Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea

NUCLEAR REGULATORY COMMISSION

10 CFR Parts 30 and 32

RIN 3150-AF70

Exempt Distribution of a Radioactive Drug Containing One

Microcurie of Carbon-14 Urea

AGENCY: Nuclear Regulatory Commission.

ACTION: Final rule.

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SUMMARY: The Nuclear Regulatory Commission (NRC) is amending its

regulations to permit NRC licensees to distribute a radioactive drug

containing one microcurie of carbon-14 urea to any person for ``in

vivo'' diagnostic use. The NRC has determined that the radioactive

component of such a drug in capsule form presents an insignificant

radiation risk and, therefore, regulatory control of the drug for

radiation safety is not necessary. This amendment makes the drug more

widely available and reduces costs to patients, insurers, and the

health care industry. This action grants a petition for rulemaking

(PRM-35-12) from Tri-Med Specialties, Inc. and completes action on the

petition.

EFFECTIVE DATE: January 2, 1998.

ADDRESS: Copies of the public record, including the final regulatory

analysis and any public comments received on the proposed rule, may be

examined and copied for a fee in the Commission's Public Document Room

at 2120 L Street, NW. (Lower Level), Washington, DC.

FOR FURTHER INFORMATION CONTACT: Dr. Anthony N. Tse, Office of Nuclear

Regulatory Research, U.S. Nuclear Regulatory Commission, Washington, DC

20555-0001, telephone (301) 415-6233 or e-mail at [email protected]

SUPPLEMENTARY INFORMATION:

I. The Petition for Rulemaking.

II. Proposed Rule, Public Comments, and NRC Responses.

III. Summary of the Final Amendments.

IV. Description of the Final Amendments.

V. Agreement State Compatibility.

VI. Finding of No Significant Environmental Impact: Availability.

VII. Paperwork Reduction Act Statement.

VIII. Regulatory Analysis.

IX. Regulatory Flexibility Certification.

X. Small Business Regulatory Enforcement Fairness Act.

XI. Backfit Analysis.

List of Subjects

I. The Petition for Rulemaking

On October 6, 1994, the Commission docketed a petition for

rulemaking (Docket No. PRM-35-12) from Tri-Med Specialties, Inc (Tri-

Med). In a letter dated August 23, 1994, Tri-Med petitioned the NRC to

amend its regulations ``to allow for the general licensing and/or

exemption for the commercial distribution by licensed pharmaceutical

manufacturers of a capsule containing one micro-Curie (Ci) of

C-14-urea for in vivo diagnostic testing.'' The purpose of this

diagnostic test is to detect the presence of the bacterium Helicobacter

pylori (H. pylori), a cause of peptic ulcers in humans.

Following the receipt of the petition, the NRC published for public

comment a notice of receipt of petition for rulemaking in the Federal

Register on December 2, 1994 (59 FR 61831). The comment period closed

on February 15, 1995. The NRC received 315 public comment letters, of

which 313 supported the petition (they were mostly form letters) and 2

letters opposed the petition.

II. Proposed Rule, Public Comments, and NRC Responses

A proposed rule was published on June 16, 1997 (62 FR 32552) that

would permit NRC licensees to distribute capsules containing one

microcurie

C-14 urea to any person for ``in vivo'' diagnostic use. The public

comment period closed on July 16, 1997.

In the preamble of the proposed rule, the NRC stated that, because

the capsules present an insignificant radiological risk to the public

and the environment, the NRC believes the capsules could be distributed

for ``in vivo'' diagnostic use to persons exempt from licensing.

This change makes the drug more widely available and reduces costs

to patients, insurers, and the health care industry.

The NRC received seven public comment letters on the proposed rule:

three from industry, three from State agencies, and one from a

physician associated with a university medical facility. Four

commenters supported the rule, one opposed the rule, and two provided

comments but did not explicitly state whether they supported or opposed

the rule. Public comments and NRC's responses are presented below.

Comment 1: Under the proposed distribution, the NRC should not be

forbidding research use of this drug by the same physicians who may use

it clinically. Research use also should be permitted under this

exemption because the radiological risk for using C-14 capsules is

insignificant.

Response: The NRC did not change the final rule in response to this

comment. A common rule entitled ``Federal Policy for the Protection of

Human Subjects; Notices and Rules'' was promulgated by 16 Federal

agencies on June 18, 1991 (56 FR 28002) and was intended to ensure the

protection of human research subjects. This rule was adopted to

implement a recommendation of the President's Commission for the Study

of Ethical Problems in Medicine and Biomedical and Behavioral Research

which was established on November 9, 1978, by Public Law 95-622. The

Federal Policy requires that Federal agencies that conduct, fund,

support, or regulate research involving human subjects ensure adequate

protection of the rights of the human subjects. The Federal policy

represents a societal determination that any research (including

research involving radioactive material) must provide for

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the following minimal protections for the human subjects: (1) that the

research is approved by an Institutional Review Board (IRB) and (2)

that the human subject gives informed consent to participate in the

research. Further, these protections must be provided regardless of

whether or not there is any risk of consequences (including

radiological consequences). This view is supported by the fact that

during the public comment period of the common rule, a commenter

suggested that all minimal risk research be exempt from the

regulations; however, the final rule did not adopt this comment.

NRC did not participate in the promulgation of the common rule.

Subsequently, the NRC adopted 10 CFR 35.6 that requires a licensee who

conducts research involving human subjects using byproduct material to

obtain informed consent from the human subjects and obtain prior

approval by an IRB. Although the NRC did not adopt the common rule, the

intention is to follow the essential requirements of the common rule.

Because the common rule does not provide an exemption for research

involving minimal risk, the Commission has determined that such

research use should not be exempt from 10 CFR 35.6.

Comment 2: Two commenters expressed concerns that the proposed rule

language, ``not exceeding one microcurie,'' appeared to indicate that

the upper limit of the radioactivity in a capsule is exactly one

microcurie of C-14. Both stated that it is not possible to make the

capsules to exactly one microcurie because of statistical deviations

during the manufacturing process.

Response: The NRC agrees with the commenters. The proposed rule did

not intend to limit the radioactivity of C-14 to exactly one

microcurie. The final rule language has been modified to read

``capsules containing one microcurie C-14 urea (allowing for nominal

variation that may occur during the manufacturing process).''

Comment 3: One commenter stated that, when the total amount of

energy released from complete decay of a radionuclide is considered,

one microcurie of C-14 has the largest energy release, because of its

long half-life, when compared to one microcurie of Tc-99m or I-131. The

commenter concluded that, given the insignificant radiation risk from

the diagnostic use of C-14 urea, the radiation risk from the diagnostic

use of Tc-99m or I-131 also would be insignificant.

Response: In comparing the hazard significance of the one

microcurie C-14 Urea diagnostic test to the extensive use of Tc-99m and

I-131, the NRC did not evaluate the dose to the patient because this

dose would be justified for medical reasons. Justification for

retaining some licensing control on the medical use of Tc-99m and I-131

while exempting the one microcurie carbon-14 urea capsules relies on

the relative occupational hazards to technicians and physicians

administering the radiopharmaceuticals.

Administering an encapsulated dosage of one microcurie C-14

involves virtually no occupational dose due to the low energy beta

radiation and minimal possibility for contamination of personnel or

facilities. On the other hand dosages of Tc-99m and I-131 entail

extracting 10s to 100s of millicurie amounts, often in liquid form,

from shielded sources of even higher activity. The possibility of

direct exposure to gamma radiation and the possibility of contamination

requires that radiation protection measures be in place to maintain

exposure to staff as low as is reasonably achievable.

Tc-99m and I-131, having relatively short half-lives, present

minimal environmental hazard. C-14 as urea is excreted from the patient

as carbon dioxide (CO2) which diffuses into the atmosphere.

Based on a calculation found in the regulatory analysis for this rule,

the current world inventory of naturally occurring C-14 results in an

average dose to members of the public of about 1.25 mrem/yr. A release

of 0.6 curies of C-14 from the 600,000 tests expected to be

administered annually, would result in an additional average annual

dose of 2 x 10-7 mrem. Comparing this estimate to the EPA

Clean Air Act reporting level of 1 mrem/year, this new test is

environmentally insignificant.

Comment 4: Because of the small quantity of radioactive material in

C-14 capsules, this product may be disposed of in the general trash. To

avoid unnecessary concern for health risks in the disposal of the

product, labels should contain a statement that the product may be

disposed of in the general trash.

Response: In the final rule, the label requirements include a

statement that the product may be disposed of in ordinary trash.

Comment 5: The Commenter agrees that the widespread use of this

product will require uniform regulations and that Agreement States will

need to make appropriate regulatory provisions to enable persons to

receive the drug for ``in vivo'' diagnostic use. To avoid confusing

licensees and users, these changes to NRC and Agreement State

regulations should be made simultaneously. The commenter urges that the

NRC take action to expedite the Agreement State regulatory changes.

Response: The NRC has urged the Agreement States to adopt

compatible changes in their regulations expeditiously. However, under

NRC's Adequacy and Compatibility Policy, Agreement States have up to

three years to change their regulations for amendments or program

requirements that are items of compatibility.

Comment 6: The NRC should address this rule in its ongoing effort

to revise 10 CFR Part 35 in its entirety. The commenter believes that

(1) this rule represents a piecemeal effort to respond to a narrow

issue and (2) the issue of reduced regulation for medical use of C-14

capsules is applicable to the same extent for virtually the entire

range of diagnostic radioisotopes.

Response: If this rule is combined with the overall 10 CFR part 35

revision, the C-14 capsules would only be available to authorized user

physicians during the revision period. Thus, the NRC decided to proceed

with this rule now because the benefits of making this capsule

available to anyone, including primary-care physicians, outweigh the

benefits of addressing this issue in the overall revision of 10 CFR

part 35.

Comment 7: An appropriate function of the regulatory regime is to

assure that personnel handling and administering radioactive drugs meet

certain basic training and qualification requirements. The proposed

exemption would impose no training or qualification requirements on

users.

