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Title 10 - Energy

CHAPTER I - NUCLEAR REGULATORY COMMISSION

PART 35 - HUMAN USES OF BYPRODUCT MATERIAL

Change in License Conditions for Certain Medical Licenses

AGENCY: U.S. Nuclear Regulatory Commission (NRC)

ACTION: Final rule.

SUMMARY: The Nuclear Regulatory Commission is amending its regula-

tions (a) to permit 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 FDA.

EFFECTIVE DATE: The amendment becomes effective on March 22, 1979.

FOR FURTHER INFORMATION CONTACT: Edward Podolak, Office of Standards

Development, U.S. Nuclear Regulatory Commission, Washington, D.C. 20555

(Phone: 301-443-5860).

SUPPLEMENTARY INFORMATION: On March 17, 1978, the NRC published for a

60-day comment period a proposed rule (43 FR 11206) to amend its regula-

tions to delete the specification of the diagnostic clinical procedures

from the lists of radiopharmaceuticals in Groups * I, II, and III of

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5 35.100. In the same proposal an amendment to I 35.14 would require

physicians to follow the product labeling for the chemical and physical

form, route of administration and recommended dosage range when they

use Groups I, II and III radiopharmaceuticals for clinical procedures not

specified in the product labeling. -In the same proposal the Commission

also proposed to update the lists in Groups I, II and III by deleting

certain chemical forms not approved by the Food and Drug Administration

(FDA). .. ._

Copies of the proposed rule were sent to all NRC medical licensees,

the States and 25 professional societies and individuals. Eighteen

comment letters were received. Seven commenters fa.vored the proposal

without qualification. Seven-commenters favored the proposal but

suggested a change. Three comme.n.t.er.s. objected to the proposal. One~

comenter discussed a point that wa.s beyond the scope of the proposal

but will be considered by NRC separately. --

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DISCUSSION OF MAJOR COMMENTS .

. The comments favoring the proposal.but- suggesting a change

suggested that NRC should. not restrict physicians to follow the product

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The most common types of NRC specific licenses for the cedical uses of.byproduct material are the Group medical licenses under 5 35.14 that Iapply to those radioactive materials listed in 5 35.100. The radio- [active materials listed in s 35.100 are divided into six groups, each :

group having similar requirements for user training and experience '

facilities and equipment, and radiation safety procedures. Groups I,II and III are lists of radiopharmaceuticals for diagnostic procedures; y

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Groups IV and V are lists of radiopharmaceuticals for therapeuticprocedures; and Group VI is a list of radioactive medical devices forboth diagnostic and therapeutic procedures. '

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labeling for the chemical and physical form, route of administration

and recomended dosage range when using radiopharmaceuticals for

clinical procedures not specified in the product labeling. Most of

these conmenters felt that the route of administration should be leftto the physician.

The example cited most often was the administration

of Tc-99m pertechnetate orally or rectally when it has been approvedby FDA only for intravenous administration.

These commenters state

that the oral or rectal route might, in some instances, be safer than

intravenous administration, for example, in an emergency situation orwhen a vein is not available for injection.

One commenter suggested

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-culation through a Swan-Ganz ~ catheter.

Two commenters pointed out that

FDA does not restrict the physician to the chemical and physical form

route of administration or recommended dosage range in the product label-ing.

One commenter expressed Wncern that the NRC restrictions would~ ~

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hinder research into new uses and dosage forms.

Some of these commenters 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

specified in the product labeling. With the exception of the restric- '

tion on the chemical and physical form of the radiopharmaceutical,:

which will still be specified in the 5 35.100 Groups, the NRC restric- ,

tions on route of administration and dosage range apply only when1...

physicians use a radiopharmaceutical for clinical procedures not

spec'ified in the product labeling. nStated alternatively, physicians

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may depart from the product labeling regarding dosage range and route

of administration when they follow that labeling regarding the FDA-approved clinical procedure. This policy is consistent with FDA'srecognition that good medical practice re ires physicians to be free

to use drugs according their best knowledge and judgment in the interestof the patient.

The compatibility between NRC and FDA policy in this

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

labeled chemical and physical form, labeled route of administration, and

labeled dosage range (when they use a radiopharmaceutical for clinical

procedures not specified in the product labeling) is'more restrictivethan FDA.

The Commission believes that these restrictions minimize therisk to patients from diagnostic clinical procedures that have not beenapproved by FDA.

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Regarding the comment about hindering research, each of the Groups -

I, II, and III includes a provision authorizing the use of products-

for which a " Notice of Claimed Investigational Exemption for a New !

Drug" (IND) has been accepted by the FDA. Research may also be con-

ducted under NRC licenses of broad scope provided the studies arei

performed in accordance with FDA regulations and are approved by the

licensee's Medical Isotopes Committee.

One commenter who disapproved of the proposed rule believes

that the existing rule provides adequate control and should not be

changed. Another commenter challenged the assumption that physicians

always use their best knowledge and judgment when using drugs forunapproved uses.

This commenter noted that the patient is generally

totally incompetent to judge whether the benefit of a procedure

exceeds the risk and that the proof of damage generally rests with4

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the patient. The third connenter who disapproved of the proposed rule

questioned how the benefit-risk decision would be made by the physician.

This commenter wanted to know if the procedure is automatically war-

ranted when there is an expectation that the procedure will yield some

useful diagnostic infomation.

In answer, the Comission believes that the use of diagnostic

radiophamaceuticals 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

labeling. Advances in medical knowledge and practice inevitably

precede labeling revision by the manufacturer and formal label approval

by the FDA. Good medical practice and patient interests are best

served when the physicians are free to use radiopharmaceuticals 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 5 35.100 groups through previous Federal

Reaister notices; and (2) the names of some chemical forms have been

changed to conform with FDA guidelines (e.g. , "diethylenetriaminepenta-

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

Under the Atomic Energy Act of 1954, as amended, the Energy

Reorgar.ization Act of 1974, as amended, and Sections 552 and 553 of

Title 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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1. In 5 35.14(b), a new paragraph (6) is added which reads asfollows:

5 35.14 Specific licenses for certain grouos of medical uses ofbyvproduct 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 (package insert) shall comply with the product labelingregarding:

(i) chemical and physical form;

(ii) route of administration; and

(iii) dosage range.* * :* * *

2. In 5 35.l''n, paragraphs (a), (b) and (c) are revised toread as follows:

5 35.100 Schedule A - Groups of medical uses of byoroduct material.(a) Group I.

Use of prepared radiopharmaceuticals for certain diagnostic

studies involving measurements of uptake, dilution and excretions

This group does not include imaging or localization studies,g

(1) Iodine-131 as sodium iodide, fodinated human serum albumin, labeled

rose bengal, triolein, or sodium iodohippurate;,

(2) Iodine-125 as sodium iodide, iodinated human serum albumin, oleic

acid or sodium iothalamate;.

(3) Cobalt-58 as labeled cyanocobalamin;

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(4) Cobalt-60 as labeled cyanocobalamin;

(5) Chromium-51 as sodium chromate or labeled human serum albumin;

(6) Iron-59 as citrate;

(7) Technetium-99m as pertechnetate; and

(8) Any byproduct material in a radiopharmaceutical and for a diagnostic

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 Administration (FDA).

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

imaging and localization studies.

(1) Iodine-131 as sodium iodide, iodinated human serum albumin, macro-

aggregated iodinated human serum albumin, colloidal (microaggregated)

iodinated human serum albumin, rose benegal or sodium iodohippurate;

(2) Iodine-125 as sodium iodide or fibrinogen;

(3) Chromium-51 as human serum albumin;

(4) Gold-198 in colloidal form;

(5) Mercury-197 as chlormerodrin;

(6) Mercury-203 as chlonnerodrin;

(7) Selenium-75 as selenomethionine;

(8) Strontium-85 as nitrate;

(9) Technetium-99m as pertechnetate, sulfur colloid or macroaggregated

human serum albumin;

(10) Ytterbium-169 as pentatate sodium;

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(11) Indium-ll3m as chloride;

(12) Any byproduct material in a radiopharmaceutical prepared from a

reagent kit listed in paragraph (c)(4) cf this section; and

(13) Any byproduct material in a radiopharmaceutical and for a

diagnostic use involving imaging or localizing for which a " Notice

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.

(1) Molybdenum-99/ technetium-99m generators for the elution of

technetium-99m as pertechnetate;

(2) Technetium-99m as pertechnetate for use with reagent kits for

preparation and use of radiopharmaceuticals containing technetium-99m

as provided in paragraphs (c)(4) and (5) of this section;

(3) Tin-ll3/ indium-ll3m generators for the elution of the indium-ll3m

as chloride;

(4) Reagent kits for preparation of technetium-99m labeled:

(i) Sulfur colloid;

(ii) pentatate sodium;

(iii) Human serum albumin microspheres:

(iv) Polyphosphates;

(v) Macroaggregated human serum albumin;

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(vi) Etidronate sodium;

(vii) Stannous pyrophosphate;

(viii) Human serum albumin;,

(ix) Medronate sodium;

(x) Gluceptate sodium; and

(5) Any generator or reagent kit for preparation and diagnostic use

of a radiopharmaceutical 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).)

Dated at Washington, D. C. this 13th day of February 1979.

For the Nuclear R ulatory Commission.

$6 Samuel J ' Chilk.

Secretary of tjae Commission

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