500 Attorneys for SYNCOR INTERNATIONAL CORPORATION September 20, 1990 ED11 ALL-STATE LEGAL SUPPLY CO.. ONE COMMERCE DRIVE. CRANFORD. NEW JERSEY 07016 1

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- M!MOWDUM ,oR: Stewart D. Ebn1t1r 1 01rtctcr D1vh1on af R*ad1at1on Safet, and S1f1;u1rds, RI Dou9l11 M. coit1n1 Act1nt Director 01vi11on of R1d11tf0n Saft, 1nd S&f1;u1rd1, Ril Ch1rl11 E, Nort11u1, D1rtctor O1v1s1cn of R1d1&t1on Safet, and S1f19uards, RIII R1c~ard L. B1ng1rt, Dfr1ctor 01v1s1on of R1a11t10n S1fet, and S1fe9u1rd1* RIV Ross A. Sctra~c, Director D1v1s1on of Radiation S1f1t, and Safe;uaraa, RV

• FROM:

SUBJECT:

Richard E. Cunn1n;haa 1 D1r1ctor 01v1s1on of Indu1tr111 ind Med1cat Nuclear S1f1ty, NMSS NOTICE OF INTENT TO REASSESS NRC RE&ULATIOHS ANO POLICY ON BYPRODUCT RADICPHARJIIACEUTICA!.S S1v1r11 quest1on1 wh1ch ma, affect udicel cart havt been raised in r1c1nt corrtspo"dence between the NRC and others r1g1rd1n1 th1 human 1pp11e1t1an of byproduct m1t1r111 *. Spec1f1ca11y. questions rtQ&rd1ng tht 1cop1 of autl\or1ty of broad 11cens11s and nuc111, ph1rm1c11s h1v1 b11n raised 11 to whither non-IND and non*NDA rad1opftarm.caut1ca1s may be used 1n hu111n app11c1tion1, and, 1.f so, under what cond1t1on1. There 1s I long history on the subject of th*

r19u1at1on of tht mtd1cat u111 of radionuc11dtl ;o1ng back to 1t 1,ast a poltcy tt1t1m1nt 1ssued 1n 1979 and pa111b1y e1r111, whtn fDA 1s1u1111d respons1b111ty for ev1lu1t10n of rad1oph1rm1c1utfc11 s111ey and 1ffic11ncy.

NMSS 1s r1exam1n1n9 th* 111ues r11s1d 1n th1 r19u11tfons and po11~ st1t1~1nts in this regard and t,op11 to resolve them shortly, Pending ccmplttion of th1s r11x1m1n1t1on 1 111 propoltd tnforclffllnt 1ctfons on ihia matt1t, 1n,1ij,1n9 those invo1vfng v1011t1on1 1111111d at S1v1r1t,y Ltv1t1 IV and Y1 should b1 referred to this Division w1th a cow to the Off1ce of !ftforcemtnt btrort 111M1nc1 1n order to 1n1ur1 consistent int appropr11t1 a1sposit1on. Among tht 1ction1 NMSS 11 cans1dtr1n9 1r11x1mpt1ons and t~, 1dv111b11ity of amending th1 r1gul1t1ons.

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Richard E. CMnn1n9h1m 1 01r1ctor 01v1s1on of Indu1tr111 anQ Med 1Cl 1 Nuclear Safety, NMSS cc: C. K1ffll'ler1r 1 GPA 8910190072 890605 PDR PRM 35-09 PDR

ALL-STATE LEGAL SUPPLY CO. ONE COMMERCE DRIVE. CRANFORD. NEW JERSEY 07016 ED 11 202-429-5120 American The Society College of *89 Ju:~ _8 p 5 :28 of Nu~l~ar Nuclear Medicine Physicians June , , lJd!:i Secretary of the Commission U.S. Nuclear Regulatory Commission Washington, DC 20555

Dear Mr. Secretary:

On behalf of the over 12,000 members of the American College of Nuclear Physicians and the Society of Nuclear Medicine, we respectfully submit the enclosed Petition for Rulemaking Change to Amend 10 CFR Part 35 to Correct Regulatory Incompatibility and Permit the Traditional Practice of Nuclear

, Medicine and Nuclear Pharmacy. By letters of May 19, 1989, the College and Society alerted each Commissioner that this petition would be filed in the near future. . ~

~ g Thank y~ forzour Jrompt consideration of our petition.

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Sincerely,

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~ ~? Barbara Y. Croft, Ph.D.

E. William Amn, &D. -

President P' ii President Ame~ican College of Nu~ear Society of N,i:l<nr Medicine Physicians cc: All Commissioners JJ SJ 0 8910190002 890605 I PDR PRM 35-09 PDR

~------------------------

PETITION FOR RULEMAKING TO AMEND 10 CFR PART 35 TO CORRECT REGULATORY INCOMPATIBILITY AND PERMIT THE TRADITIONAL PRACTICE OF NUCLEAR MEDICINE ANO NUCLEAR PHARMACY Submitted by:

The Society of Nuclear Medicine 136 Madison Avenue New York, NY 10016-6760 and The American College of Nuclear Physicians 1101 Connecticut Avenue, N.W.

Suite 700 Washingtrin, DC 20036 For further information contact:

Carol S. Marcus, Ph.D., M.D.

Director, Nuclear Medicine Outpatient Clinic Building A-13 Harbor - UCLA Medical Center 1000 W. Carson Street Torrance, CA 90509 (213) 533-2845

I. Grounds for and interest in the action requested.

A. The Society of Nuclear Medicine (SNM) and the American College of Nuclear Physicians (ACNP).

SNM and ACNP are comprised of over 12,000 individuals who partici-pate in the medical use of byproduct material. Physician members supervise the preparation and administration of radiopharmaceuticals to diagnose and treat patients. Technologist members administer radiopharmaceuticals and perform clinical procedures under the direction and supervision of an authorized user physician. Nuclear pharmacist members reconstitute radiopharmaceutical kits, compound radiopharmaceuticals, and dispense radiopharmaceuticals for medical use.

All of our members are interested in the requested action because under current NRC regulations, they cannot appropriately practice their professions. Specifically, authorized user physicians cannot prescribe certain radiopharmaceuticals or routes of administration for optimal patient care, even though they are otherwise permitted to do so by the U.S. Food and Drug Administration (FDA) and by their state medical licenses. Nuclear pharmacists have been disenfran-chized as a professional entity. Although their state licenses authorize them to prepare radiopharmaceuticals for patient adminis-tration upon receipt of a prescription by an authorized user physi-cian, current NRC regulations severely restrict their activity generally to rigid reconstitution of standard kits and dispensing doses of radiopharmaceuticals distributed by manufacturers. As with nuclear physicians, activities of nuclear pharmacists that are per-mitted by the FDA and the states are not allowed under NRC regula-tions. Nuclear medicine technologists reconstitute radiopharmaceu-ticals and perform clinical procedures under the supervision of an authorized user physician. Their normal professional activities are curtailed by the limitations imposed on nuclear physicians and phar-macists.

II. Statement in support of the petition.

A. Issues involved.

1. NRC's regulations. NRC's regulations in 10 CFR Part 35.

"Medical Use of Byproduct Material", restrict authorized user physicians to the use of radiopharmaceuticals for which the FDA has accepted a "Notice of Claimed Investigational Exemption" (IND) or approved a "New Drug Application" (NOA) (10 CFR 35.100 at Add. Ii, 10 CFR 35.200 (a) at Add. Iii, and 10 CFR 35.300 at Add. 1111). The regulations do not allow medical use licensees to modify methods of reconstituting reagent kits to meet specific clinical needs encountered in the practice of medicine (see 10 CFR 35.200 (b) at Add. Iii). Moreover, licensees are required to elute 99-Mo/99m-Tc generators and prepare reagent kits in accordance with the manufacturer's instructions. The regulations do not allow a physician to use radiopharmaceuticals to treat diseases that are not listed in the package insert (see l

10 CFR 35.300 at Add. liii}. Although NRC's regulations in 10 CFR Part 32, "Specific Domestic Licenses to Manufacture or Transfer Certain Items Containing Byproduct Material" appear to allow nuclear pharmacists to distribute radiopharmaceuticals that are not regulated or approved by FDA (see 10 CFR 32.72 (a}(2}(ii} at Add. liv and 10 CFR 32.73 (a)(2)(ii) at Add. Iv),

but this allowance is withdrawn in the radiopharmacy license document (see Add. II).

2. Interaction with other regulations.

(a) History. Radiopharmaceuticals for medical use were first made with Ernest Lawrence's cyclotron in Berkeley in 1937.

After World War II and the development of nuclear reactors, most radiopharmaceuticals were made from byproduct material. Today, about 75% of nuclear medicine procedures involve byproduct radiopharmaceuticals; the remainder involve accelerator-produced material.

