ML20202J225

Final Rules 10CFR30 & 32, Exempt Distribution of Radioactive Drug Containing One Uci of C-14 Ureas. Rule Amends Regulations to Permit NRC Licensees to Distribute Radioactive Drug Containing One Uci of C-14 Urea

ML20202J225
Person / Time
Issue date:	11/24/1997
From:	Hoyle J NRC OFFICE OF THE SECRETARY (SECY)
To:
References
FRN-62FR32552, RULE-PR-30, RULE-PR-32 NUDOCS 9712110087
Download: ML20202J225 (31)

Text

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PROPOSED RULE 5 80 / 3a. -

[& A N 3D SC*) 9T NOV 26 ~P2 ;54 NUCLEAR REGULATORY COMMISSION OFI ,(" ~: .. i 10 CFR Parts 30 and 32 RULH'. ' !< ' 0 ADJU" -

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RIN: 3150 AF70 Exempt Distribution of a Radioactive Dmg Containing One Microcurie of Carbon 14 Urea AGENCY: Nuclear Regulatory Commission.

ACTION: Final rule.

SUMMARY

The Nuclear Regulatory Commission (NRC) is amending its regulations to Mrmit 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 amedment 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.

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ADDRESS: Copies of the public record, including thu 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 Stieet, NW. (Lower Level), Washington, DC.

FOR FURTHER INFORMATION CONTACT: Dr. Anthony N. Tse, Office of Nuclear Regulatory Research, U.S. Nuclear Regulate y Commission, Washington, DC 20555-0001, telephone (301) 415-6233 or e mail at ANT @nrc. gov.

SUPPLEMENTARY INFORMATION: .

I. The Petition for Rulemakhg.

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

Ill. Summary of the Final Amendments.

IV Description of the Final Amendments. .

V. Agreement State Compatibility. (

VI. Finding of No Significant EnvironmentalImpact: Availability.

Vll. Paperwork Reduction Act Statement.

Vill. Regulatory Analysis.

IX. Regulatory Flexibility Certification.

X. - Small Business Regulatory Enforcement Fairness Act.

XI. Backfit Analysis.

. Xil. List of Subjects.

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l. The Petition for Rulemaking On October 6,1994, the Commission docketed a petition for rulemaking (Docket No.

PRM 3512) from Tri-Mod 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 andinr exemption for the commercial distribution by licensed pharmaceutical manufadurers of a capsule containing one micro-Curie (pCl) of C-14-ures 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, tta 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 woulb permit NRC loosneces to detnbute capsules containing one microcurie C-14 uros 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 en insignificant radiological risk to the public and the environment, the NRC believes, the capsules could be distnbuted for "in vivo'_ diagnostic use to persons exempt from licensing.

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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 p.Sysician 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 beC4.Jse the radiological nsk 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 determinatioi mat any research (including research involving radioactive material) must provide for 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 4

participate in the research. Further, these protections must be providtid 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 cummenter suggeste.d that all minimal risk research t>,:

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

NRC did not participate in the promulgation of the ;ommon rule. Subsequent 9, the NRC adopted 10 CFR 35.6 that requires a lic3nsee who conducts research involving human subjects using byproduct material to obtain informed censent from the human subjects and obtain prior approval by an IRB. Although the NRC did not adopt the common rule, the intent. ion 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 commer.ters expressed concems 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.

Basagnse: 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 *.apsules containing one microcurie C 14 urea (allowing for nominal variation that may occur during the m&aufacturing process),"

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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 1-131. 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 1131 also would be insignificant.

Resoonse: In comparing the hazard significance of the one microcurie C 14 Urea diagnostic test to the extensive use of Tc 99m and 1-131, the NRC did not evaluate the dose to the patient becau:e this dose would be justified for medical reasons. Justification for retaining some licensing control on the medical use of Tc 99m and 1 131 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 1131 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 act.ievable.

Tc-99m and l- , having relatively short half lives, present minimal environmental hazard. C 14 as urea is excreted from the patient as carbondioxide (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 n

the public of about 1.25 mremlyr. A release of 0.6 curies of C-14 from the 600,000 tests 6

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N expected to be admini tered annually, Lould result in an additional average annua' dose of 2X104mrem. Comparing this estimate to the EPA Clean Air Act reporting level of 1 mrem / year, this new test is environmentally insignificant.

Comment 4: Gecause of the small quantity of radioactive materialin 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 staiement that the product may be disposed of in the general trash.

