ML20202D669

Obtains Commission Approval of Notice of Final Rulemaking That Would Delete Designation of Specific Diagnostic Procedures from Group Medical Licenses

ML20202D669
Person / Time
Issue date:	11/22/1978
From:	Minogue R NRC OFFICE OF STANDARDS DEVELOPMENT
To:
References
SECY-78-615, SECY-78-615-R, NUDOCS 9902020070
Download: ML20202D669 (33)

Text

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UNITED STATES

• November 22, 1978 N'UCLEAR REG.ULAToRY Commission

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nd For:

Robert B. Minogue, Director.

ice of Standards Development From:

Executive Director for Operations' Thru:

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EFFECTIVE AMENDMENTS TO 10 CFR PART 35 TO CliANGE CO

Subject:

GROUP MEDICAL LICENSES To obtain Comission approval of a notice of final rulemaking that would delete the designation of specific diagnostic proce-

Purpose:

i dures from the group

• medical licenses, l

l This paper covers a eninor policy question.

l Category:

On March 2,1978, the Comission approved a proposed rule (SECY-78-69), that was published in the Federal Register (Enclosure 3)

Discussion _:

for a 60-day public coment periou that ended May 16, 1978. The proposal would permit physicians greater latitude, when they use certain low risk diagnostic radiopharmaceuticals, by deleting specification of the clinical procedures from the lists of radio-The propos phamaceuticals in Groups I, II and III of f 35.100.

would, at the same time, require physicians to follow the chemical and physical form, route of administration and the dosag III radiophamaceuticals for clinical procedures not specified in i

the product labeling.

When using any diagnostic radiopharmaceutical physicians may That is, they may not diagnose a make the wrong diagnosis.

condition that exists (false negative); or they may incorrectly FDA requires diagnose a condition as existing (false positive).

a-manufacturer to submit substantial evidence of effectiveness for a diagnostic agent for a particular clinical procedure before it will approve that procedure for inclusion in the package are divided into six groups, each group having 5 35.100 similar requiremer.ts for user training and experience, facilities a

• Radioactive materie.ls in a radiation safety procedures.

costs by eliminating the need for licensees to seek an amendment to their licens each time they wish to use an additional radiopharmaceutica they are licensed.for the use of any one radiopharmaceutical in a particular gr

. as an application for all radiopharmaceuticals in that group.

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Contacti N,

E. Podolak, 50 443-5946

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g the Comissioners When physicians decide to use a drug for a clinical pro-inn rt.

G ure not approved in the package insert, their decisions may be based on medical evidence found in the literature or their The physicians' personal experience with a particular product. decisions may Therefore, physicians may criteria of " substantial evidence."

be more likely to make an incorrect diagnosis when they depart from the package insert than when they follow it.

Allowing physicians to use radiopharmaceuticals for diagnostic clinical procedures not yet approved by the Food and Drug Administra tion (FDA) entails low risk to the patient, provided the chemical and physical form, route of administration and the dosage range remain the same as that approved by FDA in the product labeling.

The proposed rule (Enclosure 3) discusses the consistency between this approach and FDA policy. Essentially, FDA concludes that good medical practice requires that physicians be free to use drugs according to their best knowledge and judgmerit in the interest of the patient.

Copies of the proposed rule were sent to all NRC medical licensees, the States and 25 professional societies and individuals. is a sumary Eighteen coment letters were received.

of the comments which,are analyzed in the preamble to the final rule (Enclosure 1).

Seven comenters favored the proposal Seven comenters favored the proposal but

'without qualification.

suggested that NRC remove the restrictions on route of administra-Three comenters objected to the pro-tion and dosage range.

posal entirely, believing that patient interests are better served by the existing regulation. One comenter discussed a point that was beyond the scope of the proposal.

Some of the commenters who suggested that' NRC remove the restric-tions on route of administration and dosage range, erroneously believed that these restrictions also applied when using drugs for FDA-approved clinical procedures. Most of these commenters, however, were simply opposed to any NRC restrictions on the The physician's freedom in administering radiopharmaceuticals.

comenters who objected to the proposed rule entirely were con-cerned that patient interest might not be the primary consideration when a physician uses a radiopharmaceutical for a non-FDA-approved use.

3 The Co~-

aoners Basically, the answer to both the suggestion to have no restrictions and the concern that we are relaxing an important restriction, is that the radiopharmaceutical manufacturers have submitted to FDA substantial evidence of safety for the chemical form, route of administration and dosage range in the labeling; and patient interests are best served when the phy judgment, notwithstanding the opportunity for abuse of this freedom by some physicians.

The text of the final rule has not changed from the text of the (1) the addition of some chemical proposed rule except for:

5 35.100 groups through previous forms that have been added to the Federal Register notices; and (2) the names of some chemical forms nave been changed to conform with FDA guidelines (e.g.,

" diethylenetriaminepentaacetic acid" is now called "pentatate sodium").

Recommendation _:

The Comission:

Approve a notice of final rulemaking (Enclosu 1.

procedures in 5 35.100.

2.

Note:

The final rule would be published in the Federal a.

Register to be effective in 30 days.

All medical licensees and the appropriate congressio,1a1 committees will be informed (Enclosure 5).

b.

A public announcement such as Enclosure 2 will be c.

issued.

The Offices of Huclear Material Safety and Coordination:

of Rules and Records concur in the recommendation of this pape The Offices of the Executive Legal Director and the Gener The public announcement was prepared by have no legal objection.

the Office of Public Affairs.

OCA concurs.

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Robert B. Minogue, Director Office of Standards Development

nelosures

- Federal Register Notice of Final Rule

- Draf t Public Announcement

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- Proposed Rule (43 FR 11206}

4 - Summary of Public Comments 5 - Draft Congressional Letter Commissioners' comments or consent should be provided directly to the Office of the Secretary by cob Friday, December 8,1978.

Commission Staff Office coments, if any, should be submitted to the Commissioners If

, with an information copy to the Office of the Secretary.

the paper is of such a nature that it requires additiona) time for analytical rev NLT November 30, l?

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 ope of December 11, 1978.

published, for a specific date and time.

i DISTRIBUTION Commissioners Commission Staff Offices Exec Dir for Operations Regional Offices Secretariat

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1 Title 10 CHAPTER I

_dR REGULATORY COMMISSION PART 35 - HUMAN USES OF BYPRODUCT MATERIAL Change in License Conditions for Certain Medical Licenses l

AGENCY:

U.S. Nuclear Regulatory Commission (NRC)

ACTION:

Final rule.

The Nuclear Regulatory Commission is amending its regula-

SUMMARY

tions (a) to pennit physicians greater latitude, when they use certain low risk diagnostic radiopharmaceuticals, by no longer designating authorized clinical procedures and (b) by deleting from several licens-ing groups certain chemical forms not approved by FOA.

EFFECTIVE DATE: The amendment becomes effective on *.

F0",FURTHER INFORMATION CONTACT:

Edward Podolak, Office of Standards Development, U.S. Nuclear Regulatory Comission, Washington 0.C. 20555 (Phone:

301-443-5946).

SUPPLEMENTARY INFORMATION: On March 17, 1978, the NRC published for a 60-day coment period a proposed rule (43 FR 11206) to amend its regula-tions to delete the specification of the diagnostic clinical procedures Insert date 30 days from publication in Federal _ Register.

' Enclosure 1 1

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.autopha,paceuticals in Groups

• I, II, and III of from the lis'-

r In the same proposal an amendment to 5 35.14 t:ould require 6 3c -

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,;nysicians to follow the product labeling for the chemical an form, route of administration and recomended dosage range when_ they f

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use Groups I, II and III radiophamaceuticals for clinical procedures not specified in the product labeling.

In the same proposal the Comission also proposed to update the lists in Groups I, II and III by deleting i

l certain chemical forms not approved by the Food and Drug Administration

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l (FDA).

Copies of the proposed rule were sent to all NRC medical licensees, the States and 25 professional societies and individuals.

Eighteen coment letters were received.

Seven comenters favored the proposal l

Seven comenters favored the proposal but without qualification.

j One Three comenters objected to the proposal.

i suggested a change.

d comenter discussed a point that was beyond the scope of the proposal l

but will be considered by NRC separately. -

DISCUSSION OF MAJOR COMMENTS The coments favoring the proposal but suggesting a change l

suggested that NRC should not restrict physicians to follow the pro f

The most common types of NRC specific licenses for the medical byproduct material are the Group medical licenses under 5 35.14 t The radio-apply to those radioactive materials listed in s 35.100.are divided int active materials listed in 5 35.100 group having similar requirements for user training and experienc l

Groups I, facilities and equipment, and radiation safety procedures.

l II and III are lists of radiopharmaceuticals for diagnostic procedures; i

Groupt IV and V are lists of radiophamaceutica c.

both diagnostic and therapeutic procedures.

b.

l

. Enclosure 1 i

2 7

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_ _ __ - - ' - ~ ~ ~ - - ~ - - - - - _ _ _ _ _

labeling for the chemical and physical fonn, route of administration 4

and recomended dosage range when using radiopharmaceuticals for Most of clinical procedures not specified in the product labeling.

these comenters felt that the route of administration should be The example cited most! often was the administration to the physician.

of Tc-99m pertechnetate orally or rectally when it has been approved These comenters state by FDA only for intravenous administration.

that the oral or rectal route might, in some instances, be safer than intravenous administration, for example, in an emergency situation or One comer ter suggested when a vein is not available for injection.

that agents approved by FDA for intravenous injections should be allowed to be injected into the venous side of the circulation through an in-dwelling heart catheter or even into the pulmonary arterial cir-Two comenters pointed out that culation through a Swan-Ganz catheter.

FDA does not restrict the physician to the chemical and physical form route of administration or recomended dosage range in the product label-One comenter expressed concern that the NRC restrictions would ing.

l hinder research into new uses and dosage forms.

Some of these comenters who suggested that NRC should not restrict the route of administration and dosage range erroneously assumed that these restrictions also applied when using drugs for clinical procedures With the exception of the restric-l specified in the product labeling.

tion on the chemical and physical form of the radiopharmaceutical, which will still be specified in the 5 35.100 Groups, the NRC restric-e' tions on route of administration and dosage range apply o_niy,when nl physicians use a radiopharmaceutical for clinical procedures not y

Stated alternatively, physicians specified in the produc.t labeling.

may depart from the product labeling regarding dosage range and route of administration when they follow that labeling regarding the FDA-i approved clinical procedure. This policy is consistent with FDA's recognition that good medical practice requires physicians to be #

,e interest to use drugs according their best knowledge and judgment i-

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The compatibility between NRC and FDn policy in this of the patient.

matter is discussed in detail in the preamble to the proposed regulation The Comission recognizes that holding physicians to the (43 FR 11206).

labeled chemical and physical fonn, labeled route of administration, and labeled dosage range (when they use a radiopharmaceutical for clinical procedures not specified in the product labeling) is more restrictive The Comission believes that these restrictions minimize th than FOA.

risk to patients f' rom diagnostic clinical procedures that have not been approved by FDA.

Regarding the coment about hindering research, each of the Group I, II, and III includes a provision authorizing the use of products for which a " Notice of Claimed Investigational Exemption for a New Research may also be con-Drug" (IND) has been accepted by the FOA.

ducted under NRC licenses of broad scope provided the studies are perfonned in accordance with FDA regulations and are approved licensee's Medical Isotopes Comittee.

One commenter who disapproved of the proposed rule believes that the existing rule provides adequate control and should not be Another comenter challenged the assumption that physicians changed.

always use their best knowledge and judgment when using drugs fo This commenter noted that the patient is generally unapproved uses.

totallyincompetenttojudgewhetherthebenefitofa$rocedure

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exceeds the risk and that the proof of damage general 1y rests 4

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i the patient. The third.comen,ter who disapproved o'

.. oposed rule questioned how the benefit-risk deci'sion we ~

,e made by the physician.

This commenter wanted to know if tF-acedure is automatically war-ranted when there is an expe

.aon that.the procedure will yield some useful diagnostic infomation.

In answer, the Comission believes that the use of diagnostic radiopharmaceuticals listed in Groups I, II and III for clinical procedures not yet approved by FDA entails low risk to the patient, provided the chemical and physical form, route of administration and the dosage range remain the same as specified in the radiopharmaceutical Advances in medical knowledge and practice inevitably labeling.

precede labelinc revision by the manufacturer and formal labol approval Good medical practice and patient interests are best by the FDA.

served when the physicians are free to use radiophamaceuticals to their best knowledge and judgment, notwithstanding the opportunity for abuse of this freedom by some physicians.

The text of the final rule has not changed from the text of the proposed rule except for:

(1) the additions of some chemical forms that have been added to the 1 35.100 groups through previous Federal Register, notices; and (2) the names of some chemical forms have been changed to conform with FDA guidelines (e.g., "diethylenetriaminepenta-aceticacid"isnowcalled"pentatatesodium").

Under the Atomic Energy Act of 1954, as amended, the Energy Reorganization Act of 1974, as amended, and Sections 552 and 553 of Titia 5 of the United States Code, the following amendments to Title 10, Chapter I, Code of Federal Regulations, part 35 are pub-lished as a document subject to codification.

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, Enclosure 1 Y

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.,s),anewparagraph(6)isaddedwhichreadsas o

1.

In 1 :

follor so.14 Specific licenses for certain groups of medical uses of byproduct material.

(b)***

(6) For Groups I, II and III any licensee using byproduct material for clinical procedures other than those specified in the product labeling (padage insert) shall comply with the product labeling regarding:

(i) chemical and physical form; (ii) route of administration; and (iii) dosage range.

2.

In 5 35.100, paragraphs (a), (b) and (c) are revised to read as follows:

Schedule A - Groups of medical uses of byproduct material.

s 35.100 Use cf prepared radiopharmaceuticals for certain diagnostic (a) Group I_.

studies involving measurements of uptake, dilution and excretion.

This group does not include imaging or localization studies.

Iodine-131 as sodium iodide, iodinated human serum albumin, labeled (1) rose bengal, triolein, or sodium iodchippuratet Iodine-125 as sodium iodide, iodinated human serum albumin, oleic (2) acid or sodium iothalamate; (3) Cobalt-58 as labeled cyanocobalamin; 6

2.

(4) Cobalt-60 as labeledIyan'ocobalamin; Chromium-51 as sodium chromate or labeled human serum albumin; (5)

(6) Iron-59 as citrate; (7) Technetium-99m as pertechnetate; and Any byproduct material in a radiophamaceutical and for a diagnostic (8) use involving measurements of uptake, dilution or excretion for which a

" Notice of Claimed Investigational Exemption for a New Drug" (IND) has been accepted by the Food and Drug Adninistration (FDA).

Use of prepared radiophamaceuticals for diagnostic (b) Group II.

imaging and localization studies.

Iodine-131 as sodium iodide, iodinated human serum albumin, macro-(1) aggregated iodinated human serum albumin, colloidal (microaggregated iodinated human serum albumin, rose benegal or sodium iodohippurate; (2)

Iodine-125 as sodium iodide or fibrinogen; Chromium-51 as human serum albumin; l

(3)

I (4) Gold-198 in colloidal form; (5) Mercury-197 as chlomerodrin; (6) Mercury-203 as chiomerodrin; (7) Selenium-75 as selenomethionine; (8) Strontium-85 as nitrate; Technetium-99m as pertechnetate, sulfur colloid or macroaggrega l

(9) human serum albumin; (10) Ytterbium-169 as pentatate sodium;

-Enclosure 1 7

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Indium-113m as' chl'ortde;-

(12) Any byproduct material in a radiophamaceutical prepared from a reagent kit listed in paragraph (c)(4) of this section; and (13) Any byproduct material in a radiophamaceutical and for a

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i diagnostic use involving imaging or. localizing for which a "Notise of Claimed Investigational Exemption for a New Drug" (IND) has been accepted by the Food and Drug Administration (FDA).

(c) Group III_. Use of generators and reagent kits for the prepara-tion and use of radiopharmaceuticals containing byproduct material for certain diagnostic studies.

Molybdenum-99/ technetium-99m generators for the elution of (1) techr.otium-99m as pertechnetate; Technetium 99m as pertechnetate for use with reagent kits for (2) preparation and use of radiopharmaceuticals containing technetiu asprovidedinparagraphs(c)(4)and(5)ofthissection; Tin-113/ indium-113m generators for the elution of the indium-ll3m

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(3) as chloride; Reagent kits for preparation of technetium-99m labeled:

(4) 4 (i) Sulfur colloid; (ii) pentatate sodium; (iii)Humanserumalbuminmicrospheres:

(iv)Polyphoephates; (v) Macroaggregated human serum albumin; 9

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(vi)Etidronatesodium; I

(vii) Stannous pyrophosphate; f

(viii)Humanserumalbumin; (ix) Medronate sodium; (x) Gluceptate sodium; and (5) Any generator or reagent kit for preparation and diagnostic use of a radiopharmacoutical containing byproduct material for which generator or reagent kit a " Notice of Claimed Investigational Exemption of a New Drug" (IND) has been accepted by the Food and Drug Administration (FDA)

(Secs. 81, 167b, Pub. Law 83-703, as amended, 68 Stat. 935, 948 (42 U.S.C. 2111, 2201); Sec. 201, Pub. Law 93-438, as amended, 88 Stat.

1242 (42 U.S.C. 5841).)

_this

_ day of Dated at 1978.

For the Nuclear Regulatory Comission.

~ Samuel J. Chiik Secretary of the Comission k

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Draft Public knnouncement.

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NRC EASES RESTRICTIONS ON USE OF RADIOPHARRACEUTICA1.5 i

FOR DIAGNOSTIC PURPOSES l

l The Nuclear Regulatory Commission is amending its regulations to give doctors greater discretion in the treatment of their patients by no longer limiting the use of certain radioactive materials to specified diagnostic procedures.

The change is consistent with a proposed NRC policy statement, issued in March 1,78, indicating that the NRC would minimize intrusion into 9

medical judgments affecting patients, although it would continue to l

regulate the radiation safety of pstients where justified by the risk i

l involved.

The revised rules pemit doctors under NRC license to use specified radiopharmaceuticals for diagnostic clinical procedures that have not been I

I approved by the Food and Drug Administration (FDA) for listing on th (The FDA recognizes that the labeling of a drug does not always label.

contain the most current information available to doctors on the proper l

use of the drug in good medical practice.)

I The Commission believes that giving this additonal discretior, to doctors entails low risk to the patient involved, particularly since the rules will require that the chemical and physical form, route of adminis-tration and dosage range of the drug must be the same as specified product labeling.

[ Enclosure 2 1

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Because of the higher risk to p'atients from use of therapeutic drugs, the Comission*is continuing to require that these drugs be used for proce-dures approved by the FDA.

The amendments, which are to Part 35 of tbe Comission's regulations, i

(30 days after publication in the Federal l

are effective on Register on

_). They are substantially the same as those 4

published earlier for public coment.

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PAC. POSED IULIS 11206 celved may be erambed at the Com-tegbtration to the Veterinary Services misalon's Puhuc Document Room at

'by'ths owner, ths owner may select representative.

L'!17 E Stree '"" Washington, D.C.

and employ his own appraher who All wr!tten submissions made pursu.

ahall appraise the antmals and consult ant to this notice wiu,be clade avaII.

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.1HER DTFORMXrION 2

with the Veterinary Servlees appraiser able for pubuc inspection at the Fed-Edwa.rd. Poldolsk. Off'.ce of Stan.

and attempt to scree on the appraisal ersi. En M "T. 6595 #Beletest Et" value. If the two appratsers do not Room 734. Hysttsvale. Md.

tianis Development. U.S. Nuclear Commission. Washi=g.

agne on the appraisal value of the regular hours of bustner 2 to Regulatory the two appratsers shall 30 p.c1 Monday tr

.y. except ton, D.C. 20555, phone 301443-4910.

animals, 4:

.anvenient to select a third appraiser wha win be hol! days) in a r" SUFFI.ZMINTART INFORM \\T:CN:

employed by Veterinsry SetMees, ne the pubuc bt*

. CFR 147tb)h In the most ecc =on type cf ucense appraisers shan attempt to Mtted should bear a for the csedlest use of byproduct tnate.

Commer three agree upon an apprsisal value for the

, e.e date and page number rial. NRC restricts the physician's use referer*

antmnft Any appraisal agreed upon by oft *' ssue in the F:nzzat. Rzctsrza. of radiopharmamucals ecentiaHy to these three topraisen win be f?nd Dcne at Wash!ngton, D.C., this 13th those dfnten1 procedures approvm1 by day of Mana 194.

the Pood and Drag AdmM<tration

. - ei (FDA) in the product's labeling. The Ners.-It is hereby certitled that the eco-package inserr, a part of the producs

3. Sect!cn 54.7 (a) and (b) would be nemie and t=tlationary ef ects of t2us pro.

labeling, has scientific, medical. legal amended to read; posal have been careruns evsluated ta so. g p g.aufe e % % The estructies and disposition of" sal. cercance vita ExecutJn order to. nan, purpose of the pactate insert is to

! ELT provide the physician v..h specific In-J. E:. Am.

(a) Indemnity for affected anhnala JeffnpDeputy Adrnfr.htres2cr, formadon about the use of the tsdfo-veiertsary Sercices, pharmaceutical. This information, d

and esposed animmtt destroyed un er g.n Dec.441mued 3 tMams ami which is reviewe<i and approved b7

.this Part shall be paid cnly after Vet, -

PDA. Includes:

1-ertnary Services obtains the writte:

1. The chemtent and phystesi for=2 agreement. of the owner to accept

'frotn the United States compensation (759 M 1]

of the drug;

2. Recommended usual done and which shall be equal to two ditrds of NUCl2AR REGULATORY usual deze range:

the appraised value of each untmst COMM1551CH

3. Indications and usage (cifnical not to exceed 400 per head. -

Affected animals and exposed procedures);

animals shan be destroyed on the M CFR Port '15]

4. Route of admtetstration to which (b) premises where held. pastured or the labeling appUes:

penned at the time af app:-utab HUMAN USE3 OF BYPRODUCT

3. Contrsindicsuons: and

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6. Warnbgs.

that such animals may be MATTRIAL Under the so. called Group

• med!cs!

except moved for destruct!ca to a Icesuca Ucenses. NRC restricts the ph:t.cian's other than the prettises where ap-Change in Llconse Conditions fer choice of clbical procedures to FDA praised when movement to such locs.

approved procedures. This Ls se:cm-don is approved in advance by the '

Cue MedM Ucenns pushed by t! stint in 10 CFR I 35400 each rad!alsotope. the chemical and State representative and Veterinary AGENCT: U.S. Nucles Regulatory Services representative involved, and Com mMon.

physical form of the radiophsr=seem such animais are not to be processed for human food. The caressses of the AC'I' ION: Proposed rule, tical and the author =ed cliclest proce.

t dttres. Each time FDA approves a new a"f mMt destroyed shall be dispose <1 of.

SUMMARY

The Nuclear Reguistory by burial or incinerstion.

Commi" ton is cons derm:r imending ci!nies) procedure for a rsdfoch ceutical 11sted !n 135.100. h AC must Its regulations (a) to permit pnysthans consjder amending ) 35400 to in: ude greater latitude, when they use eer-ain the new procedure.

low risk diagnostic radfo phsr=ncet.tl.

The ;urpose of this pro::csed t.tle

4. Section 34.8 would te scended to cals, by no longer !esignating sItho. change is to delete the spec.ficadon of Mad:

rtted cualcal procedures and (b) the diagnostic cunical procedures frecs to amfs de.

delete from several I! censing groups forms not approved the lists of rsdiopha.=aceutfesis in Psywents to omiers for f 34.3 Groups I. II and III of 135.100. This in) Chmers of affeted en!mm and. certain chemicalby FDA. The CommWon tell

' "I d Mtroyed La accor. that the use of these for for diagnesuc d!agnostje radiopharmsecutiesis clinical procedures not yet sporeved cignical procedures not inclu esposed ardms!t radiopharmaceuttesis dance with this Part shall be paid an by ?DA entails low rish to the patient. Product labelint.

indemnity by the United State.s equal to two thirds of th* mppraised value of provided the chemics! and physical "The most common tyras of NRC srectne each anima! so destroyed, not to forns, route of admirtstration and the.ueenses for the zned:est uses et trorecues the same s.s exceed $300 per head.

desage ranza rem

• c.atertal are the creuo mectest ucenses fb) Veterinary Services may indem.

spectiled in the radlophar=aceutical under f $3.14 that scoir to those tsd:oscuv to the Ifmitations mstensis ust,ed in i,ss.100. T,he tsdic nify ottne-s up labeling.

spect!!ed in this Part whether or not 33,; g,, e m e,q go the State part.!cipates ' tn Lnde n!t7 DATES Ccmment period esptres May m g m gg,,4 g3 sts troups, esch n-suo ans sustist a.

R M8-quirsments for user trsicans ud exurt.

partment.(c) Acirnals presented for sporaisal ADDRI:53ES: Written comments et as purecred shall be accomcanle<3 by sus 2estions for consideration in con. 'je ge y

ao tsts of rsdioonazmaceuucals for nsc:cs:::

thett certil!cate of registry at the time nection with the preocsed amendment procedures: Croups rv aca 7 tre.'sts ::

of apprs!ss1. or they shall be appraised should be submitted to the Secretary rselecharnaceuws2s ist tuerseeutte ;roce-as trades: except that, la the absence of the Co=rnission. U.S. Nuclest Ite*

of such proof of purebreeding the u?stery Cornmission. Washington. D.C.

dures sad Group Y::s 2 tst et ts4:sacuve reedlesi devtees ::t 'coth cAJ:e.s:tc 1:4 Deputy Administrator sh:11 grsnt s 20353. Attention: Docieting and Set-t ers:euticprocedurts.

for the cwner to vice Branch. Coptes of comments re.

ressonable ttcne cbtain 3.nd present his cert!!!este of Enclosure _3 notaAt Ricistit. VCt. 43. NC. 53-Ntt0AY, MARC 4 ly, ins n

L

[e

.~

PROPOT -' JUS 11207 Th.e uw of 9.n aporoved drug for In-coa-

1. the radiopharmaceut!- tod!nated human serttm albumin, rose

..alacturers d!d not rectuest benga! or sodlum icdohtppurate:

"t sticas that have not been approved the product 1sbeting has been "-

A approval.

(2) 1 Wne.125 as sodlum lodide or fl.

' 8'd by FDA in a Fmn.u. Kr**

Under theAtontle Energ7 Act of bri..iseh:

1954, as amended, the Energy Reorga.

(3) Chrom;um.51 as human serum uuncement H0 FP.15F'

.. m.

' '. the "Labe!!ng for

.dption nl:ation Act of 1974, as amended, and alburnin:

Section 553 of t!tle 5 of the United (O Gold l'.'S in colloidal form;

ts Used in Man"*

• * * ::e :steltn2 "

s. ended nther to States Code notice is hereby given (5) Marcury.19'l as chlormerodrin:

. rs use et his best thst adoption of the following amend.

(6) '.tercury 203 as chlormerodrin

. -wue tne o'_..trast et the mtient or to ments to 10 CFR Part 35 is contem.

(7) Selenium.75 as selenomethioidae:

vrt in :'

(S) Strontium 35 as n.trate:

• . w im s f he coes co: (suow the plated'l 35.14(b). add a new paragraph (9) Technettun99m as perte".hne-

.uert. The (TD.O Conuntssioner rs ga 3, g3 (6) to read as fonows.-

tate. labeled sulfur colloid or macecag.

r / n-;mJ:es thst tha :abehs: of a gregated human serum albumin:

93 dra does not 4:says con:2ta au srN.$I tNYseI.ue of t'.e 1 35.14 Speelfic lleen es for cert 41n groupe (10) Ytterbium 1d3 as diethylenetri.

m ned neen) prset:ce. A$vinces in of medient uses of byproduct meterial, e.minepentancette acid (Sn);

(11) Indium.113m as chloride:

mt e.owacie and peset:ee !navttaety (12) Any byproduct material tn a rs-

.<*..see.ne ravtston by the ::anuf ac.

diopharmaceutteal prepared from a

ed Sr=al tabet sooroval by t.he PViod (b) * *

• reagent kit listed in paragraph (c)(4)

D.4 Admirustestion. Good medical (6) For Group. I. II and III any 11 of this section and "ce ud patent inte.es:4 t2iu.s require

. vnmetaru te free to use drugs accore. censee using byproduct rsaterial for (13) Any byproduct material in s'ra-

ne r mt nowlecte and Judgment. clinical procedures other than those diopharmaceutical and for a diagnos-urs. whem a chrstetan uses a cru for specif!ed in the product labeling (pack-tic use invntving Imaging or locall: fur

- r.et in tne accroved tabeung. he has age !nsert) shall comply with the prod. for which a " Notice of Claimed Inves.

+:oa.sicility to be wett informad aeout uct ince11as regarding:

tigational Exemption for a New Drug'*

d etNeYo'n so$dN e7 (D Chemical and physical for n:

(IND) has been accepted by the Food (11) Route of administration: and and Drug Administration (FDA1.

"e. ar.J o =.v.atais adequate mediest re-(c) Group Iff. Use of generators and (111) Dosage range.

m ue c..ws use and effects, but such reagent kits for the preparation and

.: e n ?r art.ct:ce of :nadietne is not in use of radiopharmaceuticals contain-

+

=

+

+

+

• m cf 'nt. deral reod. Dear and ing byproduct material for certain di-one Act.

2. In 135.100, paragraphs (a). (b) and agnostte studles c.: Car maston believes that the (c) are revtsed to read as follows:

(1) f.folybrienbm 99/technetittm.rMm ca si n.W#.ar=Aceuticals Ifsted in w:s :. !!

'.r.

III for diagnostic 9 35.1cf) Schedule A-Groups of medient (*[9[as p t

gal p ;;c-aures not yet approved uses of byproduct material.

(2) Technetium.99 n as pertechne-(a) Group I.

Use f prepared tate for use w:th reagent kits for prep-C N/':':'.!Mfj li p#.

radiopharmaceutice.ls for certain dias. aration and use of radio-pharmaceutt-h

, 44,r='c'.u"J.f..l..',J; strathn and the nostic studies involving measurements cais containing technettuts.99ta as of uptake, dilution and excretion.This provided in paragraphs (e)(4) and (5) i rr a

.a e : e laoal. group does not include imaging or lo-of this section:

1:t:. Ts..erebre, tr.c Commission is also calizstion studies.

(3) Tin.113/ indium.113cs generators (1) Iodine 131 as sodium lodide, lo.

for the elution of the indit'm.113m as

' '~-f7 ti[

- dinated human serum albumin la.

chloride:

b h' "nd".."bal:ng x{th respect to thes! beled rose bengal, triolein. sodlum 10 i

..s (4) Ileagent kits for preparation of

..v

....e uses Groups I. Ic dohlppurate or sodlum lothalamate; technetium.99m labeled:

... :r op ar= ~euticals for cltrJ'.

(2) Iodine 125 as sodlum fodide. lo.

(1) Sulfur colloid:

(til tron. ascorbate-dietylenetrinmine-es not specified in

..e 7; j. 0c dInsted human serum nIbumin, oleic e nft 3

b t 8 ab c anocobala-e to r -

n n e-t1 min.

(17) Human serum albumin micros-tr;:t the users of therapeutte rn.dioac.

' 7 drugs in Groups IV and V to clini, f) Cobalt.60 as labetet. cytu2ocobala.

p me.,.,

(v) Polyphosphates; il procedures approved by FDA in (5) Chromium.51 as sodfum chro-(vD Macroaggregated human serum

• . readutt labeling. The L;ses. of rn.

methe :ned! cal devices in Group VI ma*e or labeled human serum albu. albumin-

. mntinueMe restricted to c;ln). min; (vil) Distannot.s etidronate cornpler (6) Iron 59 as citrate:

(vill) Stannous pyrophosphate:

,., crT~fures dete-mined to be safe

ot!!cth e by N?.C !n con.ntitation (7) Technetium 39tn as pertechne' (ix) Human serum albumtw and a it: Adytrory Committee on the tate; and (5) Any generator or reagent kit for dicel Uses of Isotope 1.

(8) Any byproduct material in a ra.

preparation and diagnostic use of a ra.

The Co:. mission is also proposing to diopharenaceutical and for a diagnos-diopharmaceutical containing byprod..

. hte the lists in Groups I. II and IU t!c use involving measurements of uct material for which generator or Gletmst certain chemical forms not isptake, dilutton or e:teretion for which reagent kit a " Notice of Claimed In-

. roved by FDA. These chemical a "ffotice of Claimed Investfrational vestigational Exemption of.

• New

..?.s. such as. lodopyrscet, sodlum Exe.notten for a New Drug"(IND) has Drug"(IND) has been accepted by the

't.: care and rif atti: oste methylglu. been %+pted by the Food and Drug Food end Drug Administrat!on4FDA).

r ine. ware crtTinally placed in the Administration (FDA).

.:::s 'When the Atomic Ener;;y Com.

(b) Cr up Use of prepared

. m ra.:ulated the ::afety.nd effs. rad!opnarmaceuacals for diagnostic

. ' 0* r.cho::harmaceut!cais Mcorp.).

Imaging and lo<:st.1: ton stud es.

' Sees. 81. tet. l'ub. L 83 'io3. es Stat. 9.5 948 (42 U.S.C. *111. ::200: Sec. :ot. Pub. L Jr..: oyoroduct matarfal. S!n':e then.

(1) Iod!r.*r.131 a vediten iodide,1o. 93 438. sa s'.at.1242 (42 U.S.C. 5840.)

em ehen:al.*orms have been re.

d!nated humari seturn t.ibumin, t=a.

.a.ed by oth!r products and, when croaggregated lod (nated 't'unan serum Dated at Washington, D.C.,

this v I*DA 'c% c'; r the tafety at:d ef!!. albumin. colhidal (microaggregated) 13th day of March 1973.

a g

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4 0e*

s e e

t 6

9 ENCLOSURE 4 e

A e

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1. 'Mm"3 % nom m y

i -

~

'S'UM$ANOF' COMMENTS Comments Favoring Proposal J. Miton Umeman, 0.0. F.A.C 0.1., Director of Huclear Medicine, 4.

Grandview Hospital, Dayton, Ohio.

Dr. Zimmeman comments that the proposed rule change permitting the Nuclear Medicine specialist to utilize radiophamaceuticals for clinical diagnostic procedures deemed indicated by him... emanating from his diagnostic and clinical acumen...has, indeed, been a procedural need...truly a basic need for the artful practice of Nuclear Medicine.

Dr. Edward A. Dolan, Chief of Radiology, St. Joseph Mercy Hosptial, 2.

Jetroit, Michigan.

Dr. Dolan believes that the rule change will be helpful to him in his He urges NRC to adopt the daily work, saving him considerable time.

rule.

ii

. Dr. John C. Harbert, M.D., Director, Division of Nuclear Med c ne, 3.

Georgetown University Hospital, Washington, D.C.

Dr. Harbert believes that the proposed amendment is an examp government regulatory decision making at its best..He states tha s

f nclosure 4 E

1 4

s citutional the problem of applying toiadioisotope Use Comittebs -

or well established Research Comittees for minor adjustments of e-radiopharmaceuticals is costly, time c'

...ang, and most likely unnecessary.

+

i

=

\\

i Charles R. Nicolosi. M.D., Radiologist, St. John's Hospital, Red Wing, I

4.

Minnesota.

j He is glad that Dr. Nicolosi thinks that the proposal is a good one.

the proposed rule change will permit physicians greater latitude in using certain low risk diagnostic radiopharmaceuticals.

l Lawrence E. Williams, R.P.0., Hennepin County Medical Center, 5.

Minneapolis, Minnesota.

He believes that such Mr. Williams endorses the proposed rule change.

an approach will enable the physician to perform his/her job with l

greater efficiency and, hopefully, reduce the cost of medical care in nuclear medicine.

i Milo H. Fritz, M.D., Anchor Point, Alaska.

6.

Dr. Fritz is heartily in favor of the proposed change and he deeply appreciates things such as this that make life easier for

~

him.

p 2

i, i

7.

Ralph G. Robinson, M.D., V '

.,.<1sion of Nuclear Medicine, The

_ dical Center, Kansas City, Kansas; Chairman, University of Kan" FDA RadioP...aceuticals Drug Advisory Comittee.

Dr. Robinson favors the proposed rule change and also agrees that the diagnostic procedures in the group licenses entail low risk to the patient, provided the chemical and physical form, route of administration and dosage range remain the same as specified in the radiopharmaceutic labeling.

Coments Favoring Procosal with a Suggested Change _

Herbert Strauss, Assistant Chief, Nuclear Medicine; Rene J. Smith, 8.

Ph.D., Radiation Safety Officer, Veterans Administration Hospital, East Orange, New Jersey.

~

Messrs. Strauss and Smith agree basically with the proposed changes but they feel that the route of administration should be left up to For example, they cite that technetium pertechnetate the physician.

oral administration may, in some instances, be safer than intravenous administration.

Robert B. Greenberg, Legal Counsel, American Society of Hospitals 9.

Pharmacists, Washington, D.C.

3

\\

\\

\\

Mr. Greenberg, for the'AmerTcan Society of Hospital Pharmacists, endorses the proposal to delete the clinical procedures from the groups, but suggests that the words "unless otherwise indicated by good medical practice" be added to the restrictions regarding fol-

~

lowing the product labeling for chemical and physical form, route of Mr. Greenberg notes that althougn administration and dosage range.

FDA policy gives the physician discretion to use a product in any manner he sees fit consistent with good medical practice, an impor-tant practical limitation is the risk of malpractice litigation.

Mr. Greenberg cites Mulder v. Parke Davis and Co.,181 N.W. 2d 882 (Minn.,1970) which held that a physician departing from FDA label must establish that such use was reasonable or be liable for injuries Mr. Greenberg says that this confines radio-from the use of that drug.

pharmacetical use to acceptable standards of medical practice.

Mr. Greenberg gives several specific exampl'es where departing from He believes product labeling would be desirable for the practitioner.

that selection of the dosing. range, route.of administration and.

chemical and physical form of a radiopharmaceutical is a profes decision which entails considerations unique to each patient and w are not distinguishable from decisions relating to other forms of d therapy.

4

- ~ - - -

1 l

Robert N. Class, M.D.,' Chief; Nuclear Medicine Service, Veterans 10.

Administration Hospital, Cleveland, Ohio.

Dr. Class was glad to see the proposed changes but disagreed that the

~

i route of administration should be followed absolutely in accordance He suggested that if an agent is to be with the package insert.

injected intravenously, then it should be allowed to be used by injection into th1 venous side of the circulation through an in-dwelling heart catheter or even into the plumonary arterial circulation He also believes that agents that through a Swan-Ganz catheter.

distribute themselves throughout the extravascular, as well as the intravascular, body fluid spaces should be permitted to be administered directly into these other body spaces. He suggests that any agent authorized for administration intravenously should also be considered safe for oral or rectal administration as well.

Richard F. Kiepfer, M.D., Head, Nuclear Medicine, National Naval 11.

Medical Center, Bethesda, Maryland.

Dr. Kiepfer congratulates NRC on what he considers to be excellent and He suggests that restricting long overdue changes in the regulations.

the physician to the chemical and physical form, route of administratio and dosage range when he departs from the FDA-approved use, may i 5

[

'I

= = -

['

He research in new uses and dosage, forms of byproduct ma,terial.

.a limita-recomends excluding the proper investigational use, fro-

, coved by the tions, provided that such investigational use is y,

competent regulating authority.

Peter B. Schneider, M.D., Professor of Medicine, University of 12.

Massachusetts, Worcester, Massachusetts.

Dr. Schneider heartily approves the proposed rule change and welc the Comission's endorsement of the validity of the physician's However, he suggests that there are judgment in the use of a drug.

occasions where radiopharmaceuticals are best used by routes of As an example, he administration not listed on the product label.

states that Tc-99m-pertechnetate, although labeled for intravenous I

He also use, might be used orally or subcutaneously for a brain scan.

f stagests that Tc-99m pertechnetate or colloid, if administ might be used to outline the stomach WilliamH. Briner, Captain,USPHS(Ret.),AssistantProfessorof 13.

Radinlogy, Duke University Medical Center, Durham, North C Consultant to the U.S. Nuclear Regulatory Commission.

6

J k gw p I

o.

I/

f 3

a a welc6me change.

Mr. Briner believes that'the proposed obout the need to restrict physican However, he has serious misg F ior indications not in the product labeling, I

use of NDA-approved de-to the, chemical and physical form, route of admi...stration and dasage Mr. Briner feels that, at range listed for the approved indication.

the very least, this is contrary to the philosophy of Federal Drug law, and, hence, may easily be interpreted as an interference with the He cites as an example of the confusing nature practice of medicine.

of the NRC restrictions, the fact that there are 5 approved indica-q l

He tions for Tc-99m pertechnetate and four different dosage ranges.

asks, "Which indication and which dosage range would apply in any given use of the drug for an indication not in the product labeling?"

4 William H. Blahd, M.D., President, The Society of Nuclear Medicine 14.

(SNM),NewYork,NewYork.

Dr. Blahd states that the SNM applauds the Comission's decision to remove the current limitation that requires physicians licensed for Groups I, II and III to use NDA-approved radiopharmaceuticals only

~ t.

The SNM objects, however, to the proposal to for approved indications.

restrict the physician to the same chemical and physical fonn, route of administration and dosage range specified in the prduct labeling, Dr. Blahd states that when departing from the labeled indications.

7 1

I r.

aI I

mg legislat' ion un' der which the Comission 4perates is the e"

.<oid of any provision which would allow the Comission to mandate He states that other Federal laws which regulate such restrictions.

~

drugs are similarly devoid of such provisions.

=

Or. Blahd also believes that the NRC restrictions are unclear at best.

As an example, he states that there are no fewer than four dosage ranges (for five approved indications) specified in the labeling for He asks the question, "... which of the Technetium-99m Generators.

approved dosage ranges would a physician be required to follow if he wishes to use Sodium Pertechnetate Tc-99m for an indication not product labeling?"

Coments Disapproving Proposal E. Ellis Simons, Director, Division of Radiological Health, State of 15.

Nebraska, Department of Health.

Mr. Simons has reservations about NRC's proposal to delete the clinical He believes that it is procedures from the group medical licenses.

necessary to streamline the licensing procedure, but not at the expen:;e From his observations, the of the health and safety of the patients..-

8

$:c A

l w

e

.Q physician's best knowledge and ' judgment in using dru'gs for unapproved Mr. Simmons uses are not always in the best interest of the patient.

is concerned that in the highly technical and sophisticated practice of nuclear medicine, the patient is generally totally incompetent to judge whether the benefit exceeds the risk and proof of damage generally rests with the patient. Mr. Simmons believes that the NRC needs to strengthen the controls on accessibility of radionuclides for human use rather than weaken them.

David D. Sne11ings, Jr., Director, Division of Radiological Health, 16.

Arkansas Bureau of Environmental Health Services.

Mr. Snellings say that the Division of Radiological Health supports the They existing rule that specifies the authorized clinical procedure.

believe that the existing rule provides adequate control over the use of radioactive material and it should not be changed.

Ronald E. Zelac, Ph.D., C.H.P., Director Radiological Health and 17.

Biohazards Control Temple University, Philadephia, Pennsylvania.

Mr. Zelac points out that the risk associated with the usage of a radio-phamaceutical for procedures not approved by the FDA is, in most cases, 9

e, Enclosure 4 b.

o

lll probably not appreciably greater than the risk associated with usage for approved procedures. He questions the risk: "Is it automati-cally warranted if, in the opinion of the individual physiciar

..e "What procedure has yielded some useful diagnostic infonnatior' about those situations where there is no useful information provided, although the physician expected some?"

"Are there other agents available that have been specifically designed for the particular usage that will provide the desired diagnostic information with a lower radiation dose comittment?" Mr. Zelac believes that if the radiation doses to patients are, in general, large enough to warrant regulatory attention, then answers to these questions would seem to be a prudent prerequisite to the proposed regulatory changes.

Linda D. Drachman, Director, Drug Regulatory Affairs, New England 18.

Nuclear Corporation, Boston, Massachusetts.

Ms. Drachman proposes that e: ner NRC automatically incorporate radio-pharamaceuticals into the group licenses when they receive New Drug Application approval from FDA or NRC publish a conditional Federal Register amendment when FDA issues an approvable letter for the drug.

According to Ms. Drachman the amendment would become effective upon issuance of the approvable letter and would be followed by further notice in the Federal Register.

10 Ih.

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c4C0hGiSSSf0NALLETTER Dear __

_are copies of Enclosed for the information of the.

Nuclear Regulatory Commission effective amendments to its regulations in The amendments will

-10 CFR Part 35 for the medical uses of radioisotopes.

allow physicians greater leeway in their use of radioactive drugs.

Enclosed also are copies of a public announcement to be released by the Commission on this matter in the next few days.

Sincerely, Robert B. Minogue, Director Office of Standards Developst

Enclosures:

. 1.

Final Rule 2.

Public Announcemer.t

,T nelosure 5 e

e J:

My;

_