At the time the Atomic Energy Act of 1954 was passed, the FDA did not regulate radioactive drugs (although they had the mandate to do so). FDA began regulating accelerrtor-produced radiopharmaceuticals in 1968, and began regulating byproduct radiopharmaceuticals in 1974. Until that time, the preparation and use of byproduct radiopharmaceuticals had been regulated solely by the AEC. As years passed, FDA continued to refine its role in reviewing, approving, and regulating radiopharmaceuticals for research and clinical purposes. This regulatory evolution continues to the present.

(b) FDA's regulatory framework today for radiopharmacy.

Although the practices of medicine (see Add. !Iii) and pharmacy (see Add. IIIii, Add. IV, and Add. V} are exempt from FDA's manufacturing and distribution regulations by congressional mandate, they are definitely not exempt from FDA's regulations forbidding misbranding and adulteration (see Add. XI). In addition, the FDA is the enforcement arm of the drug quality standards published in the United States Pharmacopoeia (USP). In other respects, FDA now regulates all radiopharmaceuticals, whether made by manu-facturers, nuclear pharmacists or their designees in medical institutions or in centralized radiopharmacies, or nuclear physicians or their designees. FDA has the federal authority to regulate all research and clinical use of radioactive drugs directly or indirectly.

Because of the manufacturing and distribution exemption for pharmaceuticals (including radiopharmaceuticals) prepared under state laws regulating the practice of medicine and pharmacy, commercial New Drug Applications (NDA's) are not granted for these drug preparations. Nevertheless, it should be appreciated that these drugs are still recognized and regulated by FDA.

2

One mechanism of FDA radiopharmaceutical regulation is the Investigational New Drug Application (IND). An IND from a commercial manufacturer is very carefully scrutinized by FDA in terms of all aspects of manufacturing, chemistry, and the details of the clinical trial protocols. There are several well-defined phases of clinical trials designed to minimize risk to human subjects and maximize needed drug information. Physician sponsored IND's are handled with more flexibility because they involve fewer human subjects and*are for research purposes. These physicians do not become commercial manufacturers or distributors of the drugs they study. The actual clinical trials of both commercial IND's and physician-sponsored IND's take place in medical institutions which also provide Institutional Review Board (!RB) and Radiation Safety Committee oversight.

When sufficient supporting information is obtained under the various phases of a commercial IND, the manufacturer submits an NOA. When this is approved, the manufacturer may sell his drug to any appropriately licensed user.

The only FDA regulatory mechanisms recognized by NRC are the IND and NOA.

(c) Incompatibility of NRC's regulations with FDA's statute and other standards. Part 35 directly conflicts with FDA's regulatory framework because except for physician sponsored INO's, Part 35 only allows the use of radiopharmaceuticals prepared under the portion of FDA regulations devoted to manufacturers with nationwide distribution. Even in this limited scope, NRC's regulations contort the concept, intent, and application of FDA's designations "accepted" and "approved" (see Add. !Iii).

NRC's regulations also conflict with the laws of 50 States regulating the practices of medicine (see Add. VI) and pharmacy (see Add. Viii and ii). They also conflict with the Hippocratic Oath (see Add. VIII), which provides the ethical foundation for Western medicine, and the spirit of NRC's org*anic statute (see Add. IX).

3. Sunmary of issue. FDA regulates all clinical and research use of radiopharmaceuticals in many ways. Approved INO's and NDA's are only two of them. However, they are the only two avenues recognized in 10 CFR Part 3S. Part 35 needs to be amended to recognize all the mechanisms that FDA uses to authorize the use of a radiopharmaceutical. NRC's current regulations that iden-tify which radiopharmaceuticals may be used, how they may be prepared, and for which purposes they may be administered are in conflict with the long-standing regulatory framework established by other Federal and State regulatory agencies.

3

\

4. Purkw~~- Th~ purpose of this petition ror rulemaking is to amend NRC's regulations to allow the use of radiopharmaceuticals in accordan:e with FDA requirements. Acceptance of this peti-tion would, consistent with FDA jurisdiction and regulations and state law: allow nuclear physicians and nuclear pharmacists to reconstitute non-radioactive kits differently from the method recommended by the manufacturer; allow nuclear physicians and nuclear pharmacists to prepare radiopharmaceuticals whose manu-facture and distribution are purposefully not regulated by FDA; and permit nuclear physicians to determine appropriate diagnos-tic and therapeutic applications of radiopharmaceuticals, as is their professional obligation.

III. Petitioner's views and arguments.

A. Patient care.

The delivery of quality patient care often requires that a physician modify an existing clinical procedure, create a new clinical proce-dure, or use an existing product for an application not described in the package insert. Some examples are provided below.

Example 1. Modification of an existing diagnostic clinical procedure. Tc-99m-albumin colloid is approved by the FDA as a liver and spleen imaging agent. The colloid particles are phagocytized by cells of the reticuloendothelial system which reside in these organs. If the kit is reconstituted using a modification of the manufacturer's instructions, high specific activity particles may be produced. When these are incubated with the patient's white blood cells, the particles are phagocytized, resulting in radiolabeled white blood cells. These labeled cells are then injected into the patient, where sites of infection and inflammation are imaged with a gamma camera. This procedure is useful in diagnosing appendicitis, for example (see Add. Xi). Compared to alternative procedures for its purpose, the Tc-99m-albumin colloid method results in substan-tially less radiation dose to the patient.

• • Example 2. Creation of a new clinical procedure: An angiographer uses bits of gelfoam to occlude intractably bleeding varices. Gel-foam is radiolucent, so he cannot use x-rays to locate the particles once they have been introduced into a blood vessel. The radiopharm-acist can label the gelfoam with Tc-99m so that the angiographer can use nuclear medicine imaging to verify the final destination of the particles. The radiopharmacist works out a convenient labeling method so that he can prepare the labeled particles quickly on nprescription ordern from the physician (see Add. Xii).

Example 3. Creation of a new clinical procedure: A group of patients with a variety of underlying disorders needs frequent red cell transfusions. These patients develop multiple minor group antibodies, and traditional in vitro crossmatch methods to evaluate potential blood transfusions are often unsatisfactory. The immuno-hematologist requests an in vivo crossmatch using radiolabeled potential donor red cells. (This method is more accurate.) The radiopharmacist makes lyophilized stannous citrate kits to be used 4

for labeling donor red c~lls with Tc-99m. These will be injected into the intended recip;ent and their survival determined by dilu-tion measurements {see Add. Xiii).

Example 4. Use of an existing product for a therapeutic application not described in the package insert. A hematologist asks a nuclear medicine physician to administer P-32 sodium phosphate to a patient with documented thrombocythemia vera. The case is somewhat atypical because it is not associated with any other myeloproliferative dis-order. Although P-32 has been used to treat this category of disease since 1937, this particular abnormality is not listed on the package insert {see Add. Xiv).

Under NRC's regulatory framework, example I is contrary to 10 CFR 35.200 (b) (see Add. Iii), example 2 is contrary to 10 CFR 35.200 (a) (see Add. Iii), example 3 is contrary to 10 CFR 35.100 (see Add.

Ii), and example 4 is contrary to 10 CFR 35.300 (see Add. Iiii) and recently occurred in a hospital under NRC license. The nuclear physician insisted on treating his patient, and an emergency license amendment was requested. As such an amendment would be contrary to the regulations, NRC made a determination that the patient's diagno-sis was sometimes observed as an element of an indication listed on the package insert. The rulemaking change discussed in this peti-tion would completely relieve the NRC of its role of providing man-datory medical consultative services in life-threatening cases.

It is essential to point out that all four of the above clinical procedure examples are recognized and purposefully permitted under the Federal Food, Drug, and Cosmetic Act and by the States under the various laws regulating the practices of medicine {see Add. VI) and pharmacy (see Add. 1*11i and Add. Viii). At the Federal level, this

• broad authorization is not merely a matter of regulatory discretion; the exemption for medicine and pharmacy was directed by Congress in the Food, Drug and Cosmetic Act {see Add. Xi). Thus, we believe the NRC's stringent regulations for the medical use of byproduct material are at odds with Congress' clearly stated mandate to the lead Federal drug regulatory agency. They are also at odds with state laws under which all other aspects of the physician-pharmacist-patient relationship are regulated.

B. Medical Research.

Medical research is often conducted at community hospitals in addi-tion to large, nationally known research centers that hold NRC or Agreement State specific licenses of broad scope. The large re-search centers typically develop whole new classes of radiopharma-ceuticals, quality control and quality assurance procedures to ensure their safe and effective use, and develop and refine proce-dures and equipment to prepare these radiopharmaceuticals and image their biodistribution in patients with various pathologies. They also participate in research under colilllercial and physician-sponsored investigational new drug applications (INO's) and other research categories to be described below. Community hospitals may participate in regional or nationwide research programs, use 5

approved drugs for additional applications that may become estab-lished clinical procedure, as described in scientific literature, modify approved drugs to assess their utility in new clinical appli-cations, and conduct basic research that may lead to development of new radiopharmaceuticals and nuclear medicine procedures.

The FDA has established a complete regulatory framework to provide for oversight of all these activities.

Specialized staff at the FDA review physician-sponsored and manufac-turer-sponsored clinical trials before they are begun. The review team includes nuclear and other physicians, pharmacists and nuclear pharmacists, dosimetrists, statisticians, pharmacologists, chemists, radiochemists, etc. The purpose of this review is to ensure that the clinical procedure is as safe as possible, and that the clinical trial design is of sufficient quality to allow for scientific evalu-ation of the results. NRC regulations allow all authorized user physicians to participate in these IND clinical trials (see 10 CFR 35.100 at Add. Ii, 10 CFR 35.200 at Add. Iii, and 10 CFR 35.300 at Add. Iiii).

However, certain research protocol categories are exempt from the need to file IND's. Many of these involve the investigation of an approved drug for an unapproved indication and/or by an unapproved route of administration. To provide for regulatory oversight of such research, hospital-based Institutional Review Boards (IRB's) are established under HHS regulations (see 45 CFR 46.107 at Add.

XI). Their specif1c purpose is to "ascertain the acceptability of proposed research in terms of institutional co11111itments and regula-tions, applicable law, and standards of professional conduct and practice." FDA requires IRB approval of research projects that FDA regulates. As a matter of ethics and civil law, hospitals require that all research projects be authorized and monitored by their IRB's. If radioactive drugs are involved, the IRB will require approval of the institution's Radiation Safety Committee as well.

This category of research, that which does not require an approved IND, is nevertheless not permitted by NRC regulations. This impedes the development of improved medical care, and is also a source of great annoyance and frustration to the FDA, which is constantly 6adgered by investigators demanding IND's they do not even need except to satisfy NRC's requirement. At a recent forum, an FDA spokesman publicly stated that FDA had even granted some unnecessary IND's only to aid investigators who needed to comply with NRC regu-lations.

A third administrative category of medical research involves the use of rad1olabeled compounds for metabolic studies. Generally speakingt these drugs are not destined for diagnostic or therapeutic use except for the radiopharmaceuticals used in positron emission tomography (PET). To provide regulatory oversight of such research projects, FDA charters Radioactive Drug Research Committees (RDRC's) under 21 CFR 361.1 (see Add. XII). The purpose of the RDRC review is to ensure that the radiation absorbed dose to human subjects is ALARA and less than 5 rem (i.e., annual or total dose commitment) to 6

whole body, active blood-f?rming organs, lens of the eye, and gonads, and that the quant1ty of substance t~be administered is known not to cause any toxic effects in humans. Approval of appro-priate proposals involving more than 30 subjects must be promptly reported to FDA. These proposals must also be approved by the IRB and the Radiation Safety Committee. NRC regulations do not permit this category of research to be carried out, thereby impeding the development of basic science information. Although NRC does provide line-item authorizations for such research on community hospital specific licenses of limited scope, the public health and safety basis for the need of the applicant to specifically request this authorization is not apparent.

An incipient problem exists with biologicals used for research, such as radiolabeled antibodies. Although biologicals, like drugs, have approved IND's for investigational use, when biologicals are even-tually approved for general use they do not have approved new drug applications (NDA's), as do drugs. They have product license appli-cation approvals (PLA's). NRC regulations do not allow use of PLA's; only IND's and NDA's.

A very serious problem exists with the interpretation of 10 CFR Part 35 as regards medical institutions that possess specific licenses of broad scope (see Add. XVi and vii). Although the Statements of Consideration appear to leave :road licensees relatively unchanged by the revision (see Add. XVi), in practice NRC has sought to signi-ficantly limit the necessary activities of these institutions. NRC has removed the traditional and essential power of the Radiation Safety Conmittee to approve research and clinical uses of radiophar-maceuticals and has denied the traditional rights of the practice of nuclear medicine and nuclear pharmacy to these institutions ~swell.

If this trend continues, the concept of the broad license will end in NRC States and many Agreement States as well because of NRC precedent. At the present time, this situation is occurring in California and appears to be unjustified and inappropriate. Regula-tions pertaining to broad licensees need to be clarified.

The contents of Addendum XV have been assembled to show a progres-sion of interpretations of Part 35 that led inevitably to crippling restrictions on the broad medical license. An example of such a restricted license appears as Add. XVvi. NRC does not appear to have set a determined course to destroy this license concept. The contrary is probably closer to the truth. What appears to have happened is that a straightforward interpretation of part 35 logi-cally had to lead to this unfortunate state of affairs. The problem is Part 35 itself, not its interpretation.

It is to NRC's credit that when it became aware of the impact of its interpretation of Part 35 on broad medical licensees, the memo of Add. XViv was sent to all regions {and all Agreement States). After thorough consideration of this and related problems, NRC staff determined that the best course of action was to change Part 35.

This Petition is the result of that decision.

7

C. Economy.

Instructions and suggestions for compounding many radio~harmaceu-ticals are provided in the scientific and professional literature.

The actual acts of compounding and administration are authorized under state laws regulating the practices of medicine and pharmacy.

However, NRC regulations forbid the act of compounding except for the very limited act of reconstituting reagent kits in accordance with manufacturer's instructions. The only radiopharmaceuticals permitted are those that have accepted IND's and approved NDA's.

The act of radiopharmaceutical compounding, as described in state and FDA regulations, is not recognized by NRC; this effectively disenfranchises the key professional practitioners, the nuclear pharmacists. The nuclear pharmacist, who is permitted in 10 CFR 35.900 (a)(S) to be the Radiation Safety Officer, is nevertheless not entitled to practice his primary profession. Certification by the Board of Pharmaceutical Specialties in Nuclear Pharmacy is recognized in all 50 States, but NRC does not recognize the profes-sional practice of nuclear pharmacy. This needs to be rectified.

Many radiopharmaceuticals could be prepared by state-licensed nuclear pharmacists or nuclear physicians or their designees at lower cost or higher quality than for commercially available r4Qio-pharmaceuticals. Or, radiopharmaceuticals could be prepared that are not commercially available at any price but may be used for a nuclear medicine procedure which is economically competitive com-pared with an alternative procedure. This issue has gained in importance over the last few years because of health care cost con-tainment policies and government reimbursement schedules.

The Federal government is responsible for the health care costs of about 30 million patients each year, and most major third party payers incorporate the HCFA fee schedules. Each clinical procedure is reimbursed based on the professional component (the physician's fee) and the technical component (the cost of consumables, equipment amortization, service of technologists, computer scientists, radio-logical physicists, nuclear pharmacists, secretaries, receptionists, and overhead). In many cases the technical component barely covers the cost of the radiopharmaceutical of choice (see, for example, "thyroid imaging with single determination" at Add. XIII). Thus, the federal reimbursement schedule, coupled with NRC's requirement to use only NOA-approved radiopharmaceuticals, occasionally forces physicians to use radiopharmaceuticals that are not of choice. If NRC permitted the practice of nuclear pharmacy, this would allow for greater radiopharmaceutical flexibility and better and more economi-cal patient care. FDA has specifically approved the manufacture of cold kits by nuclear pharmacists (see Add. Illii and IV). NRC's refusal to permit this practice *is a severe regulatory contradic-tion.

D. Summary.

Regulatory incompatibility between 10 CFR Part 35 and FDA regula-tions and state pharmacy and medicine laws is causing serious problems in the optimal delivery of quality nuclear medicine care 8

~ l I

' )

and the implementation of nuclear medicine research. The adoptior of the amendments described below will rectify this unfortunate situation, and we urge NRC to carefully consider these much-needed changes.

IV. Text of Amendment.

The petitioners recommend that the NRC publish for public comment the following statements of consideration and proposed regulatory text:

A. Definitions.

Statement of Considerations. Certain definitions are needed to clarify the scope and purpose of the regulations. The definition of "medical institution" needs to be amended to permit appropriate flexibility and compatibility with FDA determinations. It is assumed that a clear statement of responsibility will be available for medical institutions composed of more than one entity where separate IRB's, Radiation Safety Committees, and licensing agree-ments exist.

Regulatory Text. 10 CFR 30.4 is amended by adding:

"Medical Research Use" means the intentional internal or external administration of byproduct material, or the radiation therefrom, to human subjects for research purposes.

Regulatory Text. 10 CFR 35.2 is amended by adding:

"Radiopharmaceuticaln means any drug or biologic that contains byproduct material.

"Medical Research Use" means the intentional internal or external administration of byproduct material, or the radiation therefrom, to human subjects for research purposes .

• Regulatory Text. 10 CFR 35.2 is amended by changing the definition of "medical institution" to read as follows:

"Medical Institution" means a single health care facility or a health care organization which may physically exist in multiple separate locations but is integrated through economic and/or manage-ment agreements. Several medical disciplines may be practiced in a medical institution.

B. Practice of pharmacy, practice of medicine, and medical research.

Statement of Considerations. To avoid unnecessary duplication or conflict with state and other Federal regulations that govern the practice of pharmacy, the practice of medicine, and medical research, the NRC regulations should be modified. The modifications should permit the use of radiopharmaceuticals compounded under state pharmacy and medicine laws. The NRC regulations should also be_

modified such that the licensee is required to comply with appl,-

9

cable Flr,. r"egulations. Because of the fact 1.nat state and FDA laws and regulations are subject to change and to new interpretations, and resultant policy changes, NRC should not attempt to itemize these frameworks within its own requirements. It becomes the licensee's responsibility to know and abide by the appropriate state and Federal laws and regulations.

Regulatory Text. 10 CFR 35.100 is amended in its entirety to read:

(a) A licensee may use for medical use any byproduct material in a radiopharmaceutical and for a diagnostic use involving measurements of uptake, dilution, or excretion in which:

(1) The radiopharmaceutical is manufactured and distri-buted in accordance with the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, or:

(2) The radiopharmaceutical is manufactured. prepared, propagated, compounded, or processed under an exempt category of Section 510(g) of the Federal Food, Drug and Cosmetic Act.

(b) A medical institution licensee may use for medical research use any byproduct material in a radiopharmaceutical and for a use involving measurements of uptake, dilution, or excre-tion if its use has been approved by the Radiation Safety Committee (RSC) and the Institutional Review Board (IRB) chartered in accordance with 45 CFR Part 46.

Regulatory Text. 10 CFR 35.200 is amended in its entirety to read:

(a) A licensee may use for medical use any byproduct material in a radiopharmaceutical and for a diagnostic use involving imaging in which:

( 1) The radiopharmaceutical is manufactured and distri-buted in accordance with the Federal Food, Drug,*and Cosmetic Act and the Public Health Service Act, or:

(2) The radiopharmaceutical is manufactured, prepared, propagated, compounded or processed under an exempt category of Section SlO(g) of the Federal Food, Drug, and Cosmetic Act.

(b) A medical institution licensee may use for medical research use any byproduct material in a radiopharmaceutical and for a use involving imaging if its use has been approved by the RSC and the IRB chartered in accordance with 45 CFR Part 46.

Regulatory Text. 10 CFR 35.300 is amended in its entirety to read:

(a) A licensee may use for medical use any byproduct material in a radiopharmaceutical and for a therapeutic use in which:

10

l (1) The radiopharmaceutical is manufactured and distri-buted in accordance with the Federal Food, Drug, and Cosmetic Act and the Public Health Service Act, or:

(2) The radiopharmaceutical is manufactured, prepared, propagated, compounded, or processed under an exempt category of Section SlO(g) of the Federal Food, Drug, and Cosmetic Act.

(b) A medical institution licensee may use for medical research use any byproduct material in a radiopharmaceutical for a therapeutic use if its use has been approved by the RSC and the IRB chartered in accordance with 45 CFR Part 46.

C. NRC licenses.

Statement of Considerations. Licenses issued to date under 10 CFR Part 35 only authorize medical use. To eliminate the administrative burden of amending all those licenses to allow for medical research use, the NRC will allow any medical institution licensee to also use byproduct material for medical research use.

Regulatory Text. 10 CFR 35.11 is amended by adding a new paragraph

( C} :

(c) Any medical institution licensed to use byproduct material for medical use as described in sections 35.100, 35.200 or 35.300 may also use byproduct material for medical research use described in the sections for which it is licensed.

This authorization supersedes any license condition iss~ed before (insert effective date).

D. Suppliers.

Statement of Considerations. To allow the practice of institutional nuclear pharmacy, the section that describes permissible sources of radiopharmaceuticals must be expanded.

Regulatory Text. 10 CFR 35.49 is amended by changing the current paragraph (c) regarding teletherapy sources to paragraph (d), and inserting a new paragraph (c):

(c) Byproduct material in radiophannaceuticals compounded by or under the supervision of a state-licensed nuclear pharma-cist or nuclear medicine physician if such radiopharmaceu-ticals are manufactured, prepared, propagated, compounded, or processed under an exempt category of Section SlO(g) of the Federal Food, Drug, and Cosmetic Act.

E. Free-standing Radiopharmacies.

Statement of Considerations. The NRC licenses free-standing radio-pharmacies to distribute radiopharmaceuticals, but typically requires that they only distribute FDA-approved radiopharmaceuticals 11

that have been reconstituted in accordance with the manufacturer's instructions. The NRC must amend these licenses to allow free-standing radiopharmacies licensed under 10 CFR 32.72 and 10 CFR 32.73 to also compound radiopharmaceuticals. This must be accom-plished by licensing action because those licenses have a clause that states that if the license document is more restrictive than the regulation, the license document takes precedence. Those licenses will be amended by NRC, without charge to the licensee, to:

remove the requirement to reconstitute radiopharmaceuticals in accordance with the manufacturer's instructions, and allow the com-pounding of radiopharmaceuticals under the practice of pharmacy regulations in accordance with requirements of the Food and Drug Administration and applicable State requirements. In the event of any disciplinary action by NRC, the applicable State Board of Pharmacy will be alerted.*

F. Specific Licenses of Broad Scope for Medical Research Use.

Statement of Considerations. In order to eliminate confusion regarding the conduct of medical research use under a specific license of broad scope, it is advisable to amend portions of Part 33.

Regulatory Text. 10 CFR 33.11 (a) is amended to read as follows:

10 CFR 33.11 Types of specific licenses of broad scope.

(a) A "Type A specific license of broad scope" is a specific license authorizing receipt, acquisition, ownership, possession, use, and transfer of any chemical or physical form of the byproduct material specified in the license, but not exfeeding quantities specified in the license, for purposes autnorized by the Act. The quantities specified are usually in the multicurie range. Applicants that are medical institutions may conduct medical research use in addition to conducting research and development as defined in 10 CFR 30.4.

Regulatory Text. 10 CFR 33.13 (c)(3) is amended by adding a new paragraph (iv) as follows:

10 CFR 33.13 Requirements for the issuance of a Type A specific license of broad scope.

An application for the issuance of a Type A specific license of broad scope will be approved if:

12

(3) The establishment of appropriate administr~tive proce-dure to assure:

(i ) * * *

(i i ) * * *

(i i i ) * * *

(iv) Review, approval, and recording by the Radiation Safety Committee and the Inst itut i ona l Review Board of the safety and ethics of proposed uses involving medical research use prepared in accordance with paragraph (c)(3)(ii) of this section prior to use of the byproduct material.

Regulatory Text. 10 CFR 33.17 (a)(4) is amended to read as follows:

10 CFR 33.17 Conditions of specific licenses of broad scope.

(a) Unless specifically authorized pursuant to other parts of this chapter, persons licensed under this part shall not:

( 1) * * *

(2) * * *

(3) * * *

(4) Add or cause the addition of byproduct material to any food, beverage, cosmetic, drug, or other product designed for ingestion or inhalation by, or application to, a human being unless permitted by the license document to conduct medical research use.

13

ADDENDA I. NRC regulations.

i. 10 CFR 35.100 Uptake, Dilution, Excretion ii. 10 CFR 35.200 Imaging iii. 10 CFR 35.300

• Therapy iv. 10 CFR 32.72 Radiopharmacy

v. 10 CFR 35.73 Distribution vi. 10 CFR 35.11 License required vii. 10CFR35.49 Suppliers II. Sample free-standing radiopharmacy license (NRC) that only allows FDA products reconstituted in accordance with the manufacturer's instructions. NRC Task FC 410-4, August 1985, pp. 53-57.

III. Letter from Paula Botstein of FDA dated 10 June 88 to Carol Mateus

- explaining FDA's regulatory framework emphasizing that:

i. FDA permits the research and clinical uses of NDA-app-roved radiopharmaceuticals for unapproved indications, by unapproved routes of administration, and using kit reconstitution methods other than as described in the package insert. No IND is required. The FDA does not distinguish between diagnostic and therapeutic radiopharmaceuticals.

ii. FDA permits the practice of pharmacy.

IV. Letter from Robert West of FDA dated 16 March 87 to Arun Sukerkar stating that FDA permits the in-house manufacture of cold kits; V. FDA Nuclear Pharmacy Guideline: Criteria for determining when to register as a drug establishment. May, 1984. (Also known as the "Lavender Report".)

VI. Sample definition of the practice of medicine and related definitions. Corpus Juris Secundum 70:377-379; 393-394; 411-412, 1987.

VI I. Pharmacy

1. Sample description of the practice of pharmacy.

ii. Sample state radiopharmacy license.

VIII. Hippocratic oath.

IX. Atomic Energy Act of 1954: Caution against intrusion into medicine.

X. Documentation of Clinical Examples

i. Marcus CS, Kuperus JH, Butler JA et al.: Phagocytic labeling of leukocytes with Tc-99m-albumin colloid for nuclear imaging. Nuc. Med. Biol. 1],:673-682, 1988.

14

nenneman PL, Marcus CS, Butler JM et al.: Appendicitis:

Evaluation by Tc-99m-leukocyte scan. Ann. Emerg.

Med ..ll:111-116, 1988.

11. Conroy RM, Lyons KP, Kuperus JH et al.: New technique for localization of therapeutic emboli using radionuclide

. labeling. Am. J. Roentgenol. 130:523-528, 1978.

I iii. Marcus CS, Myhre BA, Angulo MC et al.: Radiolabeled red cell viability I. Comparison of Cr-51, Tc-99m, and In-111 for measuring the viability of autologous stored red cells.

Transfusion 27:415-419, 1987.

Marcus CS, Myhre BA*, Angulo MC et al.: Radiolabeled red c~ll viability II. Tc-99m and In-111 for measuring the viability of homologous red cells in vivo. Transfusion ll:420-424, 1987.

iv. Hollander L: Treatment of malignant blood disease with radioactive ph~sphorus. Chapter 29 of Blahd WH: Nuclear Medicine, Mcgraw-Hill, NY, NY, pp. 760-774, 1971.

XI. Federal Food, Drug, and Cosmetic Act, as amended.

i. Exemptions for pharmacy and medicine.

ii. Definition of a drug.

XII. Department of Health and Human Services Regulations for research involving human subjects.

XIII. Food and Drug Administration Regulations for Radioactive Drug Research Committees:, 21 CFR 361. 1.

• XIV. Marcus CS,: Radiopharmaceutical cost, procedure reimbursement, and radiation absorbed dose: the cost of quality nuclear medicine in America. Feb. 1989.

XV. NRC Limitation of Broad Licensees i .. Statements of Consideration ii. NRC correspondence prompted by Gerard C. Wong, Ph.D., of the Radiologic Health Branch, California.

iii. Letter from the President of the American Pharmaceutical Association to VADM Lando W. Zech, Jr., and the NRC reply.

1v. Memo from NRC to all regions (and also to Agreement States): Notice of intent to reassess NRC regulations and policy on byproduct radiopharmaceuticals.

v. Letter from Paula Botstein, M.D., FDA, to Richard E.

Cunningham, NRC.

vi. The first of a series of new "broad licenses" issued in California pursuant to XIVi.

vii. NRC correspondence prompted by Raymond C. Barrall, Director of Radiation Protection, Illinois.

15

. ~>OCKET NUMBER*pft tJ ~ 35 I HOPOSED RULE 3  %>

(?S FK 8.tr5!.3)

DOCKETED

'USNRC "90 AUG 17 P3 :57 NUCLEAR REGULATORY ,COMMISSION 10 CFR PARTS 30 and 35 RIN 3150-AD43

,9 Authorization to Prepare Radiopharmaceutical Reagent Kits and Elute Radiopharmaceutical Generators; Use of Rad iopharmaceuti ca ls for Therapy AGENCY: Nuclear Regulatory Commission.

ACTION~ Interim fina 1 rule with request for comment.

SUMMARY

The Nuclear Regulatory Commission (NRC) is issuing an interim final

• rule amending its regulations related to the preparation and the therapeutic uses of radiopharmaceuticals. This interim rule allows licensees who elute generators and prepare reagent kits to depart from the manufacturer's instructions for elution and preparation in the package insert (a part of the Food and Drug Administration (FDA) approved labeling) provided the licensees meet certain conditions and limitations. The interim rule also permits NRC licensees using byproduct material in a radiopharmaceutical for a therapeutic use to depart from the package insert regarding indications and method of administration if certain requirements are met. This amendment is necessary to allow health professionals to provide diagnostic or therapeutic medical results not otherwise attainable or to reduce medical risks to particular patients because of their medical condition while continuing to protect public health and safety adequately. The interim rule applies only to radiopharmaceuticals _ ./,

for which the FDA has approved a "New D:ug Application" (NDA). r*\8 1 1,S/qi)

DATES: Effective date: From [insert date of publication] to [insert date 3 years from the date of publication].

Comment closing date: In view of the interim nature of this rulemaking, comments will be welcome at any time during the three-year period.

ADDRESSES: Submit written comments and suggestions to the Secretary of the Co1TU11ission, U.S. Nuclear Regulatory Corrmission, Washington, DC 20555, Attention: Docketing and Service Branch. Hand deliver comments to 11555 Rockville Pike, Rockville, Maryland, between 7:45 a.m. and 4:15 p.m. on Federal workdays.

Copies of the regulatory analysis, environmental assessment, and the comments received on this rule may be examined at the Commission's Public Document Room at 2120 L Street, NW. (Lowei Level), Washington, DC. Single copies of the Regulatory Analysis are available from Dr. Anthony Tse, Office of Nuclear Regulatory Research, U.S. Nuclear Regulatory Commission, Washington, DC 20555.

FOR FURTHER INFORMATION CONTACT: Dr. Tse, see ADDRESSES heading, Telephone (301) 492-3797.

SUPPLEMENTARY INFORMATION:

I. Background.

A. Nuclear Medicine.

Radioactive materials are used in drugs in the field of nuclear medicine.

Drugs labeled with radioisotopes are known as radiopharmaceuticals. In diagnostic nuclear medicine, patients receive these materials by injection, inhalation, or oral administration. Physicians use radiation detection equipment to visualize the distribution of a radioactive drug within the patient. Using this technology, it is possible to locate tumors, assess organ function, or monitor the effectiveness of a treatment. An estimated 7 million diagnostic nuclear medicine procedures are performed in this country annually.

In therapeutic nuclear medicine, radiopharmaceuticals are administered to treat 2

various medical conditions (e.g., hyperactive thyroid). An estimated 30,000 therapeutic procedures are performed each year.

B. Regulatory Program and Policy Regarding Medical Use of Byproduct Materials. ,

In a policy statement, 11 Regulation of the Medical Uses of Radioisotopes, 11 published on February 9, 1979 (44 FR 8242), the NRC stated:

(1) The NRC will continue to regulate the medical uses 1 of radioisotopes as necessary to provide for the radiation safety of workers and the general public.

(2) The NRC will regulate the radiation safety of patients where justified by the risk to patients and where voluntary standards, or compliance with these standards, are inadequate.

(3) The NRC will minimize intrusion into medical judgments affecting patients and into other areas traditionally considered to be a part of the practice of medicine.

The NRC has the authority to regulate medical use to protect the health and safety of patients, but also recognizes that physicians have the primary responsibility for the protection of their patients. NRC regulations are e predicated on the assumption that properly trained and adequately informed physicians will make decisions in the best interest of their patients.

Under the Federal Food, Drug, and Cosmetic Act, as amended, the Food and Drug Administration (FDA) regulates drug research and the manufacture and sale 1 "Medical use," as defined in 10 CFR 35.2, means the "intentional internal or external administration of byproduct material, or the radiation therefrom, to human beings in the practice of medicine in accordance with a license issued by a State or Territory of the United States, the District of Columbia~ or the Commonwealth of Puerto Rico. 11 "Medical use 11 includes the diagnostic and therapeutic use of radiopharmaceuticals in the practice of nuclear medicine, but does not include in vitro diagnostic tests.

3

of drugs, including radiopharmaceuticals. FDA has regulated the safety and effectiveness of investigational radioactive drugs since 1975, when FDA revoked its 1963 exemption of radioactive drugs from the "Investigational New Drug"

{IND) regulation. The NRC withdrew from regulating radioactive drug safety and efficacy to avoid dual Federal regulation, but continues to regulate the radiation safety of workers, patients, and the public.

Each new drug approved for human use by the FDA, including radio-pharmaceuticals, has labeling approved by FDA that includes a description of the drug, its pharmacology, indications for use, contraindications, warnings, adverse reactions, dosage and administration, and other information. The labeling of certain drugs, including some radiopharmaceuticals, includes manufacturer's instructions that specify the method of preparation. FDA reviews and approves the information in the labeling to ensure that it accurately reflects the data on safety and effectiveness on which the drug approval is based. NRC has, in the past, relied primarily on FDA s1 determination of a drug's safety and effectiveness when it is prepared and used according to the approved labeling, which some NRC regulations refer to as the package insert, as one means of ensuring protection of the public health and safety.

NRC regulations in 10 CFR 35.200(b) require medical use licensees to prepare radiopharmaceuticals in accordance with the manufacturer's instructions in the package insert (a part of the FDA-approved labeling). Similar requirements are placed on commercial nuclear pharmacies through NRC license conditions. Regulations in 10 CFR 35.300, "Use of Radiopharmaceuticals for Therapy," require, among other things, that the licensees comply with the package insert instructions regarding indications and method of administration for the therapeutic use of radiopharmaceuticals.

II. Petition for Rulemaking Filed By The American College of Nuclear Physicians and the Society of Nuclear Medicine

(

On June 8,_1989, the NRC docketed as PRM-35-9 a petition for rulemaking dated June 5, 1989, which was filed by the American College of Nuclear Physicians and the Society of Nuclear Medicine (ACNP-SNM). The ACNP-SNM are composed of over/12,000 individuals who participate in the medical use of byproduct materials. Members include physicians, technologists, and nuclear 4

pharmacists. As characterized by the petitioners, the physicians supervise the preparation and administration of radiopharmaceuticals to diagnose and treat patients. Also, technologists administer radiopharmaceuticals to diagnose and perform clinical procedures under the direction and supervision of an authorized user physician. 2 Nuclear pharmacists reconstitute radiopharmaceutical kits, compound radiopharmaceuticals, and dispense radio-pharmaceuticals for medical purposes.

Among other things, 3 the petitioners requested that the NRC amend its regulations at 10 CFR 35, 11 Medical Use of Byproduct Material, 11 to recognize their appropriate practice of medicine and to allow (1) departures from the manufacturer's instructions for preparing diagnostic radiopharmaceuticals and (2) the use of radiopharmaceuticals for therapeutic indications and methods of administration not included in the package insert approved by the FDA.

The petitioners stated that, under current NRC regulations, members of the petitioning organizations believe they cannot appropriately practice their professions. The petitioners also stated that authorized use_r physicians cannot prescribe certain radiopharmaceuticals or routes of administration for proper patient care, even though they believe they are permitted to do so by the FDA and by their State medical licenses. According to the petitioners, nuclear pharmacists have been disenfranchised as a professional ~ntity because activities that they believe are permitted by the FDA _and by--the States are not allowed under NRC regulations. The petitioners stated that, although a nuclear

- pharmacist is authorized by State license to prepare radiopharmaceuticals upon receipt of a prescription by an authorized user physician, current NRC regulations severely restrict their activity. The petitioners believe that their professional activities are curtailed by the limitations imposed by the NRC on nuclear physicians and pharmacists.

A notice of receipt of the petition with a public comment period of 90 days was published in the Federal Register on September 15, 1989 (54 FR 38239).

The Federal Register notice set forth the petitioners' proposed amendments to 2 Whenever the term "authorized user physician 11 is used, it means the "authorized user" or the physician working under the supervision of the authorized user.

3 The NRC is working to resolve the remaining issues identified in the petition.

5

10 CFR Parts 30, 33, and 35, including the deletion of the restriction regarding the preparation of radiopharmaceuticals in§ 35.200{b) and the deletion of the restriction in§ 35.300, with respect to following the package insert instructions regarding indications and method of administration (54 FR 38240). The comment period closed on December 14, 1989, and 466 comment letters have been received.

Comments were received from many different sources such as hospitals, pharmacies, and medical associates. About 60 percent of the letters were similar to a form letter written for members of ACNP-SNM. These letters indicated agreement with the petition on all essential points. Fifteen percent of the comment letters were similar to a form letter written for the staff of Syncor International Corporation, also agreeing with the assertions in the petition. Twenty-five percent of the responses were letters from other individuals.

Most letters (99 percent) supported the petition and stated that the NRC should amend its regulations to relax its current restrictions on the practice of nuclear medicine and nuclear pharmacy. The majority of these letters did not provide specific supporting rationale. Some commenters provided rationale and examples of clinical cases that the commenters believe demonstrate how the relevant NRC regulations prevent physicians from providing proper care for their patients. The commenters stated that, although a licensee may request an exemption from specific requirements in the regulations on a case-by-case basis, this exemption process is time consuming and cumbersome. The commenters believe that a delay in order to obtain NRC approval for a particular departure from the package insert may, in some cases, jeopardize the patient's health.

Some examples of clinical cases the commenters provided are described below:

(1) Licensees are not able to use Tc-99m macroaggregated albumin with high specific activity and low particle concentration to safely perform lung scans for patients who have pulmonary hypertension because the ranges of specific activity and particle concentration given in the package insert would be exceeded.

(2) Licensees are not able to add ascorbic acid as an antioxidant to Tc-99m-DTPA, which would increase stability and enhance image quality, because NRC regulations do not permit departure from the manufacturer's instructions for reconstituting reagent kits.

6

(3) When evaluating potential blood transfusions, licensees are not able to perform in vivo crossmatching using potential donor red cells radiolabeled with Tc-99m because this is not provided for in the package insert.

(4) Licensees are not able to use P-32 sodium phosphate to treat primary Thrombocythemia because this use is not specified in the package insert.

III. Need for a Rule.

Information submitted by the ACNP-SNM in the petition for rulemaking and obtained during subsequent discussions with licensees indicates that the requirements in§ 35.200(b) regarding preparation of radiopharmaceuticals and in§ 35.300 regarding indications and method of administration for therapy procedures are preventing authorized user physicians from providing certain nuclear medicine clinical procedures. License conditions similar to

• § 35.200(b) currently placed on commercial nuclear pharmacies have the same effect. Fo,r some uncommon disease states or patient conditions, in order to provide proper patient care, it may be necessary to depart from the FDA-approved instructions to obtain diagnostic or therapeutic medical results not otherwise attainable or to reduce medical risks to particular patients because of their medical condition.

The NRC believes that continued application of these restrictions governing the preparation of radiopharmaceuticals and the indications and the method of administration for therapeutic use of radiopharmaceuticals would not permit proper patient care to be provided to some patients.

Under its 1979 Medical Use Policy Statement (44 FR 8242, February 9, 1979), the NRC stated that it would regulate the medical use of byproduct material in order to protect the health and safety of workers, patients, and the public. In general, NRC regulatory requirements are oriented *to ensure that the properly prepared radiopharmaceutical is administered to the correct patient as prescribed by an authorized user physician. Aside from the requirements in§ 35.200(b) and§ 35.300, other requirements in Part 35, such as the use of dose calibrators~ are intended to ensure that the patient receives the prescribed dose. NRC's regulations need to provide a balance between adequate controls and avoidance of undue interference in medical judgments.* the high level of public health and safety protection that accrues from following the FDA-approved instructions must be balanced with the need to 7

depart from those instructions to obtain diagnostic or therapeutic results not otherwise attainable or to reduce patient risk in some uncommon disease states or patient conditions in order to provide proper patient care.

The diagnostic use of radiopharmaceuticals is, in most cases, an area of inherently low radiation risk to patients (Policy Statement, 44 FR 8242; February 9, 1979). Although there are greater risks inherent in the use of therapeutic levels of radioactive drugs, in light of the information provided with and gathered subsequent to the petition, the NRC does not believe that limiting the therapeutic use of radiopharmaceuticals in all cases to only the indications and methods of administration specified in the package insert is justified. Moreover, as stated in its 1979 Policy Statement, the NRC.

recognizes that physicians have the primary responsibility for the protection of their patients. The Commission believes that basic decisions concerning the diagnosis and treatment of disease are a part of the physician-patient relationship and are traditionally considered to be part of the practice of medicine.

The NRC has made a determination that continued application of the subject requirements, without exceptions, may adversely affect the public health and safety because the delivery of proper patient care may require, in certain instances, that some radiopharmaceuticals be prepared and administered in a manner different from that stated in the FDA-approved instructions. The NRC has reviewed the information on nuclear medicine clinical procedures and believes that adequate protection of the public health and safety can be maintained while, at the same time, providing proper patient care. Hence, the NRC is issuing an interim final rule that permits, on the direction of an authorized user physician, departures from the manufacturer's instructions in preparing radiopharmaceuticals and departures from package inserts for indications and method of administration for therapeutic use, provided a proper record of the departure is made. These records will be examined by the NRC to determine whether to extend the interim period for the rule, make the rule permanent, or revise it based on the nature of, reasons for, and frequency of departures. The NRC will provide FDA the opportunity to review this information.

Because these amendments involve relief from restrictions which if left in place could have an adverse impact on public health and safety, and because the NRC has received and considered public comments on the petition for rulemaking, 8

good cause exists for omitting the notice of proposed rulemaking and the public procedures thereon as unnecessary and contrary to the public interest, and for making these amendments effective upon publication in the Federal Register without the customary thirty-day notice. This interim rule will terminate 3 years after the date of publication in the Federal Register.

IV. Future Agency Action.

This interim rule amending 10 CFR Parts 30 and 35 represents only one phase of NRC's resolution of the ACNP-SNM petition for rulemaking. During the 3-year period, the NRC may modify the interim rule or take other regulatory action it determines necessary to protect the public health and safety. Based on continued NRC analysis of the ACNP-SNM petition, the comments on the petition and on this interim rule, experience with the implementation of this interim rule, and other information, the NRC may propose amendments to this rule or to other provisions of 10 CFR Parts 30 and 35 as part of its resolution of all the issues raised in PRM-35-9.

V. Discussion.

§ 35.200 Use of radiopharmaceuticals, generators, and reagent kits for imaging

.and localization studies .

• The NRC believes that persons licensed by the NRC to elute gerierators and prepare reagent kits should not always be bound by the requirement specified in 10 CFR 35.200(b) to follow the manufacturer's instructions for radiopharmaceuticals for which the FDA has approved an NOA. They should not be bound if they have a written directive (e.g., prescription) made by an authorized user physician directing a specific departure for a particular patient, or patients, or for a radiopharmaceutical, and which includes (1) the specific nature of the departure, (2) a precise description of the departure, and (3) a brief statement of the reasons why the departure from the manufacturer's instructions would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. The NRC recognizes that the physician may face severe time constraints during an emergency; therefore, an exception has been provided 9

in§ 35.200(c). Under the exception, a written directive is not required before preparing the radiopharmaceutical if an authorized user physician

• determines that the delay in obtaining a written directive would jeopardize the patient's health~ The written directive together with a statement of the emergency determination must be prepared within 3 working days of the emergency administration. The written directive and a record of the number of patient administrations under each departure must be retained by the licensee for a period of 5 years and made available for NRC inspection.

This interim rule does not address departures from 11 Investigational New Drug 11 (IND) generator ~lution instructions or IND protocol directions for reagent kit preparation because the departures may compromise the scientific

• integrity of the clinical investigation. Therefore, licensees must continue to follow the IND generator elution instructions and IND protocol directions for reagent kit preparation.

§ 35.300 Use of radiopharmaceuticals for therapy.

For a radiopharmaceutical for which the FDA has approved an NDA, the amendments to§ 35.300 would permit a licensee, under certain circumstances, to use therapeutic radiopharmaceuticals for indications or a method of

• administration not specified in the package insert. Specifically, these uses would be permitted if an authorized user physician makes a record of the departure which includes the specific nature of the departure and a brief statement of the reasons why the departure would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. A record of the departures from indications and method of administration and a record of the number of patient administrations under each departure must be retained in an auditable form and be available for inspection for 5 years. If a kit or generator for a radiopharmaceutical for therapy were approved by FDA (through an NDA), this interim rule does not authorize departures from the manufacturer's instructions for eluting the generator or preparing the therapy kit.

10

§ 30.34 Terms and conditions of licenses.

Commercial nuclear pharmacies are licensed pursuant to 10 CFR Part 30, "Rules of General Applicability to Domestic Licensing of Byproduct Material."

These licensees are required by a license condition similar to§ 35.200(b) to elute generators and prepare reagent kits in accordance with the manufacturer's instructions. The NRC believes that authorized users obtaining radiopharmaceuticals from commercial nuclear pharmacy 'licensees should not be bound by this restriction in the commercial nuclear pharmacy license.

Therefore, the NRC is amending 10 CFR 30.34, "Terms and Conditions of Licenses, 11 to permit actions within the scope of those permitted by the new

§ 35.200(c). For situations not within the scope of the amended§ 30.34, a commercial nuclear pharmacy licensee may file an application to have its license amended to permit specific departures from the manufacturer's instructions for identified products.

Under the interim rule,. commercial nuclear pharmacy licensees would no longer be bound by the requirement in their licenses to follow the manufacturer's instructions for a radiopharmaceutical for which the FDA has approved an NDA if they have a written directive made by an authorized user physician directing a specific departure for a particular patient, or patients, or for a radiopharmaceutical, and which iricludes the specific nature of the departure, a precise description of the departure, and why the departure from the manufacturer's instructions would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. As in§ 35.200(c), there is an exception to the requirement for a written directive before preparing the radiopharmaceutical in an emergency situation if an authorized user physician determines that a delay in obtaining the written directive would jeopardize the patient's health. In this case, the commercial nuclear pharmacy licensee shall obtain the written directive from the authorized user physician within 3 working days of the prescribed departure. The directive must contain information regarding the emergency and a 11 other required i nforma ti on. Licensees sha 11 keep those records in an auditable form and available for inspection for 5 years.

These amendments to§ 30.34 take precedence over the restrictive conditions (i.e., on eluting generators and preparing reagent kits for NDA radiopharmaceuticals) in the licenses of commercial nuclear pnarmacies.

11

Therefore, those parts of the license conditions no longer apply during the 3-year period when the interim rule is in effect. This interim rule does not address departures from IND generator elution instructions or IND protocol directions for reagent kit preparation, thus licensees shall continue to follow the IND instructions.

Continuing Applicability of Regulatory Requirements.

The NRC notes that this interim rule does not relieve licensees from the requirements to comply with other applicable NRC, FDA, and other Federal or State regulations or NRC orders or license conditions concerning possession or use of byproduct material for medical use or other purposes as specified in 10 CFR Parts 30, 32, 33, and 35. Moreover, if a radioactive biologic receives a product license approval (PLA), this interim rule does not authorize departures from the manufacturer's instructions for preparing the biologic. In addition, if a kit or generator for a radiopharmaceutical for therapy receives an approved NDA, this interim rule does not authorize departures from the manufacturer's instructions for eluting the generator or preparing the therapy kit. Neither of these approvals exists at this time and neither is authorized by current regulations.

Radiation Safety Responsibilities of Medical Use Licensees.

NRC medical use licensees are required by§ 35.21 to appoint a Radiation Safety Officer (RSO) responsible for implementing the licensee's radiation safety program. The licensee is required, through the RSO, to ensure that radiation safety activities are being performed in accordance with approved procedures and regulatory requirements in the daily operation of the licensee's byproduct material program. Nothing in this rulemaking relieves the licensee from complying with the requirements of§ 35.21.

In accordance with 10 CFR 35.22, NRC medical institution licensees are required to establish a Radiation Safety Committee (RSC) to oversee the use of byproduct material. The duties of the RSC are specified in§ 35.22(b) and include reviews, on the basis of safety, of numerous aspects of a licensee's use of byproduct material. Nothing in this rulemaking relieves the licensee from complying with the requirements of§ 35.22.

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VI. Administrative Statements.

Finding of No Significant Environmental Impact: Availability The Commission has determined under the National Environmental Policy Act of 1969, as amended, and the Commission's regulations in Subpart A of 10 CFR Part 51 that these amendments are not a major Federal action significantly affecting the quality of the human environment and therefore an environmental impact statement is not required. This interim rule amends NRC regulations to permit licensees who elute generators and prepare reagent kits to depart from the manufacturer's instructions if those persons have a written directive made by an authorized user physician that requests a specific departure for a particular patient, or patients, or for a radiopharmaceutical. This directive must provide the specific nature of the departure, a precise description of the departu~e, and the reasons why the departure from the manufacturer's instructions would obtain medical results, diagnostic or therapeutic, not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. The amendment does not address departures from IND generator elution instructions or IND protocol directions for reagent kit preparation. The NRC is also modifying its regulations to permit, if certain requirements are met, the therapeutic use of radiopharmaceuticals without following the package instructions regarding indications and method of 4I administration. The interim rule does not affect the exemption in 10 CFR Part 20 for the intentional exposure of patients to radiation for the purpose of medical diagnosis and therapy.

Although the rule may cause some patients to be exposed to higher or lower levels of radiation than otherwise expected, those exposures would be given to obtain medical results not otherwise attainable or to reduce other risks to the patient. It should be noted that current requirements do not limit the radiation dose prescribed by the authorized user physician for either diagnosis or therapy. The amendments would not relieve licensees from meeting the requirements in 10 CFR Parts 20 and 35 that restrict radiation exposure to medical care personnel in the restricted area or to the general public in the unrestricted area, or radioactive effluent releases. It is expected that there would be no significant change, either increase or decrease, in radiation 13

exposure to the public or to the environment beyond the exposures currently resulting from delivering the dose to the patient.

The Environmental Assessment and Finding of No Significant Impact is available for inspection at the NRC Public Document Room at 2120 L Street NW.

(Lower Level), Washington, DC. Single copies of the Assessment are available from Dr. Tse (see ADDRESSES heading).

Paperwork Reduction Act Statement This final rule amends information collection requirements that are subject to the Paperwork Reduction Act of 1980 (44 U.S.C. 3501 et seq.). These

- requirements were approved by the Office of Management and Budget approval numbers 3150-0010 and 3150-0017.

Public reporting burden for this collection of information is estimated to average .05 hours5.787037e-5 days <br />0.00139 hours <br />8.267196e-6 weeks <br />1.9025e-6 months <br /> per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing the collection of information. Send conunents regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden, to the Information and Records Management Branch (MNBB-7714), U.S. Nuclear Regulatory Commission, Washington, DC 20555; and to the Desk Officer, Office of Information and Regulatory Affairs, NEOB-3019, (3150-0017 and 3150-0010), Office of Management

• - and Budget, Washington, DC 20503.

Regulatory Analysis The Commission has prepared a regulatory analysis for these amendments.

The analysis examines the benefits and impacts considered by the NRC. The regulatory analysis is available for inspection at the NRC Public Document Room at 2120 L Street NW. (Lower Level), Washington, DC. Single copies are available from Dr. Tse (see ADDRESSES heading).

The Commission requests public conunents on the regulatory analysis.

Comments are welcome at any time during the three-year period that the interim final rule is in effect. Conunents on the analysis may be submitted to the NRC as indicated under the ADDRESSES heading.

14

Backfit Analysis The NRC has determined that the backfit rule, 10 CFR 50.109, does not apply to these amendments because they do not involve any provisions that would impose backfits as defined in 10 CFR 50.109(a)(l).

List of Subjects 10 CFR Part 30 Byproduct material, Criminal penalty, Government contracts,

- Intergovernmental relations, Isotopes, Nuclear materials, Radiation protection, Reporting and recordkeeping requirements.

10 CFR Part 35 Byproduct material, Criminal penalty, Drugs, Health facilities, Health professions, Incorporation by reference, Medical devices, Nuclear materials, Occupational safety and health, Radiation protection, Reporting and recordkeeping requirements.

For the reasons set out in the preamble and under the authority of the

- Atomic Energy Act of 1954, as amended, the Energy Reorganization Act of 1974, as amended, and 5 U.S.C. 552 and 553, the NRC is proposing to adopt the following amendments to 10 CFR Parts 30 and 35.

PART 30 -- RULES OF GENERAL APPLICABILITY TO DOMESTIC LICENSING OF BYPRODUCT MATERIAL

1. The authority citation for Part 30 is revised to read as follows:

Authority: Secs. 81, 82, 161, 182, 183, 186, 68 Stat. 935, 948, 953, 954, 955, as amended, sec. 234, 83 Stat. 444, as amended (42 U.S.C. 2111, 2112, 2201, 2232, 2233, 2236, 2282); secs. 201, as amended, 202, 206, 88 Stat. 1242, as amended, 1244, 1246 (42 U.S.C. 5841, 5842, 5846).

Section 30.7 also issued under Pub. L.95-601, sec. 10, 92 Stat. 2951 (42 U.S.C. 5851). Section 30.34(b) also issued under sec. 184, 68 Stat. 954, as 15

amended (42 U.S.C. 22~4). Section 30.61 also issued under sec. 187, 68 Stat.

955 (42 u.s.c. 2237).

For the purposes of sec. 223, 68 Stat. 958, as amended (42 U.S.C. 2273);

§§ 30.3, 30.34(b),(c), (f), (g), and (i), 30.41(a) and (c), and 30.53 are isiued under sec. 161b, 68 Stat. 948, as amended (42 U.S.C. 2201(b)); and

§§ 30.6, 30.9, 30.34{g), 30.36, 30.51, 30.52, 30.55, and 30.56(b) and (c) are issued under sec. 1610, 68 Stat. 950, as amended (42 U.S.C. 2201(0)).

2. In § 30.34, paragraph (i) is added to read as follows:

§ 30.34 Terms and conditions of licenses.

(i)(l) From [insert date of publication] to [insert date 3 years from the.

date of publication], each licensee eluting generators and processing radioactive material with diagnostic reagent kits for which the Food*and Drug Administration (FDA) has approved*a 11 New Drug AppJication 11 (NDA) may depart from the manufacturer's elution and preparation instructions (for radiopharmaceuticals authorized for use pursuant to§ 35.200) provided that:

(i) The licensee has a written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radiopharmaceutical, and which includes the specific nature of the departure, a *precise description of the departure, and a brief statement of the reasons why the departure from the manufacturer's instructions for preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. The licensee shall keep the written directive and record of the number of prescriptions dispensed under the departure in an I

auditable form and available for inspection for 5 years; or (ii) An authorized user physician determines, in accordance with

§ 35.200(c), that a delay in preparing the radiopharmaceutical in order to make a written directive would jeopardize the patient's health because of the emergent nature of the patient's medical condition. In this case, the licensee shall obtain the written directive made by the authorized user physician which

• *contains the notation regarding the emergency and all the information specified in*paragraph (i)(l)(i) of this section within 3 working days after the 16

prescribed departure. The licensee shall keep these records in an auditable form and available for inspection for 5 years.

(2) The actions authorized in paragraph (i)(l) of this section are permitted notwithstanding more restrictive language in license conditions unless those license conditions specifically reference§ 30.34(i).

(3) Nothing in this section relieves the licensee from complying with other applicable NRC, FDA, and other Federal or State regulations governing the elution of generators and preparation of reagent kits.

PART 35 - MEDICAL USE OF BYPRODUCT MATERIAL

3. The authority citation for Part 35 is revised to read as follows:

Authority: Secs. 81, 161, 182, 183, 68 Stat. 935, 948, 953, 954, as amended, (42 U.S.C. 2111, 2201, 2232, 2233); sec. 201, 88 Stat. 1242, as amended (42 U.S.C. 5841).

For the purposes of sec. 223, 68 Stat. 958, as amended (42 U.S.C. 2273);

§§ 35.11, 35.13, 35.20 (a) and (b), 35.21 (a) and (b), 35.22, 35.23, 35.25, 35.27 (a), (c) and (d), 35.31 (a), 35.49, 35.50 (a)-(d), 35.51 (a)-(c), 35.53 (a)-(b), 35.59 (a)-(c), (e)(l), (g) and (h), 35.60, 35.61, 35.70(a)-(f), 35.75, 35.80 (a)-(e), 35.90, 35.92 (a), 35.120, 35.200 (b) and (c), 35.204 (a) and (b), 35.205, 35.220, 35.300, 35.310 (a), 35.315, 35.320, 35.400, 35.404 (a),

35.406 (a) and (c), 35.410 (a), 35.415, 35.420, 35.500, 35.520, 35.605, 35.606, 35.610 (a) and (b), 36.615, 35.620, 35.630 (a) and (b), 35.632 (a)-(f), 35.634 (a)-(e), 35.636 (a) and (b), 35.641 (a) and (b), 35.643 (a) and (b), 35.645 (a) and (b), 35.900, 35.910, 35.920, 35.930, 35.932, 35.934, 35.940, 35.941, 35.950, 35.960, 35.961, 35.970, and 35.971, are issued under sec. 161b, 68 Stat. 948, as amended (42 U.S.C. 2201(b)); and§§ 35.14, 35.21 (b), 35.22 (b),

35.23 (b), 35.27 (a) and (c), 35.29 (b), 35.33 (a)-(e), 35.36 (b), 35.50 (e),

35.51 (d), 35.53 (c), 35.59 (d) and (e)(2), 35.59 (g) and (i), 35.70 (g), 35.80 (f), 35.92 (b), 35.200 (c), 35.204 (c), 35.300 (b), 35.310 (b), 35.315 (b),

35.404 (b), 35.406 (b) and (d), 35.410 (b), 35.415 (b), 35.610 (c), 35.615 (d)(4), 35.630 (c), 35.632 (g), 35.634 (f), 35.636 (c), 35.641 (c), 35.643 (c),

35.645, and 35.647 (c) are issued under sec. 1610, 68 Stat. 950, as amended (42 u.s.c. 2201(0)).

17

4. In§ 35.8, paragraph (b) is revised to read as follows:

~ § 35.8 Information Collection Requirements: 0MB approval.

(b) The approved information collection requirements contained in this part appear in§§ 35.12, 35.13, 35.14, 35.21, 35.22, 35.23, 35.27, 35.29, 35.31, 35.33, 35.50, 35.51, 35.53, 35.59, 35.60, 35.61, 35.70, 35.80, 35.92, 35.200, 35.204, 35.205, 35.300, 35.310, 35.315, 35.404, 35.406, 35.410, 35.415, 35.606, 35.610, 35.615, 35.630, 35.632, 35.634, 35.636, 35.641, 35.643, 35.645, and 35.647.

5. In§ 35.200, paragraph (c) is added to read as follows:

§ 35.200 Use of radiopharmaceuticals, generators, and reagent kits for imaging and localization studies.

(c)(l) From [insert date of publication] to [insert date 3 years from the date of publication], a licensee may depart from the manufacturer s 1

instructions for eluting generators and preparing reagent kits for which FDA has approved an NDA, provided that the licensee has a written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radiopharmaceutical, and which includes the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manufacturer s 1

instructions for preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. If the authorized user physician determines that a delay in preparing the radiopharmaceutical in order to make a written directive would jeopardize the patient's health because of the emergency nature of the patient's medical condition, the radiopharmaceutical may be prepared without first making a written directive. The authorized user physician shall make notation of this determination in the written directive within 3 working days after the prescribed departure.

18

(2) The licensee shall keep the written directive and a record of the

~ Tiumber of patient administrations under the departure in an auditable form and available for inspection for a period of 5 years.

(3) Nothing in this section relieves the licensee from complying with

~ther applicable NRC, FDA, and other Federal or State regulations governing the elution of generators and preparation of reagent kits.

6. In§ 35.300, the existing text is designated as paragraph (a) and a new paragraph {b) is added to read as follows:

§ 35.300 Use of radiopharmaceuticals for therapy.

(b)(l) From [insert date of publication] to [insert date 3 years from the date of publication], a licensee may depart from the package insert instructions regarding indications or method of administration for a radiopharmaceutical for which FDA has approved an NOA, provided that the authorized user physician makes a record of the departure which includes the specific nature of the departure and a brief statement of the reasons why the departure would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition.

Ljcensees are not authorized to depart from the manufacturer's instructions for

• efoting a generator or preparing any kit for a radiopharmaceuti cal for therapy.

e (2) The licensee shall obtain this record within 3 working days of the administration and keep this record and a record of the number of patient administrations under the departure in an auditable form and available for inspection for 5 years.

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(3) Nothing in this section relieves the licensee from complyi-ng with

.,:i~ other applicable NRC, FDA (including requirements governing the submission of an IND), and other Federal or State regulations governing the use of radiopharmaceuticals .for therapy.

Dated at Rockville, Maryland, this F.or the Nuclear Regulatory Commission.

e Commission.

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