Resoonse: 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 rewive 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.

Resoonse: 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 7

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.

Bgsoonse: If this rule is combined with the overall 10 CFR Part 35 revision, the C 14 capsuies would only be available to authorized user physicians dunng the revision period.

Thus, the NRC decided to oroceed with this rule now because the benefits of making this capsule available to anyone, including pnmary-care physicians, outweigh tha 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 administenng radioactive drugs meet certain basic training and qualification requirements. The proposed exemption would impose no training or qualification requirements on users.

Besponse 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 hatidling 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 generallicense, Agreement State agencies would retain the authority to adopt the generallicense or continue to require specific licensing.

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Resoonse: in the draft rulemaking plan, the NRC suggested using the general license approach. The NRC receivad 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 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 generallicense 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 altemative 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. pyloriis invasive gastroendoscopy.

Resoonse: Because the C-14 urea capsules are already available to authorized user .

physicians, the only regulatory issue in this rutemaking 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 environmentalimpact is expected to be insignificant because of the extremely low radiological harsrds associated with the use of capsules containing one 9

microcurie C-14 urea. The presence of an additional non invasive alternative procedure does not affect NRC's determination of no significant environmentalimpact.

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

'egulations.

Resoonse 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

(@ 30.14, " Exempt concentrations," and @ 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 manuiactured 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 distnbuted under

@ 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

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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 ACMul 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.

Gemment 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.

Bg1RQDag 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 releasa 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 104 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 p

the manufacturer's possession license. A user, however, can dispose the C-14 urea capsules 11

as ordinary trash. Medical users of the C-14 urea test wou!d 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, Commert.L3: 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 arid prominently placed. The commenter l

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.

r<esconse: 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 l capsules may be disposed of by users as ordinary trash. Paragraph (a)(6) of 6 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 6 32.21a before they are approved. Since paragraph (a) of 5 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.

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111, Summary of the Final Amendments 9 Final Amendment to 10 CFR Part 32 The regulations in 10 CFR Part 32 are amended to add new sQ 32.21 and 32.21a, to provide requirements for a specific license to manufacture, prepare, process, produce, package, repackage, or transfer for commercial distribution, 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 tile radioactive drug to persons exempt from licensing would not be relieved from other applicable Federal (e.g., FDA) or State requirements goveming 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 controlis 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 13

4 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 capsulas can be distributed to any person. However, other Federal or State agencies rnay limit the receipt and use of the 1

capsules in accordance with their own requirements.

The regulations in 10 CFR Part 30 are amended to add a new 9 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 exemptinn permitting receipt and use of the capsules for "in vivo" diagnostic use does not extend to use of tne capsules for research involving human -

subjects. Any person oesiring 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 $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 i (2) " Medical use" includes the administration of the drug to a human research subject, which would continue to reqilire a specific license pursuant to Part 35 under this rulemaking.

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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 licende. 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" oiagnostic 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.

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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 proposea rule may be interpreted as an exact limit of one microcurie per capsule (See Comment 2 under tne heading "Public Comment and NRC Responses). The fir;al 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.

&J2,21 Radioactive drua: Manufacture. creoaration. or transfer for commercial distributigtLgf caosules containino one microcurie carbon-14 urea each for "in vivo" diaonostic use for humans to oersons exemot from licensino: Reauirements for a license Paraaraoh (a)

This paragraph establishes the requirements for approval of a license application to manufacture, prepare, process, produce, package, repackage, or transfer for commercial 16

distribution, capsules containing one microcurie carbon 14 urea each for "in vivo" diagnostic use, to persons exempt from licensing.

Paraaraoh (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.

Paracraoh (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 9 32.72(a)(2). Specifically, these persons must be:

(1) Registered with or licensed by the FDA as a drug manufacturer; or (2) Regis'. %d 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 medicalinstitution.

Paraaraoh (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 17

contains one microcune, allowing for nominal variation that may occur dunng the manufacturing process, Paragraoh (a)(4)

This paragraph prohibits carbon 14 urea from being contained in any food, beverage, cosmetic, drug or other commodity designed for ingestion or inhalation by, or topica: application to, a human being except for the capsules as described in this section, because exempt distnbution 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.

Paragraoh (a)(5) .

Because the exempt distnbution 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 distnbution. 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.

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Paragraoh f aif 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 commeicially 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 9 32.21a(a) and (b).

Paraaraoh (b)

This paragraph declares that the regulations do not relieve licensees or applicants from complying with applicable FDA, other Federal, and State requirements goveming the I5 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.

Paragraoh (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 immediata 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 t (2) Bears the words " Radioactive Material."

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4 The date requirement is consistent with labeling requirements for other radioactive drugs with a half hfe of greater than 100 days.

Paragraoh fb)

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 Matorial. 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 distnbution. There is no prohibition against the capsule being combined with food or beverage at the time of administration so that the capsule can be iagested by the patient. This label also informs the user that this product may be disposed of in ordinary trash.

"In vivo" diaonostic use by oersons exemot 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.

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Section 30 21 Radioactive drug Caojults containina one microcur e of c'rbon-14 urea lor "in vivo" diagnostic ule for humans Paragraoh (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 microcune 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 distnbution," which is covered in paragraph (c) of this section.

Paragraoh (b)

This paragraph establishes that persons who desire to use the drug for research involving humans subjects must apply for and receive a specific Part 35 licen.se. 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.

Paragraoh (QJ This paragraph specifies that a specific license is needed to manufacture, prepare, process, produce, package, repackage or transfer such capsules for commercial distribution.

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Paraaraoh (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.- l 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 Environmentalimpact: 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 required. The final rule establishes 22.

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requirements for the manufacturc and commercial distribution of carbon 14 urea capsules to persons exempt from licensing and esta'ulishes 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 ;nsignificant 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 environmenta! 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 ANT @nrc. gov.

Vll. 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 seg ). These requirements were approved by the Office of Management and Budget, approval numbers 3150-0001,3150-0017, and 3150-0120.

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r The public reporting burden for this collection of information is estimated to average 16 hours1.851852e-4 days <br />0.00444 hours <br />2.645503e-5 weeks <br />6.088e-6 months <br /> per response, including the time for reviewing instructions, searching existing data sources, gathenng and maintaining the data needed, and completing and reviewing the collection of information. Send enmments 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 BJS1@NRC. GOV; 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 un!ess it displays a currently valid CMB control number.

Vill. 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 Leve'),

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 ANT @nrc. gov.

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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 Faimess 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 verifed 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 armlysis is not required becaum these amendments do not involve

~

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

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Xil. List of Subjects ,

10 CFR Part 30 B) product material, Criminal penalties, Government contracts, In%tgovernmental relations, Isotopes, Nuclear materials, Raciation protection, Reportir>2 and record keeping requirements.

r 10 CFR Part 32 Byproduct material, Cnminal penalties, Labeling, Nuclear mateiials, 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 adop'ing 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 26 1

under sec.104,68 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 30.8, paragraph (b) is revised to read as follows:

$ 30.8 information collection reouirements: OMB aceyg.

I (b) The approved inforrnation collection requirements contained in this part appear in S $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 thls part.

3. A new $ 30.21 is added under the undesignated center heading " Exemptions" to read as follows:

6 30.21 Radioactive drua Caosules containina carbon-14 urea for "in vivo" diaanostic 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 (1u 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 peson 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.

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(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 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 6 32.8, paragraph (b) is revised to read as follows:

6 32 8 information collection reauirements: OMB aooroval.

(b) The approved information collection requirements contained in this part appear in

@ 32.11, 32.12, 32.14, 32.15, 32.16, 32.17, 32.18, 32.19, 32.20, 32.21, 32.21 a, 32.22, 32.23, 32.25, 32.26, 32.27, 32.29, 32.51, 32.51 a, 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.

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e

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

9 32.21 Radioactive druc Nlanufacture.preDaration. or transfer for commercial distribution of caosules containino carbon-14 urea each for "in vivo" diaonostic use for humans to oersons exemot from licentina: Reouirements 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 (1y 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 9 30.21 of this chapter or the equivalent regulations of an Agreement State will be approved if:

(1) The applicant satisfies the general requirements speerfied in 9 30.33 of this chapter, provided that tiie requirements of 9 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 9 32.72(a)(2) of this Part; (3) The applicant provides evidence that each capsule contains 37 kBq (in Cl) 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 29

(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 9 32.21a is added to read as follows:

9 32.21a Same Conditions of license.

Each license issued under 9 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 i

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 affixsd 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 30

(2) Bear the words " Radioactive Material. For "In Vivo" Diagnostic Use Only. This Material ls 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

_E Trash."

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

13 13 For the Nuclear Regulatory Commission.

I.e Johpff. Hoyle, /

- Se(fetary of the Commission.

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