Response: The amount of radiation safety training needed for

personnel depends on the level of radiation risk associated with the

radioactive drug. Because C-14 capsules present insignificant radiation

risk, radiation safety training for personnel handling and

administering the capsule is not necessary, and thus, not required.

Comment 8: If the NRC promulgates the proposed rule in its present

form, the exemption will divest the Agreement States of any authority

to regulate this product under a general or specific license. Had the

NRC instead simply proposed a general license, Agreement State agencies

would retain the authority to adopt the general license or continue to

require specific licensing.

Response: In the draft rulemaking plan, the NRC suggested using the

general license approach. The NRC received nine comment letters from

Agreement States on the draft rulemaking plan; three suggested that an

exemption approach would be more appropriate because it would be less

costly to the Agreement States and their

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licensees than the general license approach.

Based on these comments, the NRC chose the exemption approach in

the final rule plan as more cost-effective than a general license

approach. The final rulemaking plan was revised accordingly and was

provided to the Agreement States. No Agreement States expressed

opposition to the NRC on the exemption approach.

Among the seven public comment letters received on the proposed

rule, two were from Agreement States and one from a non Agreement

State. All three supported the proposed rule.

Comment 9: The environmental assessment fails to consider the fact

that another equally noninvasive, but nonradiological, diagnostic

procedure (such as C-13 test) is available and provides a comparable

alternative to the C-14 test. The apparent assumption underlying the

environmental assessment is that in the absence of the C-14 test, the

only alternative for the detection of H. pylori is invasive

gastroendoscopy.

Response: Because the C-14 urea capsules are already available to

authorized user physicians, the only regulatory issue in this

rulemaking is whether the C-14 method should be made available to

individuals who are not authorized users. The purpose of the

environmental assessment is to consider and document whether the

subject rule is expected to have any significant impact to the

environment. In this environment assessment, the NRC has determined

that the environmental impact is expected to be insignificant because

of the extremely low radiological hazards associated with the use of

capsules containing one microcurie C-14 urea. The presence of an

additional non-invasive alternative procedure does not affect NRC's

determination of no significant environmental impact.

Comment 10: NRC's policy in the past has been not to exempt

byproduct material that is ingested. Any change in this policy would be

a significant departure from existing NRC regulations.

Response: This change is a departure from existing NRC regulations.

In the statement of consideration for the proposed rule, under the

heading ``Current NRC Regulations on Exemptions From Licensing,'' the

NRC stated that, although two broad material exemptions (Sec. 30.14,

``Exempt concentrations,'' and Sec. 30.18, ``Exempt quantities'')

exclude the transfer of byproduct material contained in any product

designed for ingestion or inhalation by a human being, the C-14

capsules manufactured or prepared as a radioactive drug can be

distributed to persons exempt from licensing for ``in vivo'' diagnostic

use because the capsules present an insignificant radiological risk to

the public and the environment. This exemption only applies to the

diagnostic use of capsules containing one microcurie C-14 manufactured

or prepared as a radioactive drug to make a clear distinction between

this radioactive drug that is intended for ingestion by humans and

other uses of C-14 urea and byproduct material distributed under

Secs. 30.14 and 30.18.

Comment 11: The ACMUI's (Advisory Committee on Medical Uses of

Radioisotopes) conclusions that either an exemption or general license

is appropriate for the C-14 product do not address the fundamental

aspects of nuclear safety. Its judgment was based partially on the

assumptions: (1) the product may only be dispensed by prescription, (2)

the product is approved by the Food and Drug Administration, and (3)

the office/facility using the product will be subject to Clinical

Laboratory Improvement Amendment (CLIA) regulation.

Response: The transcript from the ACMUI meeting shows the Committee

did include radiation safety in its considerations and did not consider

it to be an issue. Further, as stated in the supplemental material

supporting the proposed rule, there are no nuclear safety issues

associated with the use of the C-14 capsules for clinical diagnostic

testing. Therefore, use of either an exemption or general license is

appropriate.

Comment 12: The exemption approach does not provide the NRC with

flexibility to impose a limitation on the amount of C-14 capsules any

physician can possess in an office. In the event there is a recall of

the product, or a large amount of product becomes unusable, the NRC

will have no control over the disposal of the product.

Response: It is not necessary to impose a possession limit on the

amount of C-14 capsules because the radiation risk is insignificant.

The earth's atmosphere contains an inventory of naturally occurring C-

14 of about 3.8 million curies which is in addition to the huge

inventory of about 240 million curies in the world's oceans. The small

amount of C-14 released into the atmosphere from the use of this test

would mix with the global inventory and would have no impact on public

health. The current world inventory of naturally occurring C-14 results

in an average dose to the public of about 1.25 mrem per year, and the

release of 0.6 curies of C-14 from the total of 600,000 tests assumed

to be administered annually would result in an additional average

annual dose of

2 x 10-7 mrem. In the event that a recall is necessary,

the manufacturer may use the same process for recalling any other non-

radioactive drugs. If C-14 urea capsules are returned to the

manufacturers, they will be disposed of in accordance with the

manufacturer's possession license. A user, however, can dispose the C-

14 urea capsules as ordinary trash. Medical users of the C-14 urea test

would be unlikely to acquire significant quantities of capsules because

they can be ordered within a few days. Thus, even under a recall, the

impact of disposing of C-14 urea capsules into landfills by the user

would also be insignificant.

Comment 13: It is essential that end users be adequately informed

of the product's radioactive characteristics, so that some form of

storage, use, and disposal precautions can be followed. Thus, the

labeling must be conspicuously and prominently placed. The commenter

suggested the following: (1) the phrase ``conspicuously and

prominently'' in front of the proposed labeling ``bears the words

Radioactive Material'' should be added, and (2) the NRC should require

that the radioactive material legend, ``Radioactive Material,'' be

included on promotional brochures.

Response: Because the radiation risk from C-14 capsules is

insignificant, regulatory control of the use, storage, and disposal of

the drug for purpose of radiation safety is not necessary. In fact, the

label accompanying C-14 capsules is required to indicate that the

capsules may be disposed of by users as ordinary trash. Paragraph(a)(6)

of Sec. 32.21 requires that applicants submit copies of prototype

labels and brochures for NRC approval. The NRC will ensure that the

labels meet the requirements of Sec. 32.21a before they are approved.

Since paragraph (a) of Sec. 32.21a specifies that the label must be

durable and legible, the use of an additional phrase such as

``conspicuously and prominently'' is unnecessary. Promotional brochures

are for information only; manufacturers are not required to indicate on

the promotional brochures that C-14 is a radioactive material.

III. Summary of the Final Amendments

Final Amendment to 10 CFR Part 32

The regulations in 10 CFR part 32 are amended to add new

Secs. 32.21 and 32.21a, to provide requirements for a specific license

to manufacture, prepare, process, produce, package, repackage, or

transfer for commercial distribution,

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capsules containing one microcurie of C-14 urea, as a radioactive drug,

to be distributed to any person for ``in vivo'' diagnostic use. These

requirements are consistent with the existing requirements on other

items under the heading ``Exemptions'' in 10 CFR part 30. The amendment

includes a reminder that licensees distributing the radioactive drug to

persons exempt from licensing would not be relieved from other

applicable Federal (e.g., FDA) or State requirements governing the

manufacture and distribution of drugs.

The amendment requires that the manufacture or preparation of

capsules containing one microcurie of C-14 urea be prepared by persons

who meet the current NRC regulations to manufacture and commercially

distribute radioactive drugs. The NRC believes regulatory control is

needed to provide high confidence that the drug contains one microcurie

of C-14 urea and does not contain any other radioactive contaminants.

Final Amendment to 10 CFR Part 30

The NRC has determined that the drug in capsule form presents an

insignificant radiological safety and environmental risk, and that it

is not necessary to regulate the use of this drug for its radioactive

component. Therefore, the NRC can not justify requiring physicians, or

any other person, to meet NRC training and experience criteria directed

at the safe use of radioactive drugs, or to become an ``authorized

user.'' Hence, the capsules can be distributed to any person. However,

other Federal or State agencies may limit the receipt and use of the

capsules in accordance with their own requirements.

The regulations in 10 CFR part 30 are amended to add a new

Sec. 30.21, to permit any person to receive, possess, use, transfer,

own, or acquire for ``in vivo'' diagnostic use, capsules containing one

microcurie of C-14 urea without a license. The final regulation

includes a reminder that persons receiving the capsules would not be

relieved from other Federal or State law governing drugs. Further, in

accordance with the NRC's provisions for research involving human

subjects (10 CFR 35.6), the exemption permitting receipt and use of the

capsules for ``in vivo'' diagnostic use does not extend to use of the

capsules for research involving human subjects. Any person desiring to

use the capsules for human research would still be required to submit

an application for a specific license under part 35. The phrase ``in

vivo diagnostic use'' was selected to describe the activity authorized

in Sec. 30.21 to differentiate it from the term ``medical use''

because:

(1) ``Medical use'' limits administration to authorized users; use

of this drug would not be so limited; and

(2) ``Medical use'' includes the administration of the drug to a

human research subject, which would continue to require a specific

license pursuant to part 35 under this rulemaking.

Effects of the Final Amendments

The final amendments make the drug available to any person, for

``in vivo'' diagnostic use, without need for an NRC or Agreement State

license. Because the receipt and use of the drug are exempt from NRC

licensing, Agreement States need to make appropriate provisions in

their regulations to recognize the exempt distribution of the drug, for

``in vivo'' diagnostic use. Thus after the manufacture and distribution

of the drug, the NRC and the Agreement States will not regulate the use

of the drug as long as its use is for ``in vivo'' diagnostic use. This

means that, under NRC and Agreement State regulations, primary-care

physicians do not need to be ``authorized users'' in order to

administer the drug, and do not need to refer their patients to nuclear

medicine physicians. This should result in cost savings to patients.

Other Federal and State organizations with responsibilities for

regulating drugs will determine and regulate who can receive and use

the drug for ``in vivo'' diagnostic use. NRC will continue to regulate

the use of the drug for research involving human subjects under a

specific part 35 license.

IV. Description of the Final Amendments

The final amendments are the same as the proposed amendments except

for two minor changes. Public comments suggested that the phrase

``carbon-14 urea capsules not exceeding one microcurie'' used in the

proposed rule may be interpreted as an exact limit of one microcurie

per capsule (See Comment 2 under the heading ``Public Comment and NRC

Responses). The final rule has been modified and the phrase ``capsules

containing one microcurie carbon-14 urea (allowing for nominal

variation that may occur during the manufacturing process)'' is used.

Another public comment suggested that labels should contain a statement

that the product may be disposed of in the general trash. In the final

rule, the label requirements include such a statement.

Manufacturer and Distributors

A new section is added to 10 CFR Part 32 to permit the distribution

of the capsules to persons who are exempt from licensing.

Section 32.21 Radioactive Drug: Manufacture, Preparation, or Transfer

for Commercial Distribution of Capsules Containing one Microcurie

Carbon-14 Urea Each for ``in Vivo'' Diagnostic use for Humans to

Persons Exempt From Licensing; Requirements for a License

Paragraph (a)

This paragraph establishes the requirements for approval of a

license application to manufacture, prepare, process, produce, package,

repackage, or transfer for commercial distribution, capsules containing

one microcurie carbon-14 urea each for ``in vivo'' diagnostic use, to

persons exempt from licensing.

Paragraph (a)(1)

This paragraph limits issuance of an ``exempt distribution

license'' for distribution of the capsules to persons exempt from

licensing to only those who possess either a NRC or Agreement State

``specific license'' for possession and use of byproduct material.

Paragraph (a)(2)

To assure that the capsules contain one microcurie of carbon-14 and

present no other radiological risks, this paragraph requires that the

persons manufacturing and/or commercially distributing the capsules for

``in vivo'' diagnostic use must also meet the requirements of

Sec. 32.72(a)(2). Specifically, these persons must be:

(1) Registered with or licensed by the FDA as a drug manufacturer;

or

(2) Registered with or licensed by a state agency as a drug

manufacturer; or

(3) Licensed as a pharmacy by a State Board of Pharmacy; or

(4) Operating as a nuclear pharmacy within a Federal medical

institution.

Paragraph (a)(3)

This paragraph requires applicants to provide evidence that each

carbon-14 urea capsule contains one microcurie. The NRC's evaluation

that the capsules would result in insignificant radiation risks was

based on the capsules containing one microcurie of carbon-14 urea.

Therefore, applicants must demonstrate that the activity of each

carbon-14 capsule contains one microcurie, allowing for nominal

variation that may occur during the manufacturing process.

Paragraph (a)(4)

This paragraph prohibits carbon-14 urea from being contained in any

food, beverage, cosmetic, drug or other commodity designed for

ingestion or

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inhalation by, or topical application to, a human being except for the

capsules as described in this section, because exempt distribution of

this drug has only been evaluated for ``in vivo'' diagnostic use in the

form of a capsule containing one microcurie of carbon-14 urea. There is

no prohibition against the capsule being combined with food or beverage

at the time of administration so that the capsule can be ingested by

the patient.

Paragraph (a)(5)

Because the exempt distribution of this drug has only been

evaluated for ``in vivo'' diagnostic use in the form of a capsule

containing one microcurie of carbon-14 urea, this paragraph prohibits

incorporation of the capsules into any manufactured or assembled

commodity, product, or device intended for commercial distribution.

Further, although the drug is being distributed to persons exempt from

licensing, this paragraph requires the carbon-14 urea to be identified

as radioactive because the drug is being used for its radioactive

content; therefore, the end user must be provided with information that

the drug contains a radioactive material.

Paragraph (a)(6)

As with any product approved for distribution to persons exempt

from licensing, this paragraph requires persons who apply for a license

to manufacture or commercially distribute these capsules to submit

copies of prototype labels or brochures for NRC approval. This will

allow the NRC to confirm that the labels or brochures meet the

requirements of Sec. 32.21a (a) and (b).

Paragraph (b)

This paragraph declares that the regulations do not relieve

licensees or applicants from complying with applicable FDA, other

Federal, and State requirements governing the manufacture and

distribution of drugs.

Section 32.21a Same: Conditions of License

This section establishes the conditions required for a licensee to

commercially distribute the capsules to persons exempt from licensing.

Paragraph (a)

To inform the end user of the identity of the radioisotope, the

physical and chemical form, and the dosage of radioactivity, this

paragraph establishes that the immediate container of each capsule or

capsules must bear a durable, legible label that:

(1) Identifies the radioisotope, the physical and chemical form of

the radioisotope, the quantity of radioactivity contained in each

container at a specific date; and

(2) Bears the words ``Radioactive Material.''

The date requirement is consistent with labeling requirements for

other radioactive drugs with a half life of greater than 100 days.

Paragraph (b)

This paragraph establishes that, consistent with the intended use

of the capsules, the label affixed to the immediate container, or an

accompanying brochure, must:

(1) State that the contents are exempt from NRC or Agreement State

licensing requirements;

(2) Bear the words ``Radioactive Material. For ``In Vivo''

Diagnostic Use Only. This Material Is Not To Be Used for Research

Involving Human Subjects, and Must Not Be Introduced into Foods,

Beverages, Cosmetics, or Other Drugs or Medicinals, or into Products

Manufactured for Commercial Distribution. This Product May Be Disposed

of in Ordinary Trash.''

The intent of the requirement set out in Paragraph (b)(2) is to

make clear that the capsule must remain in the form of a capsule and is

not to be combined with one of the listed items such as food or

beverages which would result in a radioactive product other than in the

form of a capsule for commercial distribution. There is no prohibition

against the capsule being combined with food or beverage at the time of

administration so that the capsule can be ingested by the patient. This

label also informs the user that this product may be disposed of in

ordinary trash.

``In Vivo'' Diagnostic use by Persons Exempt From Licensing

A new section is added to 10 CFR Part 30 to exempt any person from

NRC or the Agreement State regulations to receive the drug for ``in

vivo'' diagnostic use for humans.

Section 30.21 Radioactive Drug: Capsules Containing one Microcurie of

Carbon-14 Urea for ``in Vivo'' Diagnostic use for Humans

Paragraph (a)

This paragraph provides an exemption to any person from the

requirements for a license to receive, possess, use, transfer, own, or

acquire capsules containing one microcurie of carbon-14 urea for ``in

vivo'' diagnostic purposes. It should be noted that the ``transfer'' in

this paragraph does not include ``transfer for commercial

distribution,'' which is covered in paragraph (c) of this section.

Paragraph (b)

This paragraph establishes that persons who desire to use the drug

for research involving human subjects must apply for and receive a

specific part 35 license. Such a license would ensure the protection of

the rights of the human subjects by requiring that the research be

approved by an IRB and that the human subjects give their informed

consent to participate in the research.

Paragraph (c)

This paragraph specifies that a specific license is needed to

manufacture, prepare, process, produce, package, repackage or transfer

such capsules for commercial distribution.

Paragraph (d)

This paragraph declares that the regulations do not relieve end

users from complying with applicable FDA, other Federal, or State

requirements governing the receipt, administration, and use of drugs.

V. Agreement State Compatibility

Under the Atomic Energy Act, certain regulatory functions are

reserved to the NRC. Among these are the distribution of products to

persons exempt from licensing, as discussed in 10 CFR part 150. Hence,

amendments related to the manufacture and commercial distribution of

the capsules (10 CFR part 32) is a Division 4 item of compatibility

(Category NRC under the new adequacy and compatibility policy).

However, amendments related to possession and use (10 CFR part 30) are

a Division 1 item of compatibility (Category B under the new adequacy

and compatibility policy) because of the need for nationwide

consistency in the use of products which are widely distributed.

Therefore, the Agreement States will need to make appropriate

provisions in their regulations to allow any person to receive capsules

containing one microcurie of carbon-14 urea for ``in vivo'' diagnostic

use in humans without need for a license.

VI. Finding of No Significant Environmental Impact: Availability

The Commission has determined under the National Environmental

Policy Act of 1969, as amended, and the Commission's regulations in

Subpart A of 10 CFR part 51, that the final rule is not a major Federal

action significantly affecting the quality of the human environment;

therefore, an environmental impact statement is not

[[Page 63639]]

required. The final rule establishes requirements for the manufacture

and commercial distribution of carbon-14 urea capsules to persons

exempt from licensing and establishes regulations to permit any person

to receive the capsules without an NRC license. The Commission believes

that the radioactive component of this drug presents an insignificant

radiation risk and, therefore, regulatory control of the ``in vivo''

diagnostic use of the capsules for radiation safety is not necessary.

It is expected that this final rule will not cause any significant

increase in radiation exposure to the public or radiation release to

the environment beyond the exposures or releases resulting from the use

of the carbon-14 capsules under the current regulations. Also, it is

expected that there will be no non-radiological impacts. One public

comment on the draft environmental assessment has been received (See

Comment 9 under the heading ``Proposed Rule, Public Comments, and NRC

Responses'').

The environmental assessment and finding of no significant impact

on which this determination is based is available for inspection at the

NRC Public Document Room, 2120 L Street NW. (Lower Level), Washington,

DC. Single copies of the environmental assessment and the finding of no

significant impact are available from Dr. Anthony N. Tse, Office of

Nuclear Regulatory Research, U.S. Nuclear Regulatory Commission,

Washington, DC 20555-0001, telephone (301) 415-6233 or e-mail at

[email protected]

VII. Paperwork Reduction Act Statement

This final rule amends information collection requirements that are

subject to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et

seq.). These requirements were approved by the Office of Management and

Budget, approval numbers 3150-0001, 3150-0017, and 3150-0120.

The public reporting burden for this collection of information is

estimated to average 16 hours per response, including the time for

reviewing instructions, searching existing data sources, gathering and

maintaining the data needed, and completing and reviewing the

collection of information. Send comments on any aspect of this

collection of information, including suggestions for reducing the

burden, to the Information and Records Management Branch (T-6 F33),

U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001, or by

Internet electronic mail at [email protected]; and to the Desk Officer,

Office of Information and Regulatory Affairs, NEOB-10202, (3150-0001,

3150-0017, and 3150-0120), Office of Management and Budget, Washington,

DC 20503.

Public Protection Notification

The NRC may not conduct or sponsor, and a person is not required to

respond to, a collection of information unless it displays a currently

valid OMB control number.

VIII. Regulatory Analysis

The NRC has prepared a regulatory analysis for the final rule. The

analysis examines the benefits and impacts considered by the NRC. No

public comments on the draft regulatory analysis have been received

during the public comment period. The regulatory analysis is available

for inspection at the NRC Public Document Room, 2120 L Street NW.

(Lower Level), Washington, DC. Single copies of the regulatory analysis

are available from Dr. Anthony N. Tse, Office of Nuclear Regulatory

Research, U.S. Nuclear Regulatory Commission, Washington, DC 20555-

0001, telephone (301) 415-6233 or e-mail at [email protected]

IX. Regulatory Flexibility Certification

As required by the Regulatory Flexibility Act of 1980, 5 U.S.C.

605(b), the Commission certifies that this rule does not have a

significant economic impact upon a substantial number of small

entities. The final rule permits physicians and other health care

providers to use an additional diagnostic test without having to obtain

an NRC license, thus, would provide cost savings to patients, insurers,

and the health care industry. The final rule does not impose any

additional obligations on entities that may fall within the definition

of ``small entities'' as set forth in Section 601(3) of the Regulatory

Flexibility Act; or within the definition of ``small business'' as

found in Section 3 of the Small Business Act, 15 U.S.C. 632; or within

the size standards adopted by the NRC on April 11, 1995 (60 FR 18344).

X. Small Business Regulatory Enforcement Fairness Act

In accordance with the Small Business Regulatory Enforcement

Fairness Act of 1996, the NRC has determined that this action is not

``a major'' rule and has verified this determination with the Office of

Information and Regulatory Affairs, Office of Management and Budget.

XI. Backfit Analysis

The NRC has determined that the backfit rule, 10 CFR 50.109, does

not apply to this rule, and therefore, a backfit analysis is not

required because these amendments do not involve any provisions that

would impose backfits as defined in 10 CFR 50.109(a)(1).

XII. List of Subjects

10 CFR Part 30

Byproduct material, Criminal penalties, Government contracts,

Intergovernmental relations, Isotopes, Nuclear materials, Radiation

protection, Reporting and record keeping requirements.

10 CFR Part 32

Byproduct material, Criminal penalties, Labeling, Nuclear

materials, Radiation protection, Reporting and recordkeeping

requirements.

For the reasons set out in the preamble and under the authority of

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

Act of 1974, as amended, and 5 U.S.C. 552 and 553, the NRC is adopting

the following amendments to 10 CFR Parts 30 and 32.

PART 30--RULES OF GENERAL APPLICABILITY TO DOMESTIC LICENSING OF

BYPRODUCT MATERIAL

1. The authority citation for part 30 continues to read as follows:

Authority: Secs. 81, 82, 161, 182, 183, 186, 68 Stat. 935, 948,

953, 954, 955, as amended, sec. 234, 83 Stat. 444, as amended (42

U.S.C. 2111, 2112, 2201, 2232, 2233, 2236, 2282); secs. 201, as

amended, 202, 206, 88 Stat. 1242, as amended, 1244, 1246 (42 U.S.C.

5841, 5842, 5846).

Section 30.7 also issued under Pub. L. 95-601, sec.10, 92 Stat.

2951 as amended by Pub. L. 102-486, sec. 2902, 106 Stat. 3123, (42

U.S.C. 5851). Section 30.34(b) also issued under sec. 184, 68 Stat.

954, as amended (42 U.S.C. 2234). Section 30.61 also issued under sec.

187, 68 Stat. 955 (42 U.S.C. 2237).

2. In Sec. 30.8, paragraph (b) is revised to read as follows:

Sec. 30.8 Information collection requirements: OMB approval.

* * * * *

(b) The approved information collection requirements contained in

this part appear in Secs. 30.9, 30.11, 30.15, 30.18, 30.19, 30.20,

30.21, 30.32, 30.34, 30.35, 30.36, 30.37, 30.38, 30.41, 30.50, 30.51,

30.55, appendices A and C to this part.

* * * * *

3. A new Sec. 30.21 is added under the undesignated center heading

``Exemptions'' to read as follows:

[[Page 63640]]

Sec. 30.21 Radioactive drug: Capsules containing carbon-14 urea for

``in vivo'' diagnostic use for humans.

(a) Except as provided in paragraphs (b) and (c) of this section,

any person is exempt from the requirements for a license set forth in

Section 81 of the Act and from the regulations in this part and part 35

of this chapter provided that such person receives, possesses, uses,

transfers, owns, or acquires capsules containing 37 kBq (1 Ci)

carbon-14 urea (allowing for nominal variation that may occur during

the manufacturing process) each, for ``in vivo'' diagnostic use for

humans.

(b) Any person who desires to use the capsules for research

involving human subjects shall apply for and receive a specific license

pursuant to part 35 of this chapter.

(c) Any person who desires to manufacture, prepare, process,

produce, package, repackage, or transfer for commercial distribution

such capsules shall apply for and receive a specific license pursuant

to Sec. 32.21 of this chapter.

(d) Nothing in this section relieves persons from complying with

applicable FDA, other Federal, and State requirements governing

receipt, administration, and use of drugs.

PART 32--SPECIFIC DOMESTIC LICENSES TO MANUFACTURE OR TRANSFER

CERTAIN ITEMS CONTAINING BYPRODUCT MATERIAL

4. The authority citation for Part 32 continues to read as follows:

Authority: Secs. 81, 161, 182, 183, 68 Stat. 935, 948, 953, 954,

as amended (42 U.S.C. 2111, 2201, 2232, 2233); sec. 201, 88 Stat.

1242, as amended (42 U.S.C. 5841).

5. In Sec. 32.8, paragraph (b) is revised to read as follows:

Sec. 32.8 Information collection requirements: OMB approval.

* * * * *

(b) The approved information collection requirements contained in

this part appear in Secs. 32.11, 32.12, 32.14, 32.15, 32.16, 32.17,

32.18, 32.19, 32.20, 32.21, 32.21a, 32.22, 32.23, 32.25, 32.26, 32.27,

32.29, 32.51, 32.51a, 32.52, 32.53, 32.54, 32.55, 32.56, 32.57, 32.58,

32.61, 32.62, 32.71, 32.72, 32.74, and 32.210.

* * * * *

6. A new Sec. 32.21 is added to read as follows:

Sec. 32.21 Radioactive drug: Manufacture, preparation, or transfer for

commercial distribution of capsules containing carbon-14 urea each for

``in vivo'' diagnostic use for humans to persons exempt from licensing;

Requirements for a license.

(a) An application for a specific license to manufacture, prepare,

process, produce, package, repackage, or transfer for commercial

distribution capsules containing 37 kBq (1 Ci) carbon-14 urea

(allowing for nominal variation that may occur during the manufacturing

process) each for ``in vivo'' diagnostic use, to persons exempt from

licensing under Sec. 30.21 of this chapter or the equivalent

regulations of an Agreement State will be approved if:

(1) The applicant satisfies the general requirements specified in

Sec. 30.33 of this chapter, provided that the requirements of

Sec. 30.33(a)(2) and (3) of this chapter do not apply to an application

for a license to transfer byproduct material manufactured, prepared,

processed, produced, packaged, or repackaged pursuant to a license

issued by an Agreement State;

(2) The applicant meets the requirements under Sec. 32.72(a)(2) of

this part;

(3) The applicant provides evidence that each capsule contains 37

kBq (1 Ci) carbon-14 urea (allowing for nominal variation that

may occur during the manufacturing process);

(4) The carbon-14 urea is not contained in any food, beverage,

cosmetic, drug (except as described in this section) or other commodity

designed for ingestion or inhalation by, or topical application to, a

human being;

(5) The carbon-14 urea is in the form of a capsule, identified as

radioactive, and to be used for its radioactive properties, but is not

incorporated into any manufactured or assembled commodity, product, or

device intended for commercial distribution; and

(6) The applicant submits copies of prototype labels and brochures

and the NRC approves these labels and brochures.

(b) Nothing in this section relieves the licensee from complying

with applicable FDA, other Federal, and State requirements governing

drugs.

7. A new Sec. 32.21a is added to read as follows:

Sec. 32.21a Same: Conditions of license.

Each license issued under Sec. 32.21 of this part is subject to the

following conditions:

(a) The immediate container of the capsule(s) must bear a durable,

legible label which:

(1) Identifies the radioisotope, the physical and chemical form,

the quantity of radioactivity of each capsule at a specific date; and

(2) Bears the words ``Radioactive Material.''

(b) In addition to the labeling information required by paragraph

(a) of this section, the label affixed to the immediate container, or

an accompanying brochure also must:

(1) State that the contents are exempt from NRC or Agreement State

licensing requirements; and

(2) Bear the words ``Radioactive Material. For ``In Vivo''

Diagnostic Use Only. This Material Is Not To Be Used for Research

Involving Human Subjects and Must Not Be Introduced into Foods,

Beverages, Cosmetics, or Other Drugs or Medicinals, or into Products

Manufactured for Commercial Distribution. This Material May Be Disposed

of in Ordinary Trash.''

Dated at Rockville, Maryland, this 24th day of November, 1997.

For the Nuclear Regulatory Commission.

John C. Hoyle,

Secretary of the Commission.

[FR Doc. 97-31514 Filed 12-1-97; 8:45 am]

BILLING CODE 7590-01-P