ML23151A587

PR-030,032 - 62FR32552 - Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea

ML23151A587
Person / Time
Issue date:	06/16/1997
From:	Hoyle J NRC/SECY
To:
References
62FR32552, PR-030, PR-032
Download: ML23151A587 (1)

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KEYWORD: ADAMS Template: SECY-067 06/16/1997 PR-030, 032 - 62FR32552 - EXEMPT DISTRIBUTION OF A RADIOACTIVE DRUG CONTAINING ONE MICROCURIE OF CARBON-14 UREA PR-030, 032 62FR32552 RULEMAKING COMMENTS Document Sensitivity: Non-sensitive - SUNSI Review Complete

STATUS OF RULEMAKING PROPOSED RULE: PR-030, 032 OPEN ITEM (Y/N) N RULE NAME: EXEMPT DISTRIBUTION OF A RADIOACTIVE DRUG CONTAINING ONE MICROCURIE OF CARBON-14 UREA PROPOSED RULE FED REG CITE: 62FR32552 PROPOSED RULE PUBLICATION DATE: 06/ 16/ 97 ORIGINAL DATE FOR COMMENTS: 07/ 16/ 97 NUMBER OF COMMENTS: 8 EXTENSION DATE: I I FINAL RULE FED. REG. CITE: 62FR63634 FINAL RULE PUBLICATION DATE: 12/ 02 / 97 NOTES ON: NRC HAS DETERMINED THAT THE RADIOACTIVE COMPONENT OF SUCH A DRUG STATUS IN CAPSULE FORM PRESENTS MINIMAL RADIATION RISK, THUS REGULATORY OF RULE: CONTROL NOT NECESSARY. SEE PRM-035-012, 59FR61831. FILE ON P1. HISTORY OF THE RULE AFFECTED: PR-030, 032 RULE TITLE: EXEMPT DISTRIBUTION OF A RADIOACTIVE DRUG CONTAINING ONE MICROCURIE OF CARBON-14 UREA PROPOSED RULE PROPOSED RULE DATE PROPOSED RULE SECY PAPER: 97-090 SRM DATE: 05/30/ 97 SIGNED BY SECRETARY: 06 / 10/ 97 FINAL RULE FINAL RULE DATE FINAL RULE SECY PAPER: 97-232 SRM DATE: 11/05/ 97 SIGNED BY SECRETARY: 12/ 09 / 97 STAFF CONTACTS ON THE RULE CONTACT1: ANTHONY N. TSE CONTACT2: MAIL STOP: T-9F31 MAIL STOP: PHONE: 415-6233 PHONE:

DOCKET NO. PR-030, 032 (62FR32552) In the Matter of EXEMPT DISTRIBUTION OF A RADIOACTIVE DRUG CONTAINING ONE MICROCURIE OF CARBON-14 UREA DATE DATE OF DOCKETED DOCUMENT 06/11/97 06/10/97 07/03/97 07/01/97 07/11/97 07/03/97 07/14/97 07/07/97 07/14/97 07/08/97 07/16/97 07/16/97 07/21/97 07/15/97 7/22/97 07/16/97 09/16/97 08/11/97 11/26/97 11/24/97 TITLE OR DESCRIPTION OF DOCUMENT FEDERAL REGISTER NOTICE - PROPOSED RULE COMMENT OF CAROLS. MARCUS, PH.D., M.D. (

1)

COMMENT OF NEW JERSEY DEPARTMENT OF ENVIRONMENTAL PROTECTION (JOHN FEENEY) (

2)

COMMENT OF GEORGIA DEPARTMENT OF NATURAL RESOURCES (THOMAS E. HILL, MANAGER) (

3)

COMMENT OF NEN LIFE SCIENCE PRODUCTS, INC. (LEONARD R. SMITH) (

4)

COMMENT OF MERETEK (KERRY C. BUSH) (

5)

COMMENT OF NEW YORK STATE DEPARTMENT OF LABOR (RITA ALDRICH) (

6)

COMMENT OF SYNCOR INTERNATIONAL CORPORATION (JACK L. COFFEY, CORPORATE VP) (

7)

COMMENT OF AMER. COL. OF NUC. PHYSICIANS/SOC. OF NUC. MED. (MARTIN L. NUSYNOWITZ, M.D., ET AL.) (

8)

FEDERAL REGISTER NOTICE - FINAL RULE

DOCKET Nl.MBER PROPOSED RULE p 30.f :3:L ( (p ~FIi. 3 ~s~) DOCKETED US RC [7590-01-P] "97 NOV 26 P 2 :54 NUCLEAR REGULA TORY COMMISSION 10 CFR Parts 30 and 32 RIN: 3150-AF?0 Exempt Distribution of a Radioactive Drug 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 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.

~~/ lf/1~ EFFECTIVE DATE: (30 days ff:01 I I date of pUtJllcatlon In the Fedel al Register). (}Ad>. frn I g_/g f/'f dC h~F/l. 03 f,3 4-

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 ANT@nrc.gov. SUPPLEMENTARY INFORMATION: I. The Petition for Rulemaking.

11.

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 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. XII. List of Subjects. 2

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 (µCi) 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 if! 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 *;n 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 0 diagnostic use to persons exempt from licensing. 3

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 ~edical 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 distrib~on, the NRC should not be forbidding research use of this drug by the same physicians who may use it clinically. Research use also 4t 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 ~ules" 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 end 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, su~ or regulate research invoMng human subjects ensure adequate protection of the rights of the human subjects. The Federal policy represents a societal detennination that any research {induding research involving radioactive material) must provide for the *ro11owing minimal protections f9r the human subjects: (1) that the research is approved by an Institutional Review Board "(IRS) and (2) that the human subject gives informed consent to 4

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 cornmon 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 1 O 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 rnicrocurie. 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)." 5

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 1-131 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 1-131, the NRG 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 1-131 while exempting the one microcurie carbon-14 urea capsules relies on the relative occupational hazards to t technicians and physicians administering the radiopharmaceuticals. Administering an encapsulated dosage of one microcurie C-14 involves vi_rtually no occupational dose due to the low energy beta radiation and mir,iimal possibility for contamination of personnel or facilities. On the other hand dosages of Tc-99m and 1-131 entail extracting 1 Os to 1 00s 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 1-131, 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 the public of about 1.25 mrem/yr. A release of 0.6 curies of C-14 from the 600,000 tests 6

expected to be administered annually, would result in an additional average annual dose of 2X10-7 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 e may be disposed of in ordinary trash. Comment 5: The Commenter agrees that the widespread use of this product will require unifonn 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 1 O 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. Response: If this rule is combined with the overall 1 O CFR Part 35 revision, the C-14 capsules would only be available to authorized user physicians during the revision period. Thus, the NRG 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 saf~ty training for personnel handling and administering the capsule is not necessary, and thus, not required. Comment 8: If the NRG 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 NRG instead simply proposed a general license, Agreement State agencies would retain the authority to adopt the general license or continue to require specific licensing. 8

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 ber 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 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 i~ue 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 9 J

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 NRG regulations. 'Response: This change is a departure from existing NRG regulations. In the statement of consideration for the proposed rule, under the heading "Current NRG Regulations on Exemptions From Licensing," the NRG 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 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 §§ 30.14 and 30.18. Comment 11: The ACMUl'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 10

approved by the Food and Drug Administration, and (3) the office/facility using the product will be subject to Clinical Laboratory Improvement Amendment (CUA) 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 t6 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 o~ans. 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 occurri~g 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 11

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 la~ling "bears the words Radioactive Material" should be added, and (2) the NRC should require that tile 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§ 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§ 32.21 a before they are approved. Since paragraph (a) of§ 32.21 a 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. 12

Ill. Summary of the Final Amendments Final Amendment to 10 CFR Part 32 The regulations in 10 CFR Part 32 are amended to add new§§ 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 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 I 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 13

drug for its radioactive component. Therefore, the NRC can not justify requiring physicians, or any other person, to meet NRC training and experience criteria dire~ed 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§ 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 oHhe 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 stilt be required to submit an application for a specificJicense 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 (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. 14

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 I 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 n999 to be "authorized usersD 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 FederaJ 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. 15

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)9 is used. Another public comment suggested that labels should contain a state_ment that the product may be disposed of in the general trash. In the final rule, the label e requirements include such a statement. Manufacturer and Distdbutors A new section is added to 1 O CFR Part 32 to permit the distribution of the capsules to persons who are exempt from licensing. § 32.21 Radioactive drug: Manufacture, preparation. or transfer tor commercial distribution of capsules containing one mjcrog.ane carbo:14 urea each for '1n vivo" diagnostic use for humans to persons exempt from licensing: Regujrements for a license Paragraph Ca) 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. 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 § 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 17

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 fo_r ingestion or 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 th~ patient. Paragraph <a}(5} Because the exempt distribution of this drug has only been evaluate~ 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. \\ 18

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§ 32.21 a(a) and (b). Paragraph Cb) 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 cond_itions 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." 19

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, B~verages, 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 ,r capsule must remain in the form of a ~psule 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 i~ 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. 20

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 humans 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 participa~e 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. 21

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 NRG 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 11in 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 required. The final rule establishes 22

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 atANT@nrc.gov. VII. Paperwork Reduction Act Statement This final rule amends information collection requirements that are subject to the I 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. 23

I The public reporting burden for this collection of information is estimated to average 16 hours ~r 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 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 unless it displays a currently valid 0MB 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 ANT@nrc.gov. 24

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 e. 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 backfrt 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}. 25

XII. List of Subjects 10 CFR Part 30 Byproduct material, Criminal penalties, Government contracts, Intergovernmental relations, Isotopes, Nuciear materials, Radiation protection, Reporting and record keeping requirements.* 10 CFR Part 32 Byproduct material, Criminal penalties, Labefog, Nuclear materials, Radiation protection, Reporting and recordkeeping requirements. For the reasons set out in the preamble and under the authority of the Atomic energy e 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 1 O 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 Stal 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.~(b) also issued 26

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§ 30.8, paragraph (b) is revised to read as follows:

§ 30.8 Information collection requirements: 0MB approval. (b) The ap'proved information collection requirements contained in this part appear in §§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 § 30.21 is added under the undesignated center heading "Exemptions" to read as follows:

§ 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 (1µ 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. 27

(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). r-

5. In§ 32.8, paragraph {b) is revised to read as follows:

§ 32.a Information collection requirements: 0MB approval. (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, 32.21a, 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. 28

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

§ 32.21 Radioactive drug: Manufacture, preparation, or transfer fQr commercial djstnbution of capsules containing carbon-14 urea each for io vivo" diagnostic use for humans to persons exempt from ncensing: Requirements for a license. (a) All application for a specific license to manufacture, prepare, process, produce, package, repackage, or transfer for commercial distribution capsules containing 37 kBq (1 µ. Ci) carbon-14 urea (allowing for nomln~I variation that may occur during the manufacturing process) each for "in vivo* diagnostic use, to persons exempt from Bcensing under.§ 30.21 of this chapter or the equivalent regulations of an Agreement State wiff be approv~ if: (1) The applicant satisfies the general requirements specified in § 30.33 of this chapter, provided that the requirements of§ 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§ 32.72(a)(2) of this Part: (3) The applicant provides evidence that each capsule contains 37 kBq (1µ. Cl) carbon-14 urea {aDowing for nominal variation that may occur during the manufacturing pro6ess); {4) The cwbon-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 racfl08ctive, 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 copie~ 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§ 32.21a is added to read as follows:

§ 32.21 a Same: Conditions of license. Each license issued under§ 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 30

(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 ol'/'~ day of November, 1997. For the Nuclear Regulatory Commission. 31

DOCKETED USNRC American College of Nuclear Physicians/Society of Nuclear Medigin~ 6 "97 SEP 1 o t-' 4 :Q GOVERNMENT RELATIONS OFFICE August 11, 1997 Secretary John C. Hoyle U.S. Nuclear Regulatory Commission Attn.: Rulemakings and Adjudications Staff Washington, D.C. 20555-0001 OFFICL OF src1:i:-_ ,PY RULE.-. i, *11,t;s ;.;"t.l ADJUDIG1. -*t.A 1S ~1AFF DOCKET NUMBER PROPOSED RULE p 3fr.r 3 2' ("~fl< 3~55.;2) RE: The Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea, 10 CFR Parts 30 and 32 in the 62 Fed. Reg. eg.32554, Monday, June 16, 1997.

Dear Secretary Hoyle:

We are writing on behalf of the American College of Nuclear Physicians (AC P) and the Society of Nuclear Medicine (SNM). Together, we represent over 14,000 nuclear medicine professionals, including physicians, pharmacists,technologists, and scientists. The issues of radiological safety and C-14 Urea are important to us, and as stakeholders, we would like to thank you for allowing us this opportunity to comment on your findings. The ACNP/SNM generally approve of the NRC's finding of "No significant radiological safety or environmental risk" for C-14 Urea capsules. However, we find the proposed rule contains prohibitions and conditions that are unjustifiable based on risk, and unnecessary intrusions into the professional practices of medicine and pharmacy. For example, page 325541, paragraph (a)(3) states: This paragraph would require applicants to provide evidence that each carbon-14 urea capsule will not exceed one microcurie (1 u(i). The NRC 's evaluation that the capsules would not result in significant 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 will not exceed one microcurie. Paragraph (a)(3) requires each capsule to not exceed 1 uCi. It is generally recognized that the Food and Drug Administration (FDA) approved manufacturing techniques allow for a plus/minus margin (usually 10%) for the final product. Although the product may be labeled as 1 uCi, it could contain activities as low as 0.9 uCi, or as high as 1.1 uCi and still meet the FDA's Current and Good Manufacturing Practice (CGMP) guidelines. The NRC appears to prohibit this common standard deviation allowance. ocrs1a,z* 162 Fed Reg 32554 Acknowledged by card.................................. 1850 Samuel Morse Drive, Reston, Virginia 20190-5316 * (703) 708-9773 I Fax: (703) 708-9777

u.S. NUCLEAR REGULATORY COMMISSK)N DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSION Ooc:uRlent Slatistlcs Postmark Dale _ q 15 9 pias ReoelWd. ___ _ I ___ _ Ad~ICo~esReprodooed,____,_ __ _ Sp~ ial DIGtri tlon_rr:-.s __ e __ -=-- (.i-t;,((a.9 e~ ?i>i<1 1? I PS

Paragraph (a)(4)2 states: This paragraph would prohibit carbon-14 urea from being contained in any food, beverage, cosmetic, drug or other commodity designed for ingestion or 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 used in the form of a capsule containing one microcurie of carbon-14 urea. Because of the capsule 's "in vivo " diagnostic use, 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)(4) appears to prohibit the use of this FDA approved product in compounding by physicians and pharmacists as may be needed to meet the needs of special patients. This prohibition is a needless intrusion into the professional practices of medicine and pharmacy. Paragraph (b)(2) on page 325553 states: (2) Bear the words "Radioactive Material. For "in vivo " Diagnostic Use Only. This Material is Not To Be Used/or 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. Paragraph (2) appears to prohibit the use of this FDA approved drug for research involving human subjects. We feel that this prohibition is another needless intrusion into the professional practice of Medicine. In conclusion, the ACNP/SNM recommends the NRC "rethink" the three specific comments mentioned above. These three concerns if left unaddressed by NRC make it impossible for the ACNP/SNM to support this as a final rule. For more information, feel free to contact Mr. David Nichols, Director of Government Relations at (703) 708-9773. Martin L. Nusynowitz, M. D. President American College of Physicians 2 62 Fed Reg 32554 3 62 Fed Reg 32554 Very Truly Yours, i~ (<<:::.ft President Society of Nuclear Medicine

isssyncor* The Service Difference~ July 16, 1997 Secretary, U.S. Nuclear Regulatory Commission Washington, DC 20555-0001 Attention: Rulemakings and Adjudications Staff Re: RIN 3150-AF?0 Syncor lntQqf ~~~~ Corporation "97 JUL 22 A10 :06 OFFI CE. or SECRETARY DOCKETING & SERVI CE BRANCH DOCKET NtltBER PROPOSED RULE Pl 3 OJ 3 :L (,:i FR:t:155:i) (1) Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea This letter is in support of the Proposed Rule to exempt one microcurie of C-14 Urea from licensing requirements. The benefits to society are substantial and the risks are truly insignificant. We strongly encourage the prompt publishing of the Final Rule so physicians may gain exempt access to this product and patients can gain the benefits from the simple diagnosis and confirmation of effective therapy. We do have some concerns about the proposed wording of the regulations which could be confusing. The title of the new section 30.21 of 10 CFR has the wording "... one microcurie of carbon-14... ". However in the text of this section and the title of section 32.21 the wording "... not exceeding one microcurie... " is used. The "not exceeding" wording would indicate there is no room for manufacturing tolerances associated with the production of this product. It would seem more reasonable to simply have wording like "... carbon-14 urea capsules of one microcurie each... ". This would then allow for reasonable manufacturing tolerances of+/- 5 to10% to be employed. Thank you for your consideration of these comments. Sincerely, ~ ~o~ Corporate Vice President Quality and Regulatory JU( 2 4 1997 ..\\cknowledged by card ** _ __._... 6464 Canoga Avenue

• Woodland Hills, CA
• 91367
• 818-737-4000

i>.S. NUCLEAR REGULATORY COMM!$~ DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSION Document StatistiCS Postmark Date _ J.,7,,../J...,B,~/q ___ f _ _,, Coples Received ___._ __ ,\\dd'I Copie~ Reproduced _ ....,3 __ _ Special Oistribution__::fse, 1>1>,g_,""R~

STA TE OF NEW YORK DEPARTMENT OF LABOR DIVISION OF SAFETY AND HEAL TH Radiological Health Unit Building # 12, Room 457 DOCKETED USHRC "97 JUL 21 P12 :52 OFFICE OF SEC RETAR Y DOCKE T! 1G & "'ER ICE BR NCH Secretary U.S. Nuclear Regulatory Commission Washington, D.C. 20555-0001 State Office Building Campus Albany, NY 12240 July 15, 1997 DOCKET NUMBER. PROPOSED RULE PR 30 J. 3 ~ Attn.: Rulemakings and Applications Staff (tp~FR3t2S:Sa) G)

Subject:

Exempt Distribution of Radioactive Drug Containing One Microcurie of Carbon-14 Urea We have commented previously on the petition for rulemaking on exempt distribution of this radioactive drug, and supported the exemption. This letter is to repeat our support for its exempt distribution. It poses no radiological hazard, will be regulated by the U.S. FDA as a drug and its wide availability will aid in the diagnosis of human disease. I would also like to make your office aware of a letter-writing campaign by a manufacturer of a competitive drug. The material being distributed contains a good deal of misinformation concerning the radiation hazard of carbon-14 urea in one microcurie quantities and may, therefore, prompt negative comments based solely on this misinformation. A copy of their mailings is attached. RNfdh Enc. C:\\WPDOCS1FRAN1R1TAILETI'ERS1l 'REA.NRC Telephone: 518-457-1202 Sincerely, ~tltiudt Rita Aldrich Principal Radiophysicist JUL 2 4 1997_ .f\\cknowledged by card._............ 111ar--.ii FAX: 518-457-5545

,j.$. NUCLEAR REGULATORY COMM1SblOr* DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSION Document Statistics Postmark Date 7P le/ '11 Coples Received. ___ Acld'I Copies Reproduced _3=---- Speclal Distribution_5.se I ::PD/s 11< l QS...

07/14/97 MON 11: 26 FAX 615 333 6202 Via FACSIMILE 518-457-5545 7 Pages Total July 14, 1997 Rita Aldrich Principal Radiophysicist Radiological Health Unit Div. of Safety & Health Building 12, Room 457 NY State Office C,mpus Albany, NY 12240

Dear Dr. Aldrich:

MBRETEK DIAGNOSTICS, INC DOCK TEO USNRC ~ ~ MERETEK '97 JUL 21 P12 :52 CONFIDENTIAL OFFICE Of Sc _,RE11\\f~ '( DOC KE *1t: *.: :; *. W

• I 'L sn....... r;:-1 The Bra:a:rh Test Company On July 1, 1997 I wrote to you to ensure you were aware of a recent proposed Nuclear Regulatory Commission role that had significant implications for Agreement State authority over the use of radiopharmaceuticab, in particular Carboo-14 labeled ur~ used in the detection and d.Jagnosis of the bacterium Helicobacter pylOl'i. The NRC poblished a proposed rule for comment in the June 16, 1997 Federal R.egist:r that would exempt from NR.C regulation the distribution of this compound.

If the NRC authorizes the distribution and use of the 14c labeled urea. by way of an exemption to its regulations, Agreement State agencies wifJ be required to fully conform their requirements to the NRC"s and will lose their existing authority to adopt more stringent standards or to continue to require specific licenses for the distribution and use of such pham,aceuticaJ compounds. [ have rec:,eived numerous calls requesting more information on the Meretek's Carbon-13 labeled breath test for H.pylori. Meretek is e09aged in the manufacture of diagnostie pharmaceuticals using the non-radioactive, stable isotope of carbon, Carbon-13. These dn1gs, in particular Be-Urea, pose no radiological risk to ps1ients. Our goal is to use non-radioactive labels that are safe, effective and completely bioequivalent to Carbon-12 when bandied by the human body. Mmy of the Departments of Radiological Health or agencies controlling the ose of radi<lpharmaccuticals were unaware of the Carbun-13 alteinativc. In fact the Mcmek 13C-Urea Breath Test For fl.pylori has been FDA approved and in use since September 1996. The comment period ends July 16,1997. For further clarification, I have attached the FDA"s approval and market clearance of the 13C-Urea brealh teSt and a key article from the American Journal of Gastroenterology covering the mode of action, validatioo and performance clwactt.."fistics of the l3c-Urca breath test. Please let me know if I can be of further assistance. Sincerely, KN Ker.ry C. Bush Chief Operating Officer ijJ 001 Corporate otli,cM :and Bm.ath Test CM!tar 618 Grzsmera P..rlr. On,a Suit 20 Naslrviilc,Tcni-37211 f'tlone 615*ll3*63.36 l'3X 615*333*&201 Rr.11th1P,;t CP.""'°'" ""° ~,e~" l~ ~~IT~ l\\1lltl... 17'1'f nr,,i,,n Rroa'1 SnirP l'tl] HniKIDn,T-~ 77t\\10 F'hon11713*799*12R2 FD. 713-'799*8395

07 / H/8i MON 11: 26 PAI 615 333 620.2 llBRETEK DIAGNOSTICS, INC lil!002 FOA TALK PAPER http:JNIYNl'.~bsnopk:s/ANSWERSlANS007S9.I FDA TALK PAP-ER Food and Drug Admlni3trallon U. s. Department Of Health and Human Sarvices Pt.lb/le fleiJNh Service 5tJO() Fishers l.Bne Rookvi1Ie, MD 10857 FDA Talk Papers are prepared by the Press Office to guide FDA personnel in respornfmg with consistency and accuracy to questions from the publlc: on subjects of current interest. Talk Papers are subject to Change as more lnfonnatlon becomes avaflabla. Talk Papers are not intended for g&neraJ dlstttbutton outside FDA, but all int'onnation in them ts publtc:, &nd full texts rue releasable upon req,u.st, T96~72 Nov. l, 1996 B,roadcaist Medial Cons\\ltl\\el: Hotline~ B~Qath Test for~- pylo~i Sharon Snider (3011 443-328~ {301} 827~3434. (800) 532-4.(40 The FDA has been receiving inqui~ie~ about a s~ple, new breath test t0 help detect a h&~terium that is the majo~ ca?.UJe of peptic ulcers. The following cai:i be uied to answe:r que.a,tionill. ~he first of its kind test is ~ha Meretek tmT Breath ~e~t Collection Kit l\\\\ade by Me.tetelc. Diagn.oatic.s, Inc., of Nashville,. Tenn. rt was clea.z::ad fox marketing by FDA to detect the H. pylori baote.t:i'Wl'I~ which il'i as.soc.i.a.t&d wi t.h ulcers. i:'J;evio-ur:sly, the -oul:r way to ~ccu;i:ately diagnose li, pylori infection was: by endoscopy with stomach biopsy -- a pxocedw::e in which the patient is sedatiad, then a tl,ibe i.s insert:.ad i.nto the stomach th1:ough the mauth and a !iample of the.stomach lining is removed for analysis. Blood tests haVit also been used to date.ct H, pylori, but with less dependable ~e~ult~, With tha new b.r:eath test; thQ pati~nt drinks a new non-radioac~ive diagnQstic drug ~QLution and then exhales into the collection kit. The prooedu.r:e is perfoDO.ed in a docto.i::' :s office and takes about 30 miuutrui. The drug, l?.ranaotin(TMJ r uses carbon 13 en.t:iched. urea., a naturally occ:u~ring, non-radioactive compound, to determina the presence or absence of an active H. pylori infectiop. 'l'he breath kit i~ sent to Meretek for analysis. Results are availabfe in a day or two. FDA I e clea:r:a.nca of tbe teat was based on data frorn :;;t~dies of 499 adulta with duodedal ulcer d.isea~e at 75 sitas in the United States and canada. Tha patients "ll:re "1!:Ka.mined with endoscopy and stomach biopsy and were al.so given the breath test. Th& restlts.showed th.at the breath test wa-, able to detect the p~esence of H, pylo~i in 95 pereent of the cases -- making it ~5 good as endoscopy ~ith biopsy in detecting the infactiQn i.u pat1ent$ with ulcers. H. pylo~i i~ a cW11n0n baateri= which ~s thought to infect the stQrnacb!; of° 35 pez::cent of.American.!1-dult.s, about 10 pflrcant of 1,1hom develop peptic u.lceri,. The others !'411-Y ~ot deve?,.op ulcezs but. have chronic.gastritis,.W"hich can ca~se ipd~ge~.ti.oA, ~"al paln..,

• ga.s:iflness, n~u.s:aa ~~~ ot~er 5t_omach probl~.. :

Tne Jfecfor:mancie of the test.* h£ti' not been established* in* patients with chronic gast~1t1s. 'l'he b~eal;;b test was cleared fo~ ma~keting.Sept. 17, 1996. iltltff 11/06/95 23:'

07/14/97 ION 11: 27 PA.I 615 333 620.2 OO(F.2,m001il'Jl~03.001l THI! ~ .f(l'.OO(AL <Ill' ~ ,~ o 1996,., Am. Cc,11. or~ MERETEK DIAGNOSTICS, INC Vol 91, Ni,..(, 1:996 l'llmd In 1.1.S.A.. Noninv~ive Detection of Helicobacter pylori Jnfection in Clinical Practice: The 13C Urea Breath Test Peter D. Klcln, Ph.D.. Boda M. ~,.M.D., Ph,D,t :RA>bert F. Ma.rti.u.. Pb.D, Kathleen S. Gnbam, M.D., Rooerl M. Genta, M.D., F.A..C.G*, and Da-vid Y. Graham, M.D, M.A.C.G* DtipartmDl.t of Me.dic:tRe and Y~ /.jfalr.r.M~dical Cem*r, Baylor Co~&"' cf M~ (11fd Ma:rChem A1uackued, lru;., Con.oord, Massa~ Objec:ttr,m To vafldate the 13C nre:a bl'\\$lli test for Ure detedum of lldkobadu pylori infection both before and after trea.bnfflt. Mdhad3: 13C urea breath tests with US-mg and J.50.mg oos:e.'l were carded out OD~ of60 1nfe.cted.and 60 noninteded :,ubjects. Result:8 were com-pared,.,;th histological eY!nDinaffon of pstric ttfopsies to estabmb detection lbmt.s. Tbe best cot..offpolnt was osed in a dlnlcaJ trial of the efficacy of the breatb tm in duodenal nker patlfflfs bd'ore and aftel' antim.krobbd therapy. 1."be iDcreniental ina."ea$e ~ge, 8 O'Ytt baselhle in U of a'infl) in ~wt:7 "CO2 sbundan(:e was ~ -with histological ev.lde!K!:! ot H.pykrl. Ootpatlmt, tertiary <:are m£dk:al <<nter, au,;J. ~ndary and prlmary care fud.litiflS were w:clndim. Olle hundred tin,>Jtty healthy asymptomailc subJem and 46:5 pammts with dl'.l(l(kmal ulcer disea!ie were.studied. The teR k:ft 3.iSCSSICd nipeambUity of breath ~ colk:d:ion and storage and sfabllity of stored sawpla Test p,mor- ~ was aoolyzed by cQnlparisun of US-mg and 1:1 250-mg C ona with measurements at 30 ~ 40 m1n postdose. nm ~ mn used to diagnose actiTe H. pylori inleclion aDd gauge s~ of antfmkrobial tflerapy. B.niJ4: The test !tit result$ 1fel"e highly reprodudbla. The wt-otr values were big~ wah 250-nig COIDpRTI:d with US.mg doses of uc urea and 40 min coinpa.m:1 with :JO mw. Using a ll.5-mg 13C (ll'ell and teat detdon Wt or 2.4% ::rt 30 mm, the ac:auaey was 94.8 C,5% comldenee internil = 92-97%) hd'w:e antimkrobia.l therapy and 95.4% (95% amfide:nce in~

• 91-98 % ) after. An incrca5e of 2A % in the ;100~ of b:ooatb 13C~ ~

30 min after a 12S-m~ do$e of 13C m"ea relbbly indicatc:d the presence fft active B. pywri bateetlor1 either before or after.mtimkrobial ther,..

apy. The °C ~

breath test pr9'¥ides a simpre and reliable and ll()nmvasive method of ~essblg H. p:,lori !rtatuS.. INTRODUCTION In Febmary 19')4, a National Jruruttltes of Beal.th Con-sensus Devclopment Conference ooo.cluded that H~lico-bacrer pylori was the awse of most cases of p;:ptic ulcer disease :and that all pmico.t& with H. pyfori infecdan.mt:1 pepliC ulcer sbou1d Il!Ccive antimicrobial the;i;npy (1). In Jt.m.c, the IJucrnadonal Agency for Re6earcb on Cancer W ork:io,a Group of the World He.utb Orsaoizarion defined H. pylori as a Group L or deflnite. human carclnogeu.. The role of H. pylori io caoccr ~broadened~ the Jl';(:()g* oitioii that cure of H. pylori infection resclts in rem.mioo of many, if not lll0$t, cases of primary B cell gastric l)'lllpb.oma (2). H. pyicrl infection h:ss therefore evolved from an ob-scure ca:nse of ga&triti$ to a pivotal colc in Ifie. pathogