ML19305F987
| ML19305F987 | |
| Person / Time | |
|---|---|
| Issue date: | 12/28/1981 |
| From: | Dircks W NRC OFFICE OF THE EXECUTIVE DIRECTOR FOR OPERATIONS (EDO) |
| To: | |
| Shared Package | |
| ML19255A661 | List: |
| References | |
| FOIA-82-138, REF-10CFR9.7, TASK-RIA, TASK-SE SECY-81-707, NUDOCS 8201250483 | |
| Download: ML19305F987 (67) | |
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RULEMAKING ISSUE (Affirmation)
Frr:
The Commissioners From:
William J. Dircks, Executive Director for Operations
Subject:
DR. GEORGE V. TAPLIN'S PETITION (PRM 35-1) REGARDING 10 CFR PART 35,
" HUMAN USES OF BYPRODUCT MATERIAL"
Purpose:
To obtain Ccmmission approval of a notice of proposed rulemaking to grant in part petition PRM 35-1 by providing an exception to restrictions in NRC regulations for a certain radioactive drug.
Catecory:
This paper covers a minor policy question.
B"ckground:
The Food and Drug Administration (FDA) authorizes the manufacture and distribution of drugs, including radioactive drugs, when it approves the manufacturer's "New Drug Application" (NDA).
FDA makes a 'inding of substantial cvidence of safety and effective-ness for the approved clinical procedures based on clinical trials performed under the auspices of a " Claimed Investigational Exemp-tion from a New Drug Application" (IND).
These approved clinical indications, as well as (1) the chemical and physical form of the drug; (2) the route of administration; and (3) the recommeaoed s
dosage range, become a part of the drug's labeling (package insert).
FDA does not have authority to regulate the way in which a licensed physician uses a drug with an approved NDA. Therefore, once a drug has an FDA-approved NDA for a single clinical procedure, a physician may use it for any clinical procedure.
The NRC, however, does have authority to regulate usage.
In exercising this authority, the NRC, until March 1979, relied or, the FDA finding of substantial evidence of. safety and effective-ness for radioactive drugs.
That is, the FDA-approved clinical
Contact:
Deborah A. Bozik 427-4566 8201250483 811226 CF sugs CF
g The Commissioners 2
procedures (e.g., kidney and brain imaging, etc.) were listed in regulations for the group
- medical licensees.
In a rule (44 FR 10358) that became effective on March 22, 1979, the Commiscion amended 635.100 by deleting specification of the clinical procedure, thereby permitting the physician greater latitude.
However, in the same rulemaking, a new S35.14(b)(6) was added which provided that, when a pnysician uses byproduct material for clinical procedures other than those approved by FDA and specified in the product labeling, the physician must t
follow the product labeling regarding the following:
(1) chemical
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and physical form, (2) route of administration, and (3) dosage range.
On March 28, 1979, the late George V. Taplin, M.D., petitioned the Commission (PRM 35-1) to remove the NRC restrictions described in 535.14(b)(6).
His primary reason was his desire to have the aerosol use of Tc-99m pentatste sodium available to NRC's group licensees for a new clinical procedure " lung function studies" (see Enclosure 1).
Although FDA has approved Tc-99m pentatate sodian for several clinical procedures, FDA has not approved it either for lung function studies (clinical procedure), or as an aerosol (physical form), or for use by inhalation (route of administration).
- Thus, while NRC regulations would permit the use of Tc-99m pentatate sodiu.a for the unapproved procedure " lung function studies," they would do so only if the chemical and physical form, route of administration, and dosage range were as specified in the FDA-approved package insert.
Dr. Taplin's petition was published in the Federal Register on May 7, 1979 (44 FR 26817) soliciting public comments.
contains the forty-five letters received from fifty-one commenters in addition to a summary and analysis of the comments.
All came from representatives of the nuclear medicine profession, and all supported the petition.
The comrehters believed that the NRC restrictions place unnecessary constraints on the physician to the detriment of patient care without any benefit to the public.
- Radioactive materials in 10 CFR Part 35.100 are divided into six groups, each group having similar requirements for user training and experience, facilities and equip-ment, and radiation safety procedures.
The purpose of this grouping is to reduce administrative costs by eliminating the need for licensees to seek an amendment to their license each time they wish to use an additional radiopharmaceutical in a group for which they are licensed.
Under the grouping procedure, an application 7or a specific license for the use of any one radiopharmaceutical in a particular group is treated by NRC as an application for all radiopharmaceuticals in that group.
4 The Commissioners 3
Various commenters pointed out that the unapproved use of Tc-99m pentatate sodium for lung function studies (1) is less expensive; (2) gives better results; and (3) is better from an occupational radiation safety standpoint than the use of FDA-approved xenon-133 for the same clinical indication.
Alternatives:
The staff considered the following three alternatives for disposi-tion of the petition:
1.
Grant the petition in full by publishing a notice of proposed rulemaking to delete $35.14(b)(6), which contains the three restrictions.
2.
Grant the petition in part by publishing a notice of proposed rulemaking to establish the first exception to the restric-tions in S35.14(b)(6) to permit the use of Tc-99m pentatate sodium for lung function studies.
(This is the radioactive drug specifically mentioned in the. petition.)
3.
Deny the petition.
piscussion:
The NRC restrictions in S35.14(b)(6) are directed at group medical licensees who are usually community hospitals anc individual physicians in private practice.
The NRC requires minimum training and experience to obtain such a license, thus enabling community hospitals to make certain essential nuclear medicine services are readily available.
These ecstrictions do not apply to the larger medical institutions possessing the NRC broad' medical licenses where both the credentials of the physicians and all proposed uses of radioisotopes are reviewed by a specifically appointed Radiation Safety Committee (RSC) which has been approved by NRC.
As mentioned before, NRC relies primarily on FDA's determination of a redioactive drug's safety and effectiveness for its group medical licensees.
However, NRC does allow physicians under group medical licenses to depart from the FDA-approved clinical proce-dures, but it puts the restrictions in 935.14(b)(6) to hold the physicians to the FDA-approved chemical and physical form, route of administration, and dosage range.
This ensures that the radio-active drugs will be used safely while allowing the individual physician to use his or her judgment in the practice of medicine to determine effectiveness.
Using radioactive drugs safely requires consideration of (1) the radiation safety of the patient and (2) the radiation safety of the worker.
The radiation safety of the patient is considered by FDA when it approves the radioactive drug.
The radiatior, safety of the worker is considered by NRC when the staff conducts a safety review before incorporating the radioactive drug into the 10 CFR 35.100 ' groups' to ensure that the radiation dose to the worker is within 10 CFR Part 20 limits and consistent with the ALARA
The Commissioners 4
principle.
Thus, restricting the physician to foll;w the chemical and physical form, route of administration and dosage range listed in the drug's labeling keeps the radiation safety to tne patient and to the worker the same as that approved by FDA and NRC--
regardless of the application of the radioactive drug.
The staff has presented the Commission with three alternatives.
If the Commission grants the petition (Alternative 1), it will relinquish most of its control over the radiation safety of the patient and an important portion of its control over the radia-tion safety of workers.
Presumably, the group medical licensees would have to gear-up to perform the radiation safety analyses that FDA and NRC have performed in the past.
However, the steff believes that such licensees, in many cases, will be unable or unwilling to perform the necessary safety analyses.
If the Commission grants the petition in part by establishing a list of exceptions (Alternative 2) or denies the petition (Alter-native 3), it will retain its present level of control over the radiation safety of patients and workers.
In the case of establishing a list of exceptions in the regulations, NRC staff would continue to review the novel procedures for occupa-tional radiation safety and begir. to review the novel procedures for patient radiation safety.
The staff is thus recommending that the Commission publish a proposed rule for comment to provide an exception ** to the restric-tions in S35.14(b)(6) for the use of Tc-99m pentatate sodium as an aerosol for lung function studies.
The staff has found that the radiation dose to the patient for this clinical procedure is comparable to using Tc-99m pentatate sodium for a brain scan which is approved by FDA (see Enclosure 3).
The staff has also found that requiring the physician to administer the radioactive aerosol with a closed, shielded system that is either vented to the outside
- This proposed rulemaking would establish the first exception to the restrictions.
In the future, other radiopharmaceuticals and uses could be added to the list with the consultation of the Advisory Committee on the Medical Uses of Isotopes (ACMUI) and after a determination of radiation safety is made by the staff.
Though this initial exception is a minor matter, it is brought to the Commission's attention because of its precedential nature.
Exceptions to be added to the list would be effective upon publication in the Federal Register and would be issued under the delegated authority of the Executive Director for Operations, unless circumstances indicate that they should be brought to the Commission's attention and published as proposed rules.
i The Commissioners 5
atmosphere or provides for collection and disposal of the aerosol is necessary to keep occupational exposures ALARA.
Therefore, the proposed rule provides for this occupational radiation safety provision.
i The staff believes that its recommendation to retain the restric-tions in 535.14(6)(b), while granting exceptions based on an NRC review strikes an appropriate balance between all three parts of NRC's statement of general medical policy (44 FR 8242) which reads as follows:
"1.
The NRC will continue to regulate the medical uses of radioisotopes as necessary to provide for the radiation safety of workers and the general public."
"2.
The NRC will continue to regulate the radiation safety of patients where justified by the risk to patients and where voluntary standards or compliance with these standards are inede,quate."
"?.
The NRC will minicize intrusion into medical judgments affecting patients and into other are s traditionally con-sidered to be part of the practice o. medicine."
Early atteupts between NRC and FDA were made to find an institu-tional solution to enable FDA to address the problem af updatir.g drug labeling which is not consistent with the state of the art (see Enclosure 4).
The proper resolution of the Taplin Petition has been debated at several medical advisory committee meetings at both NRC and FDA.
The FDA's committee is presently addressing the problem of updating the package insert to reflect new uses.
However, the FDA's resolution of this problem would require a timeframe longer than NRC considers suitable in its response to a petition.
NRC's Advisory Committee on the Medical Uses of Isotopes concurs in the staff's recommendation to grant the petition in part as the best and the most expedient manner by which to address the problem (see Enclosure 5).
R: commendation:
That the Commission:
i 1.
Approve 3 Federal Register notice of proposed rulemaking (Enclosure 6) to amend 935.14(b)(6) to permit an exception i
for Tc-99m pentatate sodium for lung function studies (Alternative 2).
i Th2 Commissioners 6
Certify that the proposed rule would not have a significant economic impact on a substantial number of small entities.
Because it is relieving in nature, the proposed rule is not expected to have a negative economic impact.
However, because of the widely different conditions under which small licensees operate, comments are requested concerning the potential effects of the rule.
2.
Note that:
Should the Commission adopt the staff's recommendation:
a.
The notice of proposed rulemaking (Enclosure 6) will be published in the Federal Register and 60 days will be allowed for public comment.
b.
The proposed rule, if adopted as a final rule, would involve neither new resource requirements nor repro-gramming of resources.
c.
The Chief Counsel for Advocacy of the Small Business Administration will be informed of the certification made under the Regulatory Flexibility Act (5 U.S.C.
605(b)) and the reasons for it.
d.
The proposed rule contains no new information collection requirements subject to the Paperwork Reduction Act (Pub. L.96-511).
e.
Under 951.5 (d) of 10 CFR Part 51. neither an environ-mental impact statement nor a n.orzive declaration need be prepared because the propost 9mendment is insignif-icant from the standpoint of environmental impact.
f.
A value/ impact statement has not been prepared.
The proposed rule does not impose a significant burden on the licensees.
In fact, the rule is reli ving in nature because it will permit medical licensees to provide diagnostic services that are prohibited under current regulations.
g.
Analysis required by the periodic and systematic review of the regulations has not been performed for this pro-posed rule.
The task force that currently is considering the rewrite of Part 35 will conduct such an analysis.
h.
The Subcommitte on Nuclear Regulation of the Senate Committee on Environment and Public Works, the Sub-committee on Environment, Energy and Natural Resources of the House Committee on Government Operations, the Subcon.mittee on Energy and the Envit onment of the House Committee on Interior and Insular Affairs, and the Sub-
i e
The Commissioners 7
committee on Energy Conservation and Power of the House Committee on Energy and Commerce will be notified (Enclosure 7).
i.
A public announcement will be issued (Enclosure 8).
j.
The Federal Register notice of proposed rulemaking will be distributed to affected medical licensees and to other interested persons.
William. Dircks Executive Director for Operations
Enclosures:
1.
Petition 2.
Public Comments and Analysis 3.
Radiation Dose for Lung Function Study 4.
Minutes of FDA-NRC meeting 5.
ACMUI Poll 6.
Proposed Rule 7.
Draft Congressional Letter 8.
Draft Public Announcement Commissioners' comments or consent should be provided directly to the Office of the Secretary by c.o.b. Thursday, January 14, 1982.
4 Commission staff office comments, if any, should be submitted to the Commissioners NLT January 7, 1982, with an information copy to the Office of the Secretary.
If the paper is of such a nature that it requires additional time for analytical review and comment, the Commissioners and the Secretariat should be apprised of when comments may be expected.
This paper is tentatively scheduled for affirmation at an open meeting during the week of January 18, 1982.
Please refer to the appropriate Weekly Commission Schedule, when published, for a specific date and time.
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University of Cahforme. Las Aneeles, writtan comn ents or steges?!cns Cahforma, has EIed ws:h de &c rrr cencerning te ;r sttics for rde making as FR 257ts Regulatory Commission a petitions for shedd send thetr comments to de Punaished s/2ns rule making dated Mar :L is E.
Sd::retary of is C:==:sstem. US comes pwind emnoso stacas requestieg ths Carnix.m to Am=ad its Nudear Regdat:ry Commission, regulation %;nas L*ses ofA product Wash =gT D.C. =553. Attent:nr j
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ar=endments requee the phpic;scs to p,,g,,, gyg, Victor E. Anderson.59 Baird Avenua.
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- comm.ne,wiad emones 7/16as Nulsboro New Jersey.Re I' ding of chemical and phys & cal form. route af Petition fo Rde Making was published administra tion and donase.cartpr winrs pg in 2e rederal Register on February 28.
they perfum clinical procedna that W:J f 44 FR.n:64); the comment penod have not bew.n approved by FDA.These Gott Noctear. Inc.; Fmng of Pet!!!ori for would have expired Apri! 30.1979. Mr.
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Anderson a petition reqsested the physiciaca perfons & FDA apprened Commission to amend its regu!stioA clinical proemi.aras that are !;sted in the Notice is hereby given that Mr. Wa!!er
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requirement that payscans mest wie an Cc=n 5. tion a petition for rulemaking.
approved radiephar=aceutical stnetly h petitiener proposes that the physicsts vn Ove level-tra!r.ce. Ne< c.
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- 1.
Merle K. Loken, M.D., Ph.D., Division of Nuclear Medicine, Department of Radiology, University of Minnesota Hospitals, Box 382 Mayo, Health Sciences Center, University of Minnesota, 420 Delaware Street S.E., Minneapolis, Minnesota 55455 (May 31, 1979)
Refere6fe ismade to the FEDERAL REGISTER, Volume 44, Number 89, May 7, 1979, relating to the petition filed by Dr. George V. Taplin.
I would like to endorse the petition filed by Dr.' Tablin, which would permit greater latitude for physicians using diagnostic radiopharmaceuticals.
This latitude would permit ohysicians to perform clinical procedures with these radiopharmaceuticals which are not specifically listed on the package
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insert.
Dr. Taplin has given a specific example of a use for Technetium-99m DTPA as an aerosol for studying pulmonary ventilation. This is becoming a very well recognized and useful procedure for evaluation of pulmonary venti-lation.
It would be desirable to have the regulations permit exceptions such as this for the administration of low risk diagnostic radiopharmaceuticals.
2.
W. H. Blahd, M.D., Chief, Nuclear Medicine Service, VA Wadsworth Medical Center, The Society of Nuclear Medicine, 475 Park Avenue South, New York, NY 10016 (May 25, 1979)
I wish to support Dr. George V. Taplin's petition for rule making, dated March 28, 1979.
I believe that the amendments to 10 CFR Part 35, wnich specifically limit physicians use of FDA-approved radiopharmaceuticals to the route of administration and dosage range indicated in the package insert, are unnecessarily restrictive.
It is my opinion that the route of administration and dosage range should be a discretionary matter, determined by medical judgment when a physician uses an approved radic-pharmaceutical for a clinical procedure that is not included in the package
, insert information.
It is my understanding that it is also incumbent upon the physician to obtain anc retain complete records and reports of all such cases.
Dr. Taplin cites an instance of an agent (Tc-99m DTPA) widely used in nuclear medicine as an intravenous injsetion for brain and kidney imaging that cannot be used as an aerosol for lung imaging since such use is not described in the package insert.
Existing regulations would therefore preclude the use of this excellent low-risk, low-radiation procedure in patients with serious pulmonary disease.
I would urge that the Commission revise its amendments to 10 CFR Part 35 to permit physicians greater discretionary use of FOA-approved radiopharmaceuticals when such uses will benefit patient medical care.
A summary and analysis of these comments appears at the end of this enclosure.
1
3.
hichael J. Eymontt., M.D., John R._Hansell, M.D., fiospital of the University of Pennsylvania, 3400 Spruce Street, G1, Philadelphia, PA 19104 (May 11, 1979)
The undersigned have seen the above-mentioned petition in the Federal Register, and are in agreement with the principles stated by Dr. Taplin, andwigto,addourvoicesofsupportforhiypetition.
Our decision to lend our support to this. pet,jtion represents our own opinions as part of the Nuclear Medicine' Community and d as not necessarily reflect the view of the instituti.ons,with which we are associated.
arie A. Capitanto, M.D.,
H". Theodo e Harcke, M.D., Richard I. Markowitz, M.D.,
4.
Barbara J. Wolfson, M.D., Phy111sann Loy, R.T., Jonathan L. Williams, M.D.,
St. Christopher's Hospital for Children, 2600 North Lawrence Street, Philadelphia, Pennsylvania 19133 (l'ay 10, 1979) i We the undersigned support the petition for rule making submitted by George V. Taplin, M.D., dated March 28, 1979.
In our opinion the request to the Commission to amend its regualtion entitled, " Human Uses of Byproduct Material," 10 CFR Part 35, is entirely appropriate and in the best interest of our patients. We endorse Dr. Taplin's view that the requirement is in direct opposition to the objectives of both the Nuclear Regulatory Commission and Food and Drug Administration.
Therefore, we request that the commission review and amend the regulation that limits the usage of low dose radiopharmaceuticals to those included within the package insert.
5.
Glen.W. Hamilton, M.D., Chict, E clear Medicine, Steven M. Larson, M.D.,
. Asst. Chief, Nuclear Medicine, Veterans Administration Hospital, 4435 Beacon Avenue So., Seattle, Washington 98108 (May 24, 1979)
We are writing in support of the rule change' suggested by Dr. George V.
Taplin.
It is our experience and impression as practitioners in nuclear medicine, that this is a most important rule change request.
In our experience, there have been numerous times that radiopharmaceuticals can and should be used in the patients' best interest in a manner that is not outlined or approved in the current package insert.
In addition to the example mentioned by Dr. Taplin, a recent case in point involves the use of Sn pyrophosphate (Sn-PYP) for red blood cell labelling for nuclear cardiology studies.
Sn-PYP, which was previously approved for use in bone scanning, was found to be an excellent clinical agent for tagging red blood cells. The package insert mentions nothing about RBC labelling with Sn-PYP.
The regulations, as proposed by the NRC, could in certain instances put the nuclear physician in the unfortunate position of obtaining inferior patient studier in the interest of adhering to poorly thought-out regulations.
We would therefore strongly support Dr. Taplin's rule amendment change.
2
b 6.
Harold L. Atkins, M.D., Department of Radiology, School of Medicine, Health Sciences Center, State University of New York at Stony Brook, Long Island, NY 11794 (May 25, 1979)
I would like to support the petition of George V. Taplin, M.D., in i
relation to the use of low risk, ciagnostic radiopharmaceuticals for
-clinical procedures not approved by the F 0 A.
The regulation as preposed by the'R:R.CU prevente the physician from using his best judgment in the care of his patient.
It will prevent the oevelopment of new applications for materials already proved to be safe./'
The use of radiopharmaceuticals is 'ge~nerally regarded as safe.
Surveys and registries of adverse reactions tave demonstrated this, especially in comparison to radiographic procedures which utilize contrast agents.
The proposed regulation will markedly inhibit progress in providing useful, low risk diagnostic modalities for improved patient care.
The package insert should not be used as the authoritative word in the practice of medicine.
It should not replace the clinical judgment for which the physician is trained.
7.
Paul J. Chase, D.O., John F. Kennedy Memorial Hospital, Professional Radiology Associates, P.A., Laurel Road, Stratford, New Jersey 08084 (June 6, 1979)
This letter is in support of Dr. George Taplin's petition for rule making dated March 28, 1979 ttquesting the Commission to amend its regulation
" Human uses of Byproduct Material" 10 CFR Part 35.
I believe that qualified nuclear physicians should have the latitude to use low risk diagnostic radiopharmaceuticals by no longer designating the
,FDA authorized clinical procedures but that they should also have the latitude of not being restricted by the manufacturers package insert as i
regards chemical and physical form, route of administration and dosage range when performing clinical procedures that have not been approved by the FDA.
By allowing this freedom, the development of new applications of approved l
drugs including Technetium 1.abeled DTPA and others will be able to progress --
so that better health care can be rendered at the clinical level.
i This modification will not injure or hurt patients and will allow an l
initiative and pursuit of interest on the patient's behalf that must not j
be lost in regulation after regulation.
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I would worry more about the 50,000 REM level inside the Three Mile Island plant than I would about harrassing dedicated nuclear physicians.
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David A. Goodwin, M.D., Chief, Nuclear Medicine Service, Veterans Administration Hospital, 3801 Miranda Avenue, Palo Alto, California 94304 (May 25, 1979)
I completely concur with the petition of Dr. George V. Taplin that the Commission reconsider and rescind the requirement that physicians must use appipved,radiopharmaceuticals strictly in accordance with manufacturers package insert.
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Nuclear Medicine has an unrivaled record of safety in the Jse of radio-pharmaceuticals.
The March 22, 1979. amendment is unduly restrictive and
. in direct opposition to the current objectives of both the NRC and the FDA as Dr. Taplin states.
In particular, I use technetium labeled DTPA for lung ventilation studies and have done so for six years without incident.
It is an extremely valuable test which ought to be available to all prac-ticing nuclear medicine physicians.
9.
E. James Potchen, M.D., Professor and Chairman, Michigan State University, Department of Radiology, B220 Clinical Scier.ces Building, East Lansing, MI 48823 (May 29, 1979)
As a practicing academic radiologist and past president of the Society of Nuclear Medicine, I would like to strongly endorse the statements made by Dr. George V. Taplin of Los Angeles published in the Federal Register, Volume 44, No. 89, May 7, 1979.
The points that Dr. Taplin makes are not only consistent but essential to a rational utilization of radiopharma-ceuticals in both the practice of medicine and in the development of improved approaches in their use in patient sanagement.
The previcus statement by the NRC " Human Uses of Byproduct Material",
10 CFR, Part 35, effective March 20,'1979 clearly did not take cognizance of the real world in which nuclear medicine is both practiced and investi-gated.
Dr. Taplin's contributions toward aerosol inhalation with techne-tium have been significant both in improving our understanding of pulmonary disease and in developing technologies appropriate to the management of ill patients. Without the opportunity,to continue to avail ourselves of these technologies, we severely constrain an ability to make a useful contribution to our patients. Obviously, this serious oversight must be corrected.
Any information'or assistance you could supply would be j
sincerely pppreciated.
- 10. Michael B. Dooley, M.D., President, Pennsylvania College of Nuclear Medicine, A Chapter of the American College of Nuclear Medicine and the American College of Nuclear Physicianc, 20 Erford Road, Lemoyne, PA 17043 (May 11, 1979)
This letter is in support of the petition for rule making filed by Dr. George V.
j Taplin regarding the use of FDA approved radiopharmaceuticals.
Besides Technetium-99m DTPA, there are other radiopharmaccuticals that could be used if it were not for the restriction recently enacted by the N.R.C.
(e.g. Technetium-99m Sulfur Colloid for G.I. reflux).
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1 We endorse Dr. Taplin's comments and wish to add that since, the cost of submitting an IND for a manufacturer is so significant, we do not foresee that new uses will ever get approved by the FDA in many circumstances, where the investment, would not be considered worthwhile by the manufacturer.
Thus, effectively, many clinically useful procedures will not be available for usepy physicians in spite of.the fact that their judgement dictates it to be proper in the management of their patients.
The N.R.C. is ambiguous in this issue. 20n the one hand, it allows a licensee to use 20 mci of Technetium-99m DTPA intravenously to image any-thing in a patient, but at the same time, forbids the use of 200 uCi of th'e same radiopharmaceutica1 to be administered orally for a gastric empty-ing study.
We unreservedly support the adoption of Dr. Taplin's petition.
11.
Charles D. Teates, M.D., Division of Nuclear Medicine, University of Virginia Medical Center, Charlotte.sville, Virginia 22908 (May 18, 1979)
I would like to comment on the petition filed by George V. Taplin, M.D.
I completely agree with the opinions expressed by Dr. Taplin.
I believe that the amendments to 10 CFR Part 35, to permit physicians greater latitude in administering diagnostic radiopharmaceuticals do contain some unnecessary restrictions.
These restrictions are somewhat illogical and do not allow physicians the latitude that they have with other types of drugs. As an example, Tc-99m Sulfur Colloid is approyed f,or liver, spleen, an.19one marrow imaging.
This same material is als6 useful when instillen into the peritoneal space prior to giving therapeutic doses of radioactive colloids.
Such use prevents infusing' therapeutic colloids in loculated
. spaces where dangerously high tissue radiation may occur.
Such a use of a diagnostic agent could prevent a therapeutic disarter.
There are a number of radiopharmaceuticals that have proven quite useful in such non-approved applications.
The Food and Drug Administ ation acknowledges the fact that the nackage insert frequently lags oehind medical developments.
For this ^3:393
'5e same latitude sho~uld be allowed as with non radioactive drugs.
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m a include using radiopharmaceuticals in a route of adminis-tration nra w aed in the package insert.
This is particularly important now that Uu !.c is considering changing the Radiation Safety Committee so that it'pi $ ably would not have the same level of expertise required of a Medical Isotope Committee.
I am very pleased that the NRC has relaxed its rules regarding administra-tion of radiopharmaceuticals but I believe that it shouid proceed to make the regulations regarding the use of radioactive drugs the same as for non-radioactive drugs.
The real risk from the use of radiopharmaceuticals is considerably less than it is for non-radioactive drugs.
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C. Craig Harris, M.S., Associate Professor of Rad 4 ology, Past president, Society of Nuclear Medicine, Duke-University Medical Center, Durham, North Carolina 27710 (May 24, 1979)
I write to support most vigorously the petition of George V. Taplin, M.D.,
requesting that ;he Commission reconsider and rescind the requirement that physicians must use an approved radiopharmaceutical strictly in accord with the mamtfactures' package insert.
IagreewithDr.Taplininhiscomment!?Thtschangeisindirectopposi-tion to the current objective of,both the NRC and FDA which permit physi-cians to use approved drugs accordirng to their best knowledge and judgment
.gnd in the best interest of the patient."- The FDA does not restrict the route of administration of in approved diagnostic drug, the specific point of the clinical example offered in Dr. Taplin's petition.
The Society of Nuclear Medicine commented on the proposed rule making (44FR10358) and, while generally supportive of the liberalization of rules to permit the phy3ician to use his best judgment with regard to diagnostic radiopharmaceuticals, the Society specifically opposed the excessive restriction to FDA approved clinical procedures, and specifically opposed restriction of route of administration.
It seems to me that the final regulations, at least in this point, is disparate with the general philosophy of the stated intent of the prcposed rules (F.R. Feb. 20, 1979).
In my opinion, Dr. Taplin has made his point well with his comments and the proffered reprint.
I urge the Commission to lift unnecessary and possibly harmful restriction to package-insart-listed procedures with diagnostic radiopharmaceuticals, particularly with regard to route of administration.
- 13. " Leonard M. Freeman, M.D., Montefiore Hospital and Medical Center, Albert Einstein College of Medicine, Department of Nuclear Medicine, Montefiore Hospital and Medical Center, 111 East 210th Street, Bronx, N.Y. 10467 (May 24, 1979)
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I wish to srpport the petition of George V. Taplin, M.D. (Docket Number PRM-35-1) that was published in the May 7, 1979 issue of the Federal Register (Voi. 44, No. 89).
In this petition, Dr. Taplin righ+ ~ully requests you to amend your recent regulation " Human Uses of Byproduct Material," 10 CFR Part 35, effective March 20, 1979.
The current amendment removes the specific FDA clinical procedure listing previously associated with certain low risk diagnostic radiopharmaceuticals.
It does impose, however, a totally unwarranted burden on the physician by requiring him to follow the manufacturer's package insert regarding chemical and physical form, route of administration,and dosage range when they perform clinical procedures that have not been approved by the FDA.
I am in complete agreement with Dr. Taplin's statement that the development of new safe applications af approved drugs will be adversely affected by
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4 your regulation.
He specifically has proven the 'value of 99"Tc-DPTA aerosol '
ior inhalation studies of lung ve,ntilation. Two other promising techniques that come to mind involve the use of orally administered 99"Tc-sulfur col-loid for studying gastro esophageal reflux and gastric emptying time.
In both cases, investigative work suggests that these simple, innocuous studies are more sensitive and involve considerably less radiation than their radiogyhic,examinationcounterparts.
I believe that the qualified physician;is the individual who is best suited to make this decision and should not be.tindered in the manner set forth in your regulation.
I appeal to,you,to amend this regulation to reflect the change requested.
- 14. William G. Myers, Ph.D., M.D., Research Professor of Nuclear Medicine, The Ohio State University Hospital, 410 W. 10th Ave., Columbus, OH 43210 (May 24, 1979)
This is in support of the petition [ Docket No. PRM-35-1] of Professor George V. Taplin, M.D. that the USNRC rescind its stipulation so as not to recommend a radiodrug be used strictly in accord with the manufacturers' package irssert.
In my opinion, no manufacturer of a radiodrug will wish to stifle initiative and innovation in applications of its product for the benefit of a patient ir. the best judgment of his physician, who is licensed to practice medicine in any state.
Especially would this be unlikely in the case of Professor Taplin, who was the medical scientist who originated the*use of "inside-out" imaging of the human lung, in 1963.
Since then, his method has become applied by thousands of physicians worldwide to aid them in-the diagnostic process in many tens
.of thousands of patients. Such overwhelming acceptance of his leadership should continue to be rewarded.
Ofparamountconcernisthatthe99hc-DTPA acrosol system developed by Professor Taplin manifestly is superior insofar as it greatly reduces exposures t_c, radiation.
o Enclosed is a copy of my 25-Feb-66 let'ter which indicated my high regard for Professor Taplin as a highly competent physician in the development of applications of "The Peaceful Atom" in the service of Medicine.
Since then, I have been elected Historian of the 10,000-member Society of Nuclear Medicine.i In this position, I sense that Professor Taplin has the complete confidence of the nuclear medicine community.
15.
Patrick O'Connell, M.D., Pathologist, Shenandoah Valley Pathology Laboratories, Inc., Winchester Memorial Hospital, South Stewart Street, Winchester, Virginia 22601 (May 24, 1979)
I am writing to support Doctor George V. Taplin's petition to amend the recent N.R.C. regulation " Human Uses of Byproducts Material",10 CFR Part 35, effective March 20, 1979.
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I have read all of Doctor Taplin's reports on the*use of Tc-DTPA for aerosol inhalation lung imaging ah I am very impressed with his resultc.
d In this day of increasing medical costs Doctor Taplin offers a method for inhalation lung imaging which is over 100 times cheaper than the current method which uses radioactive Xenon-133.
Doctor Taplin's method does not require an elaborate expensive system to trap the radioactive material and his results are actually superior.to those with Xenon especially after having'dbne 'a' perfusion lung scar..
Ifeelthatsomereadilyavailableandriaso^nablycheapmethodfor inhalation lung imaging is an urgent necessity to try and cut down on the number of pulmonary arteriogranis 'that are ordered as a result of thf reports on perfusion in, aging alone.
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16.
Harold A. O'Brien, Jr., Ph.D., Adjunct Associate Professor of Radiology and Chairman, State of New Mexico Radiation Technical Advisory Council, The University of New Mexico, Albuquerque, New Mexico 87106 (May 23,1979)
I am writing in support of the petition of George V. Taplin, M.D. to amend the recent Nuclear Regulatory Commission regulation " Human Uses of Byproduct Material," 10 CFR Part 35, effective March 20, 1979.
In accor-dance with this regulation physicians must use an approved drug strictly in accord with the manufacturer's package insert. This new regulation would restrict physicians from using approved drugs according to their best judgment and knowledge, and will hinder the development of new safe applications of approved drugs.
6 It is my understanding that agreement states, including New Mexico, will be required to modify their Radiation Protection Regulations to bring them in compliance with federal regulations.
As chairman of the State of New Mexico's Radiation Technical Advisory-Council, I must register my opposi-
, tion to this restrictive regulation and recommend its amendment to permit physicians greater latitude in the application of low risk diagnostic radiopharmaceuticals.
Failure to do so will, in my opinion, adversely impact the advancement of nuclear medicine practice in our state.
17.
Eugene L. Saenger, M.D., Professor of Radiology, Vice-Chairman, Department of Radiology, Eugene L. Saer.ger Radioisotope Laboratory, Cincinnati General Hospital, 234 Goodman Street, Cincinnati, OH 45267 (May 29, 1979)
In regard to the petition for rule making submitted by George B. Taplin, M.D.
as published in the Federal Register Vol. 44 No. 89, Monday May 7, 1979 page 26817, I wish emphatically to support this petition.
Dr. Taplin, one of the leaders in the field of nuclear medicine and an individual who in his lifetime has developed many important radiopharma-ceuticals which have given great benefit to sick patients throughout the world, objects to a limitation of the Nuclear Regulatory Commission which requires that physicians rigidly follow the package insert of the Food and Drug Administration regarding the chemical and physical form of the agent, 8
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route of administration and dosage range in carrying out clinical procedures -
which have not been approved by FDA.
This requirement is not one imposed by FDA; in fact, they have specifically stayed away from the area of impeding the judgment of the physician in regard to these drugs.
This matter is of extreme importance since in addition to the specific concern of Dr. Taplin in regard to technetium-99m labeled DTPA it applies broadly to all radioactive drugs used ip,'tht-field of nuclear medicine.
Having studied this broad questio'n-for a number of years I aa unaware of
.any judgment exercised either by the NRC or the FDA which demonstrates that the judgment of either of these agencies is an improvement over the judgment of a physician in the care of an individual patient.
The argument purportedly advanced by NRC could be extended to mandate the length of a surgical incision er the number of days for which a patient requires antibiotics or other drugs in the treatment of a specific illness.
I attach to this letter a statemcr.t by the Nuclear Regulatory Commission concerning this goal of minimizirg such needless interference with the development of regulatory procedures issued in the Federal Register Vol. 43 No. 150 of Thursday, August 3, 1978 in response to a request of President Carter.
It is essential that those of us concerned witn teaching, patient care and clinical research be protected from this type of harrassment as it is a serious threat to the health of the citizens of the United States.
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- 18. William M. Smoak, III, M.D., Professor of Radiology, Unia;ersity of Miami School of Medicine, Chief.of Clinical. Nuclear Medicine and Ultrasound Services, Mount Sinai Medical Center, 4300 Alton Road, Miami Beach, FL 33140
(May 31, 1979)
I am writing in >Jpport of the filing of petition for rule making, George V. Taplin, M.D., published in the Federal Register, volume 44, number 89, Monday, May 7, 1979, page 26817.
I am in accord with Dr. Taplin's petition for a change in ruling and believe that his recommendations have significant merit.
Specifically, I support his request that the commission reconsider and rescind the requirement that physicians must use an approved radiopharmaceutical strictly in accord with the manufacturers package insert.
I believe that it is in the best interest of the patient that this modification be considered.
19.
Michael Hayes, M.D., Director, Nuclear Medicine, Memorial Hospital Medical Center of Long Beach, 2801 Atlantic Avenue, Long Beach, California 90801 (May 31, 1979)
I wish to emphatically agree with and support the petition of Dr. George'I.
Taplin to rescind requirement that physicians use approved radiopharmacer-ticals strictly in accord with manufacturers' package inserts.
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Such requirements, although obvioIisly well meant, will in fa a have a poor long term effect - it will ensure the stagnation of medical practice either forcing continued use of outmoded techniques or encourage people to find ways around the rules.
The Commission's authority should not be spent in such a dubious way but preserved for more fundamentally important issues.
It is common knowledge that package inser.ts.gre designed primarily to protect a manufacturer legally - to folbw them to the letter is as often as not detrimental to the interests,of the specific patient.
- 20. ' Howard J. Dworkin, M.D., Chf ef, Departmeni of Nuclear Medicine, William Beaumont Hospital, 3601 West 13 Mile Road, Royal Oak, Michigan 48072 (June 1, 1979)
This letter is to comment upon a petition filed by Dr. George V. Taplin, Division ol Nuclear Medicine, University of California, Los Angeles, California for rule making requesting the Nuclear Regulatory Commission to amend its regulation, " Human Uses of Byproduct Material," 10 CFR Part 35.
I support Dr. Taplin's request to permit physicians greater latitude when working with certain low-risk diagnostic radiopha,maceuticals, that they no longer be required to use an approved -drug (radiopharmaceutical test agent) strictly in accordance with the manufacturer's package insert.
I view this new limitation as being more restrictive than the current FDA regulation, which leaves the route of administration to the judgment of the physician in charge.
This new NRC regulation would preclude the use of certain radioactive drugs which might potentially be of benefit to patients when used by an appropriately trained physician.
In addition, grehter flexibility of dosage range thah' presented in the package insert is also advisable.
I strongly support Dr. Taplin's cl_ aim that, "This change is in direct opposition to the current objectives of both the NRC
.and FDA which permit physicians to use approved drugs according to their best knowledge and judgment and in the interest of the patient.
In my opinion this new reaulction will hinder the development of new safe appli-cations of approver rugs..."
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- 21. Wil B. Nelp, M.D., Professor of Medicine and Radiology, Head, Division of Nuclear Medicine, University Hospital, Univer;ity of Washington, Seattle, Washington 98195 (May 31, 1979)
I am responding to the petition filed by Gcorge V. Taplin, M.D. (Docket Number PRM-35-1) published in the Federal Register, Vol. 44, No. 89 on Monday, May 7, 1979.
j I am very much in accordance with Dr. Taplin's petition and give it my full support.
I feel strongly that the NRC should rescind the requirement i
that physicians must use an approved radiopharmaceutical strictly in accordance with the manufacturer's package insert.
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- 22. John H. Lawrence, M.D., Donner Lchoratory and Donher Pavilion, Berkeley, California 94720 (May 31, 1979) ~~
I am writing to you in support of the petition of Dr. George V. Taplin, Professor of Nuclear Medicine at the University of California at Los Angeles.
This petition is Docket No. PRM-35-1, and is published in the Federal Register.
It requests the Nuclear Regulatory Commission to amend 195 retbnt regulation (" Human Uses of Byproduct Material"),10 CFR Part 35, effective March 20, 1979.
This new regulation requires that physicians must use an approved drug (radio 6harmaceutical test agent such as Tc-DTPA), strictly in accord gith the genufacturer's package insert.
This new limitation is more restrictive than the current FDA Regulation which leaves the route of a,dministration to the jurisdiction of the physician.
The new NRC regulation would preclude the use of Tc-99m DTPA as an aerosol for inhalation lung imaging.
I agree with Dr. Taplin, and this letter is a note of concordance and support for his petition.
23.
C. Douglas Maynard, M.D., Pr esident, The Society of Nuclear Medicine, 475 Park Avenue Sotch, New York, N.Y. 10016 (May 28, 1979)
I would like to take this ocportunity as President of the Society of Nuclear Medicine to reiterate the Society's stand in regard to allowing the practicing physician to select the route of administration and dose range that he feels appropriate for a particular clinical nuclear medicine procedure.
This again is in line with previous testimony that our Society presented in this regard. We fully support the statement by Dr..~ George V.
Taplin, DiviLion of Nuclear Medicine, University of California, Los Angeles, California dated March 28, 1979.
If we can provide any additional informa-tien nlease (o not hesitate to let us-know.
I 24.
Harold L. Chandler, H.D., Mount Auburn Hospital, 330 Mount Auburn Street, Cambridge, Massachusetts 02138 (May 28, 1979)
I wish to register my strong support for the position taken by George V.
Taplin, M.D., Federal Register /Vol. 44, No. 89/ Monday, May 7, 1979/
Notices Page 26817, in opposing the item published in the Federal Register (44 FR 10358).
This amendment clearly constrains intelligent physician use of these agents to the detriment of patient care, while adding no recognizable benefits to the public.
25.
Robert J. Cowan, M.D., Director, Division of Nuclear Medicine, President, Southeastern Chapter, Society of Nuclear Medicine, Wake Forest University, Bowman Gray School of Medicine, 300 South Hawthorne Road, Winston-Salem, North Carolina 27103 (May 29, 1979) i 11
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I am writing you in support of a petition filed by George V. Taplin, M.D.
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which was published in the FederaT Register on Monday, May 7,1979.
This petition requests that the Nuclear Regulatory Commission alter its recent recommendations on " Human Uses Of Byproduct Material".
Specifically, it requests removal of the requirement that physicians when employing a radio-pharmaceutical for a clinical purpose not approved by the FDA limit their route of administration and dosage strictly 'to those in accordance with the manufat:fbrerpackage insert. This would unnecessarily restrict clinical application of radionuclides for medical, purposes and would undoubtedly hender the further development of newerfapplications of drugs already approved for other use.
I doubt,that the NCR wish to so severely restrict physicians in their application of)pproved radiopharmaceuticals.
One example of the undue re'striction would be the use of Technetium DTPA which has recently been evaluated for lung imaging through administration by inhalation.
Other examples could be sited.such as the oral administra-tion of Technetium sulfur colloid to evaluate gastric reflux, pulmonary aspiration or gastric emptying or the administration of colloid materials subcutaneously to evaluate regional lymph nodes.
In order to permit physicians appropriate latitume when-employing low risk diagnostic radiopharmaceuticals, this restriction on strict adherence to the manufacturer insert should be removed.
26.
Zachary D. Grossman, M.D., Associate Professor of Radiology, Division of Nuclear Medicine, State University of New York, Upstate Medical Center, 750 East Adams Street, Syracuse, New York 13210 (May 24, 1979)
I am writing to you in support of the petition by Dr. George V.' Taplin (Docket Number PRM-35-1) recently published in the Federal Registry.
Dr. Taplin requests that the Nuclear Regulatory Commission amend its recent regulation " Human Uses of Byproduct Material", 10 CFR Part 35,
' effective March 20, 1979".
As Dr. Taplin has amply established in the case of Tc-99m DTPA, the recent regulation by the NRC would be unduly restrictive ar.d, in fact, would eliminate an effective and safe use of this pharmaceutical.
Other safe and effective alternative uses of approved pharmaceuticals would also be prevented; for example, the use of Tc-99m MAA for the determination of Leveen shunt patency (see enclosed preprint).
I am sure that on due consideration the Nuclear Regulatory Commission will revise its regulation in accordance with Dr. Taplin's arguments and in accordance with the public interest.
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Ismael Mena, M.D., Professor, Radiological Sciences, Director, Nuclear Medicine Division, UCLA School of Medicine, Harbor General Hospital Campus, 1000 Carson Street, Torrance, California 90509 (June 12, 1979)
L This concerns the filing of a petition by George V. Taplin, M.D. (Docket No. PRM-35-1 published in the Federal Registry, May 7, 1979, requesting the 12
a Commission to amend its regulation " Human Uses of* Byproduct Material,"
This amendment requires the physicians to follow the package insert regarding the chemical and physical form, route of administration and dosage range when they perform clinical procedures that nave not been approved,by FDA.
i Dr. Taplin requests that the Commissioo reconsider and rescind the require-ment that physicians must use an approved rhiopharmaceutical strictly in accord with the mar facturers paqkage insert.
Dr. Taplin refers specifically to the use of Technetium 99m DTPA as.'an aerosol by inhalation for lung imaging.
TcDTPA has been approved by FDA Tor brain and kidney imaging using doses varying between 5 and 20 millicuries per examination and administered intravenously.
Tc-DTPA is an ubiquitous radiopharmaceutical used for many years in Nuclear Medicine in several other applications within the dose range stated by FDA.
Namely, among these applications the most important are: Tc-DTPA aerosol studies by inhalation for lung imaging, Tc-DTPA measurements of gastric empty eng time using 500 microcuries to 1 millicurie, extremely useful studies such as cisternography for deter-mination of CSF leaks where the dose is 1 millicurie.
Aerosol studies are extremely useful for the differential diagnoses of perfusion defects in perfusion lung scans with Tc-macroaggregates in pul-monary embolism.
Gastric emptying is quite in vogue and extremely useful for studies of esophgeal and pyloric regurgitation, and cisternography performed with Tc-DTPA is a very useful procedure for the demonstration of cerebrospinal fluid leaks.
For these reasons I coincide with Dr. GeorgeV. Taplin and resp'ectfully request that the Commission reconsider and rescind the requirement that physicians must use an approved radiopharmaceutical strictly in accord with the manufacturers package insert.
In particular, when staying within the dosage approved by the Food and Drug Administration and the Nuclear Regulatory Commission. This will provide the latitude for nuclear physi-cians to work within the regulations of our institutional human use commit-tees and radiation safety committee and use our ingenuity in the task of
" slaying the common dragon of disease."
28.
Marshall Brucer, M.D., 5335'Via Celeste, Tucson, Arizona 85718 (June 6, 1979) i I support the petition of George V. Taplin, M.D. (Docket No. PRM-35-1) that opposes the regulation requiring physicians to use approved radioactive drugs only in strict accord with the m wafacturer's package insert.
I have had experience in the writing of package inserts for radioactive drugs.
Such inserts are not written to advance any patient's welfare.
Package inserts are written by professional Package Insert Writing Committees solely for the purpose of fulfilling the existing requirements of federal Package Insert Review Committees.
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Package Insert Review Committees yresumably base their requirements on scientific literature involving previous use of the radioactive drug.
Such literature describes an illegal use of the drug in question unless it is preceded by an Investigative New Drug License.
Theoretically any physician, but actually only an organization with considerable financial support, can obtain an Investigative New Drug License.
In current practice the pharma-ceuticat hotts~es who finance new drug applical. ions also finance the studies that feed the literature read by the Package Insert Review Committees who pass judgment on the pharmaceutical housP s* Package Insert Writing Commit-tee.
(I disregard a few scademiq pharmacology departments because their contribution is negligible until it becomes available through these same
-commercial channels.)
I do not imply that this merry go-round of bias is an indictment of the pharmaceutical industry; at least they recognize the imperfection of their product.
It is an indictment of the NRC whose only legitimate reason for existence is public safety.
Because radiation is omnipresent, maintenance of public safety involves two functions:
minimization of risk and maximization of benefit. Any regulatory agency that devotes itself exclusively to either half of these paired aspects is not doing its job.
A requirement that physicians use radioactive drugs only by out-of-date package insert instr tions is Folely risk minimization.
It shows that NRC does not undrcstand the ontogeny of a typical package insert.
Some simplified examples will illustrate:
- Tc-DTPA was scientifically introduced in the late 1960s as a tirain scan-ning agent with a fast kidney excretiorr pattern. A few years later it was introduced commercially as a kidney scan agent.
The manufacturer already had a,profitr.ble brain agent but did not have a glomerular excretory agent.
This' decision was made by an accountant.
But after *Tc-DTPA was available
'and " approved", its advantages as a brain scan agent became apparent to physicians.
Within a few years the manufacturer's accountant changed his mind because the brain / kidney scan ratio was about 100--and so he took the
" renal" out of the product's name.
" Availability" to the mass market is the single most important factor in any scanning agent's popularity.
- Tc-Sn pyrophosphate became,a valuable cardiac blood pool agent because of its primary fault as a bone scan agent:
its tin content labeled red cells.
The disadvantage became an advantage not because the bone scan agent is the best way to administer tin but because it was "available".
- Tc pertechnetate became a thyroid trapping agent, not because of the scientific validity of a package insert but because we spent about four years fighting neck contamination in brain scans.
Radioactive Gallium spent 4/5ths of its entire existence as a bone scan agent.
Not until it became "available" to a mass market did its true value become apparent.
For about 13 years *Tc-sulfur colloid has had a Kuppfer's cell localiza-tion, although for 25 years studies with *Au-colloid proved this impossible.
In vivo rac'iopharmaceutical localization is primarily determined by radio-14
pharmaceutical " availability" in the mass market.' If you don't believe this, you have never had experienFe as a scientific editor.
There is no nuclide--and I include all 2,452 of them--that has a metabolism confined E a ringle organ.
If the NRC were truly concerned with promoting public safety they would require that every nuclide scan be accompanied by a simultaneous scan of a clinically. uninvolved organ, thus assuring the first step ihhnte'r'pretation quality control.
Con'firmation of a clinical diagnosis is an important reas+n for scanning.
But,wh far more important is a fishing expedition.,en a diagnosis is not obvious, Dr. Taplin's specific request for aut'horization of inhalation scans will affect only a few patients., But his disacJreement with the elevation of the Package Insert to the Supreme Court affects most patierits. When Congress authorized the creation of the NRC, I don't think they envisioned the Volstead Act of 1979.
29.
Buck A. Rhodes, Ph.D., Director of Radiopharmacy, The University of New Mexico, Albuquerque, New Mexico 87131 (June 1, 1979)
I agree with Dr. Taplin that the Commission should reconsider and rescind the requirement that physicians must use an approved radiopharmaceutical strictly in accord with the manufacturer's package insert.
Such a requirement is a direct interference in both the practice of medi-cine and the practice of pharmacy.
Although radiopharnceuticals are usually most safely and effectively used in accordance with the instructions on the package insert there~are often situations when the best medical care i's provided by the physician and/or the pharmacist using their expertise to modify radiopharmaceutical used to fit the particular needs of an irdividual patient or clinical situation.
.Thus this regulation decreases, rather than enhances, the overall quality of health care delivery in this country.
30.
Gerald L. DeNardo, M.D., Director, Nuclear Medicine, 4301 X Street, Folb II-E, Sacramento, California 95817 (June 8,;1979)
I wish to support the petition for rule making by George V. Taplin, M.D.
which requests that use of diagnostic radiopharmaceuticals not be restricted to FDA authorized clinical procedures.
NRC has responsibility to encourage minimum appropriate radiation exposure to the general populace, to radiation handlers and to the patient.
In fulfilling this responsibility, it also must not deny patients procedures whose benefit exceeds real or theoretical radiation risks, nor societal benefits of legitimate biomedical investigations.
Radiation exposure is determintd by the amount and type of radiopharmaceutical and not by the purpose of the administration or the por-tion of the anatomy imaged or otherwise studied.
To delve into the latter considerations is to deny the patient or society the benefits of the judge-ment of the physician scienth t.
Indeed it is unrealistic to attempt to do so since there is no practical way to control the process.
By way of example, if one uses a radiopharmaceutical approved by the FDA for liver 15
A.u:
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imaging and then moves the detector so that the l'ungs are visualized, is one in violation? A negative answer seems obvious to us workers in the field.
To be more ridiculous, in the same set of circumstances, a large field of 1
view camera allows one to visualize the kidneys simultaneously with the liver, and this obviously cannot be a vio~stion.
Indeed, the physician may be providing additional benefit to the patient.
Historical precedent clearly indicags th,1t the physician is to be the judge of the benefits of approved drugs within the bounds of peer review and medical malpractice.
y a.
31.
Jack K. Goodrich, M.D., Radiology Ass,ociates of Erie, 104 East Second Street, Erie, Pennsylvania 16507 (June 7, 19797 I am writing to support the petition of George V. Taplin, M.D., Emeritus Professor of Nuclear Medicine and Radiological Sciences at the University of California, Los Angeles, which was published in the Federal Register (Docket Number PRN-35-1).
Dr. Taplin's cogent remarks, criticism and objective suggestions with regard to the rule making amendments concerning,
" Human Uses of By product Materials", 10 CFR Part 35, effective March 20, 1979, enunciate clearly the concerns of thousands of practicing physicians who deliver Nuclear Medicine services to hundreds of thousands of patients throughout these United States.
Dr. Taplin, a pioneer in Nuclear Medicine with specific far reaching contributions in the area of pulmonary function testi,1g using radioactive materials, has chosen a radiopharmaceutical test ager relating to his work in the pulmonary field as an example of the unreasonable limitations that would be placed on the practice of medicine should your amendment be placed in effect.
As a former Chairman of the Medical Advisory Comittee on Radiop'harmaceuti-cals and Contrast Agents for the Bureau ofTrugs, Food and Drug Administra-tion, I am fully aware of the concerns felt by that agency for the protec-tion.of the general public, at the saine time observing the clearly described
.-tenets that relate to the practice of medicine by qualified physicians under the provisions of the Food, Drug and Cosmetic Act, as amended.
The package inserts prepared by manufacturers under the close scrutiny, guidance and regulations by the Food and Drug Administration are intended to guide the clinical applications required by.the physician who has the patient management and therapeutic responsibilities.
The proposed acendment wou'd seriously impinge on the practice of medicine and, indeed, harmfully restrict the ese of radioactive materials in the care of patients.
's amendment f*ould set an inappropriate precedent with respect to the t broader scbpe of prercription drug use in the practice of medicine in ti..
United States.
I urge you in the strongest terms to withdraw this amendment, seek more coherent counsel from the practitioners of medicine, specifically Muclear Medicine, and then reconsider whether or not there is a need to amplify on the present regulations which govern the human uses of by product material.
I enclose my curriculum vitae which defines the axtent of my practice in patient care, medical education and scientific organizational affairs applicable to this commentary.
lo _
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o 32.
Philip M. Johnson, M.D., Professoi of Radiology, Director, Division of
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Nuclear Medicine, College of Physicians & Surgeons of Columbia University, 630 West 168th Street, New York, N.Y. 10032 (June 4, 1979)
This is with regard to a notice published in the Federal Register, Volume 44, No. 89," Monday, May 7, 1979, page 26817 tit 1pd George V Taplin, M.D..
" Filing ef P'etition for Rule Making." Doctor Taplin has requested that the Commission reconsider and rescind t.he rgguirement that physicians must use an approved radiopharmaceutical strfctly in accord with the manufacturer's package insert.
e, Boctor Taplin is an international!y recogdized pioneer investigator in the specialty of Nuclear Medicine.
In particular, he has developed the use of radioactive aerosols for clinical evaluation of abnormalities of pulmonary ventilation.
Enforcement of the present requirement (noted above) would prevent further investigation and clinical use of this important diagnostic modality.
Beyond that specific case, however, the requirement precludes a physician from using an approved drug according to his best knowledge and judgement and in the interest of the patient.
I agree with Doctor Taplin that this new_ regulation will interfere with development of new and improved applications of drugs.
The requirement is an unnecessary intrusion of a governmental agency into the practice of medicine.
Although the intent of the requirement is praiseworthy, its unintended effect is not.
Therefore I strongly support Doctor Taplin and others calling for revocation of the requirement.
l 33.
Milo M. Webber, M.D., Division of Nuclear Medicine, The Center for the Health Sciences, Los Angeles, Californi'a'90024 (June 6, 1979)
I am. sending you this letter to express my full support of the petition of
. George V. Taplin, M.D. who requested that the commission reconsider and rescind the requirement that physicians must use an approved radiopharma-ceutical strictly in accord with the manufacturers package insert as published in the Federal Register (44 FR 10358).
The whole purpose of a patient seeing a physician is to have that physician address himself to the problems of the patient and to diagnose and devise a method of overcoming the patient's illness.
Over the years the ingenuity of physicians has led to the development of near miraculous techniques in both the diagnosis and treatment of human disease.
Physicians must be free to adapt and modify existing techniques to specialized situations if we are to see an optimal result of the use of existing knowledge as well as continuing development of new knowledge which will form the shape of medical care in the future.
The referenced regulation takes away the physician's prerogative to vary the dose levels and the indicators in the case of radionuclides.
This type of regulation - in my considered opinion - will prove to be counterproductive.
It will provide a chilling effect on the innovative spirit and it will tie the hands of those physi-cians who have gccd and valid clinical reason to vary from the instructions given in the manufacturers package insert.
17
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Frankly, I am very surprised that~such a regulation was ever approved by the I
Commission in the first place, I believe that it should be rescinded as soon as possible.
- 34. Walter Wolf, Ph.D., Professor and Director, Radiopharmacy Program, John Stauffer Pharmaceutical Sciences Center, University of Southern California, 1985 Zonal Avenue, Los Angeles, Califor.nia 50033 (June 19, 1979) y Reference is made to the Federal,Registe'r 44 39, p. 26817, May 7, 1979, Docket No. PRM-35-1, in which comme ~nt's are In,vited in relation to the
< petition of Dr. George V. Taplin who requested that the Commission reconsider and rescind the ' requirement that physicians must use an approved radiopharmaceutical strictly in accord with the manufacturers' package insert.
I wholly concur with the intent of this petition.
Radiopharmaceuticals that have been approved by the FDA have been determined to be safe, non-toxic, and effective for the procedure approved.
The petitioner wishes that responsible and qualified physicians in nuclear medicine be allowed to use such agents at dosages and by routes of adminis-tration other than those listed on the package irsert.
While the use of an approved drug for a nonapproved use requires, according to the rules, that we go back to square one, there is a mechanism that the FDA has instituted that might prove equally useful for the NRC in this consideration.
The Radioactive Drug Research Committees (RDRCs) have been set,up by the FDA in order to allow approval, at the local-level, of radioactive drug studies that are limited in number and scope, and hence neeo' not be reviewed by the FDA itself.
'It is proposed that the NRC authorize the RDRCs to grant such authority for radiopharmaceutical usage as Dr. Taplin proposes, subject to review of an appropriate protocol, and with no changes in the additional approvals that are required by the Radiation Safety Committees and the IRB's (Institutional Review Boards) of each: institution.
This expanded use of th'e RDRCs would be in consonance with the philosophy of delegating review and control authority to responsible local specialists and committees.
In at least one institution (the LAC-USC Medical Center) the RDRC has already become the Hospital Drug Committee for Radioactive Drugs, reviewing all their research use in its drug related aspects.
f I hope the above concepts, supporting Dr. Taplin's proposal, will assist the Commission in reaching a decision.
18
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- 35. James J. Conway, M.D., 2300 Children's Plaza, Chitago, Illinois 60614 (June 29, 1979)
-~
I wish to respond to docket number PRM-35-1.
I am in support of George V.
Taplin's M.D. petition to amend the recent regulation published in the Federal Register, volume 44, number 35 on Tuesoay, February 20, 1979, which states "The Commission believes that the use of diagnostic radiopharma-ceuticatt li'sted in groups I, II, and III fo'r clinical procedures not yet approved by FDA entails low risk to the p,atient, provided the chemical and physical form, route of administration,*and the dosage range remain the same as specified in the radiopha,rmaceutical labeling.
My objection to this ruling,is that it inf'ringes upon the physicians right to practice medicine and that the Nuclear Regulatory Commission is assuming the physician's responsibility by this regulation.
I read with great interest and approval The Nuclear Regulatory Commission's policy statement, published in the Federal Register, volume 44, number 29 on Friday, February 9,1979 in which the statement is given that "NRC will not control physician's prerogatives on patient selection, instrument selection, procedure selection, drug selection, and dose level for most diagnostic uses of radioisotopes".
I presumed that this position was adopted because of the acknowledged low risk involved with these radio-pharmaceuticals.
It would seem that the Nuclear Regulatory Commission's contidence in the qualified practitioners of Nuclear Medicine to use these low risk agents woukd apply also to the route of administration, particularly when the dosimetry calculations support their use.
In addition, it is my understanding, as a member of the FDA radiopharmaceu-tical drug advisory panel, that labels which-accompany products are intended as guidelines and not as reoulations.
Labeling often lags behind scientific data accumulated on drug products, and-therefore should be used as a guide-
,.1.ine' at the discretion of the prescribing physician.
The new NRC regulation prempts the intention of labeling to serve as a guideline in the case of these low risk radiopharmaceuticals, and as a consequence the Nuclear Regulatory Commission is infringing upon the qualified physician's respon-sibilities in practicing medicine.
It is requested that the regulation be amended to permit the route of administration of these agents at the discretion of the qualified physician.
36.
Roger H. Secker-Walker, M.D., Professor of Medicine and Physiology, St. Louis University Medical Center, School of Medicine, 1325 S. Grand Blvd., St. Louis, MO 63104 (June 25, 1979)
I am writing in support of Dr. George V. Taplin's petition for Rule Making dated March 28, 1979 and published in the Federal Register, Vol. 44, No. 89, Monday, May 7, 1979; page 26817.
I would urge tnc Commission to reconsider and rescind the requirement that physicians muct use an approved radiopharmaceutical strictly in accordance with the manufacturer's package insert, as required by the 19
Commission Amendment to its regulation 10 CFR Part 35, published in the Federal Register (44 FR 10358).
~
As Dr. Taplin points out, this amendment would prevent the use of Technetium 99m DTPA as an aerosol by inhalation for lung imaging.
Dr. Taplin and his colleagues have shown that this use of Technetium 99m DTPA provides information to the physician which can prove useful in the diagnot,ts arfd management of a variety of pul'monary disesses.
In the process, the patient is exposed to lower levels of radiation than are received during the approved uses of Tectineflum 99m DTPA for kidney or brain scanning.
37.
Paul B. Hoffer, M.D., Profe'ssor of Diagnostic Radiology, Director, Section of Nuclear Medicine, School of Medicine, Yale University, 333 Cedar Street, New Haven, Connecticut 06510 (July 2, 1979)
I strongly concur with Dr. Taplin's request that the Commission reconsider and rescind the requirement that physicians must use an approved radiopharmaceutical strictly in accord with the manufacturers package insert.
The enactment of the ruling without this modification will not only prevent useful applications of current radiopharmaceuticals but also place certain current physician practices in jeopardy.
The rule without Dr. Taplin's modification assumes that physicians who handle and administer radiopharmaceuticals are generally ignorant.of dosimetry considerations or effects of administration of these. agents by alternate routes.
This hypothesis is incorrect. The NRC has established requirements which include extensive trainirig in dosimetry and other aspects of radionuclide administrati.on-prior to licensing.
If the NRC
, believes that, in spite of this, licensees are ignorant of the dosimetry considerations associated with alternative routes of administration, it should achieve improvement in this area by increasing training requirements.
The proposed regulation without Dr. Taplin's modification will prevent early useful application of techniques which involve no increased patient risk.
Moreover the enforcement of the proo2 sed rule without Dr. Taplin's mMifi-cation would make virtually.every clinical practitioner in nuclear medicine guilty of non-compliance.
For example it is common practice for many practitioners to give small quantities of 99mTc-Suifur Colloid orally to define the location of the stomach.
This practice would become a violation.
Even accidental sub-cutaneous or intramuscular injection of a small av unt of radiopharmaceu-tical during intravenous administration would constitute a violation.
I believe the proposed rule without Dr. Taplin's modification would have little benefit and great harm.
Further;aore I believe it will be generally disregarded by physicians engaged in providing good medical care to their patients.
If the purpose of the original rule was to remove the FDA and 20
j NRC from dictating the actual pra_ctice of medicin'e it would best be achieved by including Dr. Taplin's proposed modification.
38.
Frank H. DeLand, M.D., Member NRC Advisory Committee on the Medical Uses of Isotopes, Professor and Chairman, University of Kentucky Albert B.
Chandler Medical Center, Department of Nucle,,ar Medicine, Lexington,
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Kentbck7 40636 (July 5,1979)
Inviewoftherapiddevelopmentsandbb'a'ngesthatoccurinDiagnostic Nuclear Medicine procedures, a rigi.d,or fixed rule such as that in the Federal Register with respect to the package insert (44 FR 10358, effective March 22, 1979, ammendments. to its regulation 10 CFR Part 35) inhibits dissimination of safe and officacious procedures.
I would like to recommend that the amendments rec,uiring the physicians to follow the package insert regarding chemical and physical form, route of administration, and dosage range, be either rescinded or modified so that new safe diagnostic procedures utilizing approved radiopharmaceuticals within tPS approved dosage range be available to physicians for their used based on their clinical judgement.
39.
Peter J. Holm, M.D., Radiologist, Porter Medical Center, Middlebury, Vermont 05753 (June 30, 1979)
I am writing in support of the petition for rule making (Docket # DRM-35-1) filed by Dr. George V. Taplin on March 28, 1979 pertaining to 10 CFR Part 35.
Inhalation lung imaging has become a virtunity necessary part of the adequate diagnostic work up of pulmonary embolus.. Xenen, although available, produces rather poor images.' *A great many unnecessary exams with xenon are performed as it must precede the perfusion scan, which often-proves normal. With the Technetium aerosol, the ventilation scan
. is performed rationally, on those patients who need it.
Your proposed amendment in the regulations would seem to block the use of this valuable procedure.
40.
John Glenn, United States Senator, Unfted States Senate, Washington, D.C. 20310 (June 22, 1979)
Your consideration of the attached from Dr. Eugene L. Saenger of Cincinnati, Ohio would be most appreciated.
(See Comment #17) 41.
Robert E. O'Mara, M.D., Professor of Radiology, Chief, Divisicr. of Nuclear Medicine, The University of Rochester Medical Center, 601 Elmwcod Avenue, Rochester, New York 14642 (July 3, 1979)
I would like to support the petition of Dr. George V. Taplin, noted in the Federal Register /Vol. 44, No. 89/ Monday, May 7, 1979 (Docket No. PRN-35-1) concerning physician judgement in the use of byproduct material.
I agree wholeheartedly with Dr. Taplin's petition concerning the specific example of technetium-99m DTPA.
21
More importantly, I feel that this.new licitation'is far more restrictive than current FDA regulations which leave the route of administration under the jurisdiction of the practicing physician.
I feel that this new amend-1 ment to regulation 10 CFR Part 35 is in opptaition to prior expressed i
objectives of both NP.C and FDA and would hallmark an entry of the Regula-tory Commission into the individual practice of medicine.
Forthelere'a' sons,Iwholeheartedlysupport'thepetitionasoriginatedby Dr. Taplin.
s J
42.
C. John Tupper, M.D., President, Ca'liforni.a Medical Association, 731 Market
' Street, San Francisco, California 94103 (July 12, 1979) i This letter is written in support of Doctor George V. Taplin's petition for rule making, dated March 28, 1979, requesting the Nuclear Regulatory Commission to amend its regulations on " Human Uses of Byproduct Material,"
Limitations placed on physicians as to the route of administration and dosages as indicated on the package insert of FDA-approved radiopharmaceu-ticals are restrictive.
It is our opinion that the route of administra-tion and dosage range should be a discretionary matter dctermined by medical judgement when a physician uses an approved radiopharmaceutical for a clinical procedure that is not included in the package insert information.
Existing regulations may in some instances, preclude the ust of such approved radiopharmaceuticals for procedures of medical value in patients with specific medical problems.
We therefore urge the Commission to further amend 10 CFR Part 35 to allow physicians discretion in the use of FDA-approved radiopharmaceuticals when such.use is in the best interest of medical care.
Thank you for an opportunity to present our views and comments on the regulations.
i 43.
George V. Taplin, M.D., Emeritus Profe'ssor of Nuclear Medicine and Radio-logical Sciences, Past President National Society of Nuclear Medicine, University of California, Los Angeles, Division of Nuclear Medicine, The Center for,the Health 3ciences, Los Angeles, California 90024 (August 13, 1979)
I am writing in response to my petition dated March 28, 1979, requesting the Nuclear Regulatory Commission to amend its regulation " Human Uses of Byproduct Material", 10 CFR Part 35.
l i
The petition requested the Commission to reconsider and rescind the requirement that physicians must use an approved drug strictly in accord with the manufacturers package insert. The petition stated that the new NRC limitation in this respect is definitely more restrictive than the 22
o current FDA regulation which leaves the route of administration to the jurisdiction of the physician.
mf specific disagreement with this new restriction is that it would preclude the use of Technetium 99m DTPA as an aerosol by inhalation for lung imaging.
This request is considered a petition for rule making as provioed in 10 CFR 2.802 of the Commission's regulations.
I understand my petition has beetdocketed to recognize my request anti has been assigned Docket No. PRM-35-1 and a notice of the petition and request for comments has been publisher: in the Federal Registry.'f[ ^
I would like to bring to your att'ention at this point that I have received
< ho. correspondence from you concerning the ' petition, although it ts 5 weeks past the July 6 deadline fo'r persons to comment on the petition either favorably or otherwise.
Furthermore, you have not furnished me with copies of any of the comments which have been received in response to the notice of the filing.
I recognize that you may well have been busy with other matters which is likely to consume the bulk of your time during the next two moni.hs.
It has been brought to my attention by Mr. Ken George of Union Carbide Corporation that in a recent telephone conversation with you that the use of a radioaerosol could still pose radiological safety problems similar to those with Xenon-133 gas and that this radiation exposure might still restrict or impose special rules on the use of radiodiagnostics in aerosol form.
Personally, I have heard from several physiciant who are now having difficulty in meeting all the NRC rules for the use of Xenon-133 gas.
I would like to point out to you that the problems are fantastically smaller with the aerosol vs. the Xenon method of inhalation lung imaging.
In the first place, the half-life of 6 hours6.944444e-5 days <br />0.00167 hours <br />9.920635e-6 weeks <br />2.283e-6 months <br /> for the technetiurg-is 20 times shorter than the 5 day half-life of Xenon-133.
Furthermore, the bacteria filters used to collect the expired air from the patient are reported by the manufacturer to exclude bacteria. larger than 0.2 micrometers in diameter.
In fact, they fail to pess cigarette smoke, whica measures approximately
,30 mi111 micrometers in size.
Furthermore, in our experience with radioaero-sols of various types over the past 14 years, our radiological safety personnel have never found evidence of contamination with any of the radio-aerosols used.
These include Technetium 99m sulfur colloid, Technetium 99m DTPA, Technetium 99m human serum albumin and Indium-113m albumin colloic.
These agents are being used throughout the United States, Europe, South America and Japan by those physicians licensed to use radioactive diagnostic indicators.
We have used these aerosoir legally on the basis of the FDA regulations; and the regulations of our state and local radiation safety and human use protection committees.
There is no valid reason why any o' these low risk agents which produce less radiation exposure to the patient than similar radiographic examinations should not be used by any physician licensed to use low risk radioactive indicators according to their best interest and judgment and for the benefit of the patient.
Certainly, the latest restriction of the NRC not only stifles research and development but prevents the use of widely toplicable and highly useful diagnostic agents in the practice of medicine.
More than 40 publications-are available in the open literature (from 1955 - 1979).
j 23
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At this time, I would like to bring to your attention that during the past several weeks I have received more than 30 highly favorable responses to my petition from the key people in the practice of Nuclear Medicine in the United States including the recent and current president of the society plus nearly half of the members of the beard of trustees.
In general, their comments strongly favor my limited petition.
In addition, they believe that many other agents in.the same c,ategory are not being used for similahrra't'ional reasons and certainly not on the basis of good medical experience and judgment.
Personally, I would like to make the comment that in 1963 it took 6-8 months to get worliWide application of albumin macro-aggregates for a perfusion scanning which are far more hazardous than the inhalation of an aerosol of the same type albumin.
If I had tried to introduce albumin macroaggr.egates for perfusion scanning in 1975 in this country, I would still be awaiting response and approval from the FDA and the NRC and possibly this might not be obtained for as long as 5 to 10 years.
I would now like to bring to your attention a letter dated May 29, 1979, to the Secretary of the Commission by the highly esteerred radiologist Eugene L. Saenger, Professor of Radiology, Radioisotope Laboratory, Cincinnati, Ohio.
[ Quotes Dr. Saenger's letter at length.
See Comment #17.]
These copies are being forwarded to speed action on my petition because Mr. Podolak is consumed with other important business during the next 2 months.
P.S. If no response is received in 2 weeks, expect to be bombarded with even more influential letters.
/
,e 44.
K. D. George, Senior Development Scientist, Union Carbide Corporation, Medical Products Division, P.O. Box 324, Tuxedo, New York 10987 (August 21,
.1979)
We believe that in the case of approved low-risk diagnostic radiopharmaceu-ticals, the physician should, in the interest of good medical judgment, not be requird to follow the package insert for all clinical procedures utilizing these drugs.
We, therefore, support and endorse the referenced petition.
In the specific instance cited in the petition, namely the use of 99"Tc-DTPA in aerosol form, some concern has been expressed about the radiological safety aspects of the radiodiagnostic in this form.
Comparison has been made with gaseous 133Xe, which has safety considerations different from those of the usual IV-injected liquid drugs.
It is desired to point out that the aerosol form of DTPA (and similar agents) is typically a fine mist of liquid droplets with particle sizes around 1-2 micrometers.
Thir. aerosol is easily controlled and, unlike xenon gas, is easily trapped with 100%
efficiency.
Forther, unlike xenon, which is merely delayed in passage by a charcoal trap, the trapping of an aerosol is permacnt.
The man-flow bacterial filters that are used in inhalation therapy to filter out 0.2 mm pathogenic bacteria have been found to be completely effective in trapping 24
A exhaled radioactive aerosols.
In fact, there are* commercially available units for producing and trapping such aerosols that employ bacterial filters.
Other safety advantages of 99"Tc aerosols derive from the limited disper-sion of the droplets which, unlike a gas, do settle by impaction and gravity, and from the much shorter half-life of Tc-99m compared to Xe-133.
An early and favorable action on this petition is considered to be a positive contribution to good health ce.ro and to the diagnosis of life threatening illnesses.
,.y 45.
Robert L. Meckelnburg, M.D., Dela' ware Medical Laboratories Inc., Pike
, Creek Center, Wilmington, Delaware 19808 (May 10, 1979)
I strongly concur with the petition of Dr. Taplin to delete the present limitations on the use of approvec radiopharmaceuticals for non-listed indications. The use of the radiopharmaceutical in question, technitium 99m DTPA as an aerosol for lung ventilation scanning is quite cogent.
This particular agent's use would obviate some of the most difficult problems in radiation control in nuclear medicine laboratories that are continuing to utilize radioactive zenon as a scanning agent.
The radioactive gases require the most elaborate control systems in nuclear medicine laboratories and emit exposure to all concerned whereas the use of an aerosol readily reduces this exposure and in particular practically eliminates the airborne contamination in the surrounding atmosphere.
It is extremely unlikely that the commercial manufacturer of the radiopharma-ceutical will go to the time and expense for submitting an IND for this new application.
Thus, under the present rules the chance for, utilization of an improved methodology would be stified.-
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Summary and' Analysis of Comments:
l These 45 comment letters from 51 respondents all support Dr. Taplin's petition.
The respondents are prestigious representatives of the nuclear medicine profes-sion.
The primary reason Dr. Taplin petitioned NRC to remove its restrictions on the chemical and physical form, route of administration and dosage range of radio-active drugs (restrictions that apply only to NRC group licensees and only when physicians are using FDA-approved radoactive drugs for clinical procedures that do not have FDA approval) was his concern that the aerosol use of Tc-99m DTPA be available for lung function studies.
Tc-99m DTPA has been approved by FDA as an injection for clinical procedures unrelated to lung function studies.
Tc-99m DTPA has not been approved by FDA either as an aerosol (physical form) or by inhalation (route of administration) or for lung function studies (clinical procedure).
Thus, its use is prohibited by S 35.14(b)(6) for group licensee because the physical form and route of administration do not conform with the FDA approved labeling and the drug would be used for an unapproved clinical procedure.
25 i
n L
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J' The comenters supported the use of Tc-39m DTPA for lung fuIction studies as a low risk, clinically useful procedure.
Some stated that Tc-59m DTPA was che ;per and more readily available than Xenon-133.
Most of the commenters also addressed the broader thrust of the petition--that the NRC restrictions were interference in the practice of medicine.
They pointed out that phypiciap.s needed greater latitude in their use of radioactive drugs, that the dosage range and route of administration were discretinnary metters, and that the physician is best suited to make a decision as 'to how to use a radioactive drug.
Several commenters stated'that the package insert is not f
authoritative, that the labeling is merely guidelines which lag behiwJ the technology, and that it is in the best interest.of patierts for physicians to t a radioactive drugs in a manner not in the package insert.
Several comenters gave examples of unapproved uses of FDA-approved radicacthe drugs:
(1) Tc-99m sulfur colloid administered orally for studying gastro esophageal reflux and gastric emptying time; (2) Tc-99m suflur colloid injected into the peritoneal space prior to administering therapeutic doses of radioactive colloids; (3)
Tc-99m Sn pyrophosphate for red blood cell labeling; (4) Tc-99m MAA for LeeVeen shunt patency; and (5) Tc-99m for gastric emptying time and cisternography for determination of cerebrospinal fluid leaks.
Several commer.ters pointed out that under FDA regulation a physician can use any approved drug without restriction for any clinical procedure because FDA.
does not regulate the practice of medicine.
They believe that the NRC rest:4c-tions will have a chilling effect on innovation, preven'.,the development of new applications and cause the stagnation of medical precticerby chaining the physicians to outmoded techniques.
Many commenters cited thy unrivaled safety record of nuclear medicine where adverse reactions are low.
The restrictions on the chemical and physica'i f6rm of ruficactive drugs, routs i
of administration and dosage range (restrictions which apply inly for clinical' procedures -not approved by FDA) were intro ~d0ced by the Commission in March 1979
[44 FR 10358), when the Commission relaxed its regulations for the group medical licensees by no longer designating the authorized clinical procedures for diagnostic radiopharmaceuticals.
Prior to this, all group medical licensees were restricted to the FDA-approved clinical procedures.
The Commission introduced the restrictions'Iin 5 35.14(o)(6) in order to ensure the safety of FDA-approved radioactive drugs for clinical procedures that have not been approved by FDA.
FDA approves a radioactive drug as safe and effective for specific c1Mnical procedures (indications).
The safety determination is related to the ' chemical and physical form, route of administrations, and dosate_
range.
Therefore, the Commission decided to restrict physicians to the FDA-approved chemical and physical form, route of administration, and dosage range when the physician de;mrts from the FDA-approved clinical proced'.:re.
The staff recognizes that the regulations in 5 35.14(b)(6) are more restrictive than FDA regulations which do not constrain physicians to any of the provisions 26
in the package insert.
However, FDA cautions that the physician departs from
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the package insert at his own risk and with the knowledge that use of the drug for that particular (unlabeled) purpose is not supported by substantial evidence of safety and effectiveness.
Also, FDA regulations prohibit radioactive drug manufacturers 1 rom marketing (advertising, distributing, and selling) radioactive drugs for unapproved uses.
However, the4taff believes that the NRC restrictions are necessary to ensure the safety of radioactive drugs when they are used for clinical procedures that do not brie FDA approval.
Therefore, th( staff is recommending that the Commission make an exception to the restrictions in its regulations to permit Tc-99m pentatate sodium for lung funct' ion studies.
Even with the exceptions, the st'aff recognizes that the'NRC restrictions will have an effect on innovation for group licensees. liowever, the group licensing concept was not designed for research although it does allow the use of investi-gational radioactive drugs.
NRC has two typis of specific licenses for the human use of byproduct material:
the medical license of broad sccpe and the group medical licerse.
l Typically, the broad medical licensee is a large research institution or university hospital. The broad medical licensee establishes its own internal controls for the use of byproduct material in humans.
These licenstes are not limited to the use of FDA-approved radioactive drugs.
In order to obtain a medical license of broad scope, the applicant must demonstrate adequate facilities, personnel, program controls, and equipment to administer this substantial responsibility.
In contrast to the medical license of broad scope, the group medical.-license was designed to allow physicians and communi-ty bcspitals with limited facilities, personnel, program controls, and equipment wide access to nuclear medicine services.,Due to their technical limitations, group medical licensees bive greater controls placed on them.
For evample, the " groups" in $35.100 contain only' radioactive drugs that are the subject of an FDA-approved "New Drug Application" (NDA), or a Notice of Clained Investigational Exemption for a New Drug" (IND) that has been accepted by FDA.
Some commenters erroneously believed that the NRC restrictions on cheraical and physical form, route of administration u d dosage range apply to all NRC medical licensees, or that the restrictions apply when the physician is using an FDA-approved radioactive drug'for an FDA-aprroved use.
The NRC restrictions do not apply to broad licensees nor do they apply to FDA-approved uses.
Therefore, the staff is proposing an exception to the regulations to permit Tc-99m pentatate sodium for use in lung functix studies.
This would occur only after a determination of radiation safety is made by the staff, as would be the case for any other procedure that might be added to the list of exceptions in the future.
27 Exlosure 2
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6 ENCLOSURE 3 i.
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i RADIATION DOSE FOR LUNG FUNCTION STUDY The radiation dose from Tc-99m pentatate sodium for lung function studies (3 mci usual dosage) is:
0.03 rad to the whole body; 0.21 rad to the lungs; 0.16 rad to the kidneys; and 0.66 rad to the bladder.
By comparison, the radiation dose'from Tc-99m pentatate sodium for a brain scan (20 mci usual dosage) is:
0.32 rad to the whole body; 0.84 rad to the kidney; and 11.1 rad to the bladder.
Also by comparison, the radiation dose from Xe-133 (20 mci usual dosage) for a lung function study is:
0.0008 rad to the whole body and 0.30 rad to the lungs.
From the standpoint of occupational exposure and exposure to the general public, Tc-99m pentatate sodium, at least theoretically, has advantages over Xe-133 because the aerosol is easier to collect than the gas.
As a practical matter, occupational radiation exposures from preparing the aerosol may cancel this advantage.
However, the staff has found that requiring the physician to administer the radioactive aerosol with a c1osed, shielded system that is either vented to the outside atmosphere or provides for collection and disposal of the aerosol is necessary to keep occupational exposures as low as is reasonably
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achievable (ALARA).
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N ENCLOSURE 4 a
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i Minutes of FDA-NRC Meeting On the afternoon of December 7, 1979, 30 members of the Food and Drug Administration (FDA) and the Nuclear Regulatory Commission (NRC) met to discuss three isssas:
(1) NRC restrictions on unapproved uses of FDA approved radio-l pharmaceuticals; (2) the regulation of nuclear pharmacy; and (3) communications.
The meeting was held at the Parklawn Building, Rockville, Maryland.
The prin-cipals were Richard E. Cunningham, Director, Division of Fuel Cycle and Material l
Safety, Office of Nuclear Material Safety and Safeguards, NRC, and Jerome A.
Halperin, Deputy Director, Bureau of Drugs, FDA.
This was the second in a series of meetings between the FDA and NRC on the regulation of radioactive drugs, a task which is shared by the two agencies.
NRC Restrictions on Physicians' Use of Approved Drugs for Unapproved Clinical Procedures Essentially, under NRC regulations in 10 CFR Part 35.14(b)(6), NRC " Group" medical licensees using FDA-approved diagnostic radioactive drugs for clinical procedures that are not included in the drugs' labeling as approved indications are required to comply with the drug labeling regarding (1) chemical and physical form, (2) root of administration, and (3) dosage range.
An "FDA-approved" radio-active drug is one which has been approved for marketing and for which a "New Drug Application" (NDA) has been filed.
"Appreved" indications are those proce-dures listed in the drug's labeling for which the manufacturer has demonstrated t.1e drug to be safe and effective. The standard of effectiveness for those 1
uses specified in the package insert is " substantial evidence" based upon adequate and well-controlled studies (clinical trials in humans).
The crux of the problem addressed at this meeting is that FDA regulations do not restrict the individual physician's use of a drug solely to those indica-tions listed in the approved labeling.
FDA believes that the approved labeling represents an authoritative statement of those uses for which substantial evidence of effectiveness has been shown.
However, a physician is not precluded, under FDA statutes and regulations, from using any drug for indications not-included in the package insert in the diagnosis or treatment of a patient.
The NRC under its statutes and regulations is responsible for protection of the public health and safety in the use of byproduct material.
These statutes and regulations provide authority to the NRC to regulate physicians' use of radiopharmaceuticals and to take into account the safety and efficacy of drugs administered to patients.
In order to avoid duplication of regulation, the NRC accepts FDA's assurance thao these radioactive drugs are safe and effective i
for the labeled indications
e., FDA-approved NDA) or that clinical studies have been authorized by FDA demonstrate safety and effectiveness (i.e., IND accepted by FDA).
Under NRC regulations most physicians are limited to using radioactive drugs for their labeled indications or for indications within the limits of the " Group" license.
(The "Gresp" medical licenses authorize use of NDA or IND drugs.) " Broad" medica 7 licensees are tst limited by NRC to this same restriction.
They may per/orm research and development of new radioactive drugs t
and drug uses, prov ded the licensee's Medical Iso;.oes Committee reviews and approves:
(a) t'.e training and experience of the physician-user, (b) the proce-dures used to ensure drug quality, (c) the in-vitro and animal studies indicating t
that use in patients is appropriate, (d) the oretrici to ce followed including 2
i such factors as patitnt selection, dosage range, radiation dosimetry and anti-cipated results, and (e) radiatinr. safety procedures to be followed.
l Mr. Cunningham expressed his belief that NRC should limit radioactive drug uses to approved indications unless NRC has reasonable assurance that health and safety will not be jeopardized.
Because drug safety and effectiveness are under FDA's purview, NRC looks to FDA for the needed assurance.
FDA has e mechanism, the IND, for authorizing the investigation of new drugs or new uses of drugs.
The specific question was whether FDA would agree to issuing individual INDs to physicians who want to use radiopharmaceuticals for unapproved indica-tions.
The IND, " Notice of Claimed Investigational Exemption for a New Drug,"
is FDA's regulatory mechanism for a sponsor, usually a drug manufacturer, to obtain the clinical data on human subjects that is necessary to demonstrate the drug's safety and effectiveness required for marketing approval.
An indi-vidual physician may also sponsor an IND.
Under NRC regulations, IND rsdio-active drugs are essentially exempt from the NRC restrictions on unapproved uses of -pproved drugs.
Thus, NRC believes the physician-sponsored to IND could become the primary mechanism for using approved drugs for unapproved uses without the NRC restrictions on chemical and physical form, route of administra-tion and dosage range.
NRC favors this approach, because there would be some Federal (FDA) control over unapproved uses of approved radioactive drugs.
From FDA's standpoint, requiring individcal physicians to obtain INDs for unapproved uses is u. acceptable.
Physician-sponsored INDs are generally not productive for developing the quality of clinical data necessary for estan-lishing substantial evidence of effectiveness.
They cre primarily intended for research purposes.
FDA believes that no useful purpose would be served o" requiring such INDs and, moreover, such a requirement woula impose an impossible 3
workload on its already strained resources and would divert its staff from higher priority IND or NDA reviews.
Mr. Halperin stated that FDA will not agree to a requirement which will impose such a burden upon the Bureau of Drugs or upon physicians who use radioactive drugs.
In FDA's opinion, these INDs are unneces-i sa ry.
NRC believes that an NDA-drug which a physician uses for non-NDA purposes, particularly if a different route of administration or dose range is employed, can raise substantial questions about safety.
Several possible solutions to this problem were proposed.
While none was optimal, the group did agree that NRC would identify the most common " unapproved" uses it has found through its inspections of physician licensees, license amend-ment requests and inquiries from Agreement Statos.
NRC will provide FDA with any literature references or any other data or information which might support the effectiveness for unapproved uses.
At the same time, FDA agreed to work with the radiopharmaceutical companies and its Radiopharmaceutical Drug Advisory Committee t' determine if substantial evidence of effectiveness for the
" unapproved" uses exists so that they can be added to the drug's labeling as approved indications.
NRC believed it had less than six " unapproved" uses that it will refer to FDA.
Two other potential solutions, which were put on the back burner because of FDA-identified problems, are:
(1) The expanded use of FDA's Radioactive Drug Research Committees and (2) standardized investigational protocols.
Nuclear Pharmacies Nuclear pharmacies were identified by both agencies as a vexing aspect to the regulation of radiopharmaceuticals.
Activities of nuclear pharmacies may range from performing simple manipulations, :cch as measuring individual doses 4
of FDA-approved radioactive drugs to performing complex radiochemical procedures and preparing radicactive drugs or " cold" kits from raw materials.
A nuclear pharmacy's busir.ess may extend from servicing a single medical institution to dispensing radioactive drugs to hospitals in a large geographic region.
In most cases, however, activities are confined within the state borders in which it is located.
One important aspect of the problem is the difficulty in estab-lishing when a nuclear pharmacy has gone beyond the ordinary practice of pharmacy (compounding and dispensing) and becomes a drug manufacturer.
In fact, it is likely that many nuclear pharmacies are both, i.e., pharmacy and manufacturer, simultaneously.
Both FDA and NRC have become concerned about the scope of the operations of some nuclear pharmacies.
Both agencies also expressed concern about the products prepared and distributed by pharmacies, which 'n some cases are like small manufacturers.
For its part, FDA is preparing guidelines for nuclear pharmacies which will define those operations which it believes are manufac-turing and, thus, are beyond the normal pharmacy practices provisions of the federal Food, Drug and Cosmetic Act and FDA regulations, including good manu-facturing practices (GMPs) and certain labeling and recordkeeping provisions.
Drug manufacturers are subject to all such provisions and are inspected at least once every two years for compliance.
For its part, NRC is not making a distinction between nuclear pharmacies and radioactive drug manufacturers for purposes of assuring patient safety and is only licensing nuclear pha~wacies to provide physicians with FDA-approved radioactive drugs, i.e., those radioactive drugs that have an FDA-approved NDA or for which FDA has accepted an IND.
NRC indicated it will use FDA's guidelines to determine whether the establishment should be licensed as a nuclear pharmacy j
or a manufacturer.
However, NRC plans to continue its policy of limiting all of 5
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its medical licensees (including nuclear pharmacies) to using those radioactive drugs for which the safety and effectiveness have been established through FDA's NDA process or are being established through FDA's IND process.
Mr. Halperin expressed the view that NRC's position does not recognize a legitimate role of pharmacy, i.e., to compound and dispense a unique prescription for an inoividual patient upon the prescription of a physician.
He noted that not all radioactive drugs will be the subject of an NDA or IND and that a physi-cian may choose to employ such a drug for a specific purpose.
The NRC agrees that the role of a pharmacy might be different from that of a manufacturer',
but it begs the fundamental issue, i.e., no matter what the source of the drug, the patient should be entitled to similar assurances of safety under NRC statutes and regulations.
In order to aid the public's understanding of how the two agnecies regulate nuclear pharmacies, FDA agreed to include a paragraph in its guidelines to alert readers that NRC's policy may be more restrictive.
Interagency Communication The last subject discussed at the meeting was communication between the two agencies.
One stumbling block which can be minimized is FDA's Freedom of Information (FOI) regulations.
Presently, FDA documents must be cleared through FDA's FOI procedures before they can be given to NRC.
This problem is being mitigated by FDA expediting NRC requests.
The ultimate solution, however, may be for NRC and FDA to have a Memorandum of Understanding, in accordance with FDA's FOI regulations, which would allow information to flow freely from FDA to NRC.
In the interim, FDA will respond to specific information requests from NRC on an ad hoc basis.
There is no apparent problem with information flowing in the other direccion, i.e., NRC to FDA.
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In the future, both agencies agreed to cooperate in dealing with problems of common interest.
The problem of nuclear pharmacies is a good example. There has been a substantial exchange of inspection information between NRC and FDA, and both agencies plan to coordinate their efforts in this area in the future.
The meeting concluded with an agreement that smaller groups will meet whenever necessary to discuss specific items of mutual concern.
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ENCLOSURE 5 r
I L
f POLL OF THE ADVISORY COMMITTEE ON THE MEDICAL I
USES OF ISOTOPES In late February 1981, the staff polled the members of the Advisory Committee on the Medical Uses of Isotopes (ACMUI) by telephone on the all-or-nothing question of either retaining or deleting the restrictions in 535.14(b)(6).
Of the eight members and one consultant who were available, five members favored retaining the restrictions in S35.14(b)(6), and +hree members and one consultant favored deleting the restrictions.
In June and July of 1981, the staff again polled the members of the ACMUI by telephone on the question of p, posing an exception from the restriction in l
635.14(b)(6) for Tc-99m pentatate st - ' ' lung function studies.
Of the eight members and one consultant who seie available, six members and one consultant favored the proposed exception.
Two members preferred to reserve judgment until the ACMUI meeting in August.
i At the most recent meeting of the ACMUI on August 31, 1981, it was the consensus of the Committee that exceptions to the restrictions in 935.14(b)(6),
i such as the use of 1c-99m pentatate sodium for lung function studies, be granted j
after a determination of radiation safety is made by the staff.
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ENCLOSURE 6 a
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[7590-01]
NUCLEAR REGULATORY COMMISSION 10 CFR Part 35 PHYSICIAN'S USE OF RADI0 ACTIVE DRUGS AGENCY:
Nuclear Regulatory Commission.
ACTION:
Proposed Rule.
SUMMARY
The Nuclear Regulatory Commission (NRC) is considering amending-its regulations in order to provide an exception from certain regulatory i
requirements for Tc-99;. pentatate sodium used for lung function studies.
Present NRC regulations state that when a physician uses a drug approved by the Food and Drug Administration (FDA), such as Tc-99m pentatate sodium, for an unapproved use, such as lung function studies,the physician must follow FDA-approved labeling for (1) chemical and physical form, (2) n ute of administration, and (3) dosage range.
Under the proposed amendment, the physician would be able to use Tc-99m pentatate sodium for lung func-tion studies without regard to these restrictions.
In the future, NRC may list other radioactive drugs and clinical procedures as exceptions to the FDA-approved labeling restrictions.
This proposed rule would relieve a majority of NRC's medical licensees from regulatory requirements.
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DATES:
Comment period expires
, 1981.
Comments received after this date will be considered if it is practical to do so, but x
Insert date 60 days after publication of proposed rule in Federal Register.
1
[7590-01) assurance of consideration cannot be given except as to comments received on or before this date.
ADDRESSES:
Eubmit written comments and suggestions to:
the Secretary of the Commission, U.S. Nuclear Regulatory Commission, Washington, D.C.
20555, Attention:
DockekingandServiceBranch.
Examine copies of comments received at: the Commission's Public Document Room at 1717 H Street NW., Washington, D.C.
FOR FURTHER INFORMATION CONTACT:
Deborah A. Bozik, Office of Nuclear Regulatory Research, U.S. Nuclear Regulatory Commission, Washington, D.C. 20555 (Phone 301-427-4566).
SUPPLEMENTARY INFORMATION:
By letter dated March 28, 1979, George V.
Taplin, M.D., (deceased) filed a petition for rulemaking to remove NRC restrictions which apply when physicians use FDA-approved radioactive drugs for clinical procedures that do not have FDA approval.
NRC RESTRICTIONS
.NRC licenses institutions and individual physicians in private l
practice to use byproduct material on humant under the group 1 medical license.
' Radioactive materials in S35.100 of 10 CFR Part 35 are divided into six-groups, each group having similar requirements for user training and experience, facilities and equipment, and radiation safety procedures.
The purpose of this grouping is to reduce administrative costs by elimi-nating the need for licensees to seek an amendment to their license each l
time they wish to use an additional radiopharmaceutical in a group for which they are licensed.
Under the grouping procedure, an application for a specific license for the use of any one radiopharmaceutical in a partic-ular group is treated by NRC as an application for all radiopharmaceuticals in that group.
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The group medical license was designed to allow physicians and community hospitals wide access to nuclear medicine services. The
" groups" in 535.100 of 10 CFR Part 35 contain only radiopharmaceuticals that are the subject of an FDA-approved "New Drug Application" (NDA), or a " Notice of Claimed Investigational Exemption for a New Drug" (IND) that has been accepted by FDA.
NRC regulations in 535.14(L)(6) of 10 CFR Part 35, which apply to the group medical licensees, provide that when a physician uses byproduct material for clinical procedures other than those approved by FDA and
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specified in the product labeling (package insert), the physician must follow the product labeling regarding:
(1) chemical and physical form, I
(2) route of administration, and (3) dosage range.
These restrictions do not apply to the larger medical institutions possessing the NRC broad medical licenses where both the credentials of the physicians and all proposed uses of radioisotcpes are reviewed by a specifica111y appointed Radiation Safety Committee (RSC) which has been i
approved by NRC.
b BASIS FOR NRC RESTRICTIONS Using radioactive drugs safely requires consideration of (1) the radiation safety of the patient and (2) the radiation safety of the worker.
The radiation safety of the patient is considered by FDA when it approves the radioactive drug.
FDA approves an NDA if it finds substantial evidence of safety and effectiveness for the drug's intended use (clinical indica-tion).
This FDA finding is based, in part, on clinical data submitted by the NDA sponsor.
The appreved drug has labeling (package insert) that i
speciTies the FDA-approved clinical indication, chemical and physical 3
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form, route of administration and dosage range.
However, FDA does not require that the physician follow the drug labeling, because FDA does not regulate the 'ractice of medicine.
The radiation safety of.the worker is considered by NRC when the staff conducts a safety review before incorporating the radioactive drug into the 10 CFR 35.100 ' groups' to ensure that the radiation dose to the worker is within 10 CFR Part 20 limits and consistent with the ALARA principle.
NRC relies primarily on FDA's determination of a radioactive drug's safety and effectiveness for its group medical licensees.
However, NRC does place restrictions on the chemical and physical form, route of administration, and dosage range--restrictions *,at apply only when the physician departs frora the FDA-approved clinical indication.
The basis for NRC's restrictions is that if the effectiveness of the. clinical procedure has not been established (i.e., it does not have FDA approval),
then NRC is relying on the safety of the FDA-approved chemical and physical form, route of administration, and dosage range.
Stated alternatively, by restricting the physician to the FDA-approved chemical.
and physical form of the radioactive drug, route of administration, and dosage range, NRC is attempting to ensure the safety of the radioactive drug and radiation safety to both the worker and the patient while allowing the physician leeway regarding the effectiveness of the clinical procedure.
THE PETITION A petitioner, Dr. Taplin, requested that the Commission rescind its restrictions on the FDA-approved chemical and physical form, route 4
[7590-01]
of administration, and dosage range of the radioactive drug when a physician uses the radioactive drug for clinical procedures that have not received FDA approval.
See petition for r>1emaking (PRM-35-1) published in the Federal Register (44 FR 26817) on May 7, 1979.
The petitioner stated that these NRC regulations were definitely more restrictive than'the current FDA regulations.
Specifically, the petitioner pioneered the use of Tc-99m pentatate sodium (formerly called DTPA) as an aerosol for lung function studies, and wanted this clinical procedure to be available to all NRC group licens'ees.
The petitioner stated that the Tc-99m pentatate sodium lung function study provides additional clinical information over the FDA-approved xenon-133 lung function study and with a lower radiation exposure than other FDA-approved uses of Tc-99m pentatate sodium.
Tc-99m pentatate sodium has not been approved by FDA as an aerosol (physical form) or by inhalation (route of administration) or for lung function studies (clinical indication).
Thus, this use is prohibited by 935.14(b)(6) for NRC group licensees, because the drug would be used for an unapproved clinical indication, and because the physical form and route of administration do not conform with the FDA-approved labeling.
FOOD AND DRUG ADMINISTRATION FDA regulations prohibit radioactive drug manufacturers from market-ing (advertising, distributing, and selling) radicactive drugs for unapproved uses.
Normally, when a drug is being marketed for a different route of administration, FDA requires either that the original NDA be supplemented to show that the drug is safe and effective for that route of administration; or, if that route of administration is also for an 5
[7590-01]
entirely different clinical purpose, FDA frequently requires an entirely new NDA, supported by controlled clinical trials to demonstrate that the drug is effective for that use.
However, FDA regulations do not restrict the individual physician's use of a drug solely to those indications listed in the approved labeling.
FDA believes that the approved labeling represents an authoritative statement of those uses for which substantial effectiveness has been i
i shown.
Basically, under FDA regulatiSis, a physician may use a drug for a clinical indication, chemical and physical form, dosage range or route of administration not expressly labeled in the package insert.
FDA cautions that the physician does so at his own risk and with the know-I ledge that use of the drug for that particular (unlabeled) purpose is not supported by substantial evidence of safety and effectiveness.
In addition, early attempts between NRC and FDA were made to find an institutional solution to enable FDA to address the general problem of drug labeling for unapproved indications.
Medical advisory committee meetings at both NRC and FDA ha,a also attempted a resolution of Dr. Taplin's petition which is part of the general problem of updating drug labeling.
The Commission is aware that FDA is considering a program to add recent but "well established" clinical indications to the labeling of previously approved radioactive drugs.
FDA has identified drugs in widespread use for unlabeled clinical indications.
h PUBLIC COMMENTS The Commi:sion sclicited public comments on the petition.
The comment period expired July 6,1979.
Forty-five letters were received.
A copy of these public comments is available for public inspection and l
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copying at the Commission's Public Document Room at 1717 H Street NW.,
Washington, D.C.
Single copies of the comments may be obtained by written request from the Office of Nuclear Regulatory Research, U.S.
Nuclear Regulatory Commission, Washington, D.C. 20555.
All of the letters supported the petition.
The commenters are representatives of the nuclear medicine profession.
They believe that the NRC restrictiort unnecessarily constrain the physician to the detriment of patient care without any benefit to the public.
Many of them claim that the unapproved use of Tc-99m pentatate sodium for lung scans is a clinically useful, low-risk diagnostic procedure.
Several commenters gave other examples of unapproved uses of FDA-approved radioactive drugs, for example:
(1) Tc-99m sulfur colloid administered orally for studying gastro-esophageal reflux and gastric emptying time; (2) Tc-99m sulfur colloid injected into the peritoneal space pric to administering therapeutic doses of radioactive colloids; (3) Tc-99m Sn pyrophosphate for red blood cell labeling; (4) Tc-99m MAA for LeeVeen shunt patency; and (5) Tc-99m DTPA for cisternography for determination of cerebrospinal fluid leaks.
COMMISSION ACTION The Commission has given careful consideration to both the petition and the public comments and has decided to propose an exception to the t
restrictions in 635.14(b)(6) for Tc-99m pentatate sodium used for lung function studies.
This proposed rule would thus allow all of NRC's medical licensees to use Tc-99m pentatate sodium for lung function studies, thereby granting the petition in part.
Based on the need to use Tc-99m pentatate sodium for lung function studies, and based on the finding that the radiation dose to the patient from this procedure is 7
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within the range of radiation doses for other FDA-approved diagnostic nuclear medicine procedures, the Commission believes that an exceptien to the estrictions in 935.14(b)(6) for this radioactive drug is warranted.
(The radiation dose from a 3 mci dosage of Tc-99m pentatate sodium by inhalation is:
0.03 rad to the whole body; 0.21 rad to the lungs; and 0.66 rad to the bladder wall.) Nevertheless, the Commission still finds that its restrictions in 935.14(b)(6) on the unapproved uses of FDA-appnved radioactive drugs are es m tial to ensure the safety of those radioactive drugs whose effectiveness for unapproved (by FDA) clinical procedures has not been established.
This proposed rule would establish the first exception to the restrictions ir, 935.14(b)(6).
Future radiopharmaceuticals and uses are expected to be added to the list after a determination of radiation safety is made by NRC. Any future ainendmeit of this nature would be effective upon publication in the Federal Register unless circumstances indicate that it should be brought to the Commission's attention and published as a proposed rule.
THE PROPOSED RULE The proposed rule would apply to two categories of NRC medical licensees in 10 CFR Part 35.
Under 535.11, it would apply to medical institutions.
Under 935.12, it would apply to physicians in private practice outside medical institutions who are also group medical i
licensees under S35.14.
However, the p*oposed rule does not apply to broad medical licensees licensed under 10 CFR Part 33.
The proposed rule provides an exception for Tc-99m pentatate sodium from the restrictions in 935.14(b)(6) when it is used for lung function 1
8
[7590-01) studies. Under 935.14(b)(6), as presently written, when a physician uses an FDA-approved drug, such as Tc-99m pentatate sodium, for an unapproved use, such as lu,g function. studies, the physician must follow the FDA-approved labeling regarding (1) chemical and physical form, (2) route of administration, and (3) dosage range.
This requirement prevents the.use of Tc-99m pentatate sodium for lung function studies because the physical form would be different (aerosol), the route of administration would be different (inhalation), and the dosage range would be different (3 mci).
Under the proposed exception, Tc-99m pentatate sodium could be used as an aerosol for lung function studies.
Physicians would adninister.the radioactive aerosol with a closed, shielded system that either is vented to the outside atmosphere through an air exhaust or provides for collection and disposal of the aerosol.
In the future, NRC may add other radioactive druas and clinical procedures to this exception.
REGULATORY FLEXIBILITY CERTIFICATION Based upon the information available at this stage of the rulemaking proceeding and in accordance with the Regulatory Flexibility Act of 1980, 5 U.S.C. 605(b), the Commission hereby certifies that, if promulgated, this rule will not have a significant economic impact upon a substantial number of small entities.
The proposed rule affects about 2,000 specific licenses under 9935.11, 35.12, and 35.14 of 10 CFR Part 35.
These licenses are issued principally to medical institutions.
Small business E
entities, primarily physicians in private practice, comprise about 275 of the specific medical licenses.
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Because the proposed rult relieves NRC's medical licensees from regulatory requirements, it is not expected to have a significant economic impact on these licensees.
However, the NRC is seeking comments and suggested modifications because of the widely differing conditions under which small medical licensees operate.
Any small entity subject to this regulation which determines that, because of its size, it is likely to bear a disproportionate adverse economic impact should notify the Commission of this in a comment that indicates:
(a) The licensee's size in terms of annual income or revenue, number of employees and, if the licensee is a treatment center, the number of beds and patients treated annually; (b) How the proposed regulation would result in a significant economic burden upon the licensee as compared to that on a larger licensee; i
(c) How the proposed regulations could be modified to take into i
account the licensee's differing needs or capabilities; (d) The benefits that would be gained, or the detriments that would be avoided to the licensee, if the proposed regulations were modified as i
suggested by the commenter; and (e) How the regulation, as modified, would still adequately pro?ect the public health and safety.
Under the Atomic Energy Act of 1954, as amended, the Energy Reorgan-
.tation Act of 1974, as amended, and Section 553 of Title 5 of the United i
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[7590-01) i States Code, notice is hereby given that adoption of the following amend-ments to 10 CFR Part 35 is contemplated.**
i e
PART 35 - HUMAN USES OF BYPRODUCT MATERIAL 1.
The authority citation for Part 35 reads 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).
Section 35.14 is also issued under sec. 201, Pub. L.93-438,- 88 Stat.
1243 as amended by Pub. L. 94-79, 89 Stat. 413 (42 U.S.C. 5841).
Section 35.31 is also issued under sec. 202, 89 Stat. 1244 (42 U.S.C. 5842).
For the purposes of section 223, 68 Stat. 958, as amended (42 U.S.C.
i 2273); S35.31(c)(4) and (5) issued under 161(b), 68 Stat. 948 (42_U.S.C.
2201(b)).
2.
Section 35.14 is amended by revising paragraph (b)(6) and adding paragraphs (b)(7) and (b)(8) to read as follows:
635.14 Specific licenses for certain groups of medical uses of byproduct material.
a (b)
(6) Except for those radiopharmaceuticals listed in paragraph (b)(7) of this section, for Groups I, II, and III any licensee using byproduct i
- Additions to the present text are underlined.
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material for clinical procedures other than those specified in the product labeling (package insert) shall comply with the product labeling regarding:
(i) Chemical and physical form; (ii) Route of administration; and (iii) Dosage range.
(7) The following radiopharmaceutical(s), when used for the listed clinical procedure (s), are not subject to the restrictions in paragraph (b)(6) of this section:
(i) Technetium-99m pentatate sodium as an aerosol for lung function studies.
(8) Radioactive aerosols must be administered with~a closedt shielded system that either is vented to the outside atmosphere through an air exhaust or provides for collection and disposal of the aerosol.
a Dated at.
, this day of
, 1981.
For the Nuclear Regulatory Commission.
Samuel J. Chilk, Secretary of the Commission 12
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e ENCLOSURE 7 3
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DRAFT CONGRESSIONAL LETTER V
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Enclosed for the information of the subcommittee are copies of a Notice of Proposed Rulemaking to be published in the F,ederal Regis-ter.
This proposed rulemaking grants part of a petition for rulemaking that was filed by George V. Taplin, M.D. (deceased).
Dr. Taplin requested that the Commission 1
remove certain restrictions on the physician's use of radioactive drugs.
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A physician can use Food and Drug Administration (FDA) approved radioac.tise -
drugs for clinical procedures that have not received FDA approval.
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under NRC regulations, the physician must follow the drug labeling regarding
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the following:
(1) chemical and physical form; (2) route of administration; i
and (3) dosage range.
ItisthejarestrictionsthatDr.Taplinsoughttohave T
i NRC rescind.
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3 Specifically, Dr. Taplin was concernad that these restrictions would prevent the use of Tc-99m pentatate sodiua for lung function studies--a clinical l
i procedure that he had developed.
Fifty-one commenters, all members of the I
a medical profession, supported Dr. Taplin's position.
The NRC restrictions to FDA-approved chemical and physical form, route of i
administration, and dosage range were introduced to ensure the safety of q
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f radioactive drugs that were being used for clinical procedures that. had not -
received FDA approval of effectiveness.
The Commission remains convinced that these restrictions in general are necessary; however, the Corsefssion belicves that there is good cause to propose an exception for Tc-99m pentatate sodium for lung function studies.
Therefore the Commission is publishing in the Federal Register for 60 days public comment a cotice of prspostd rulemaking te
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grant an exception for the use of Tc-99m pentatate sodium for lung function studies.
Further, in the future, NRC may add other radioactive drugs and clinical procedures to form a list of exceptions.
A copy of a draft public announcement on the proposed rule is attached for your information.
Sincerely, Robert B. Minogue, Director Office of Nuclear Regulatory Research
Enclosures:
1.
Federal Register Notice of Proposed Rulemaking 2.
Draft Public Announcement
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Enclosure.7
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ENCLOSURE 8 I
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DRAFT PUBLIC ANNOUNCEMENT (To be prepared by the Office of Public Affairs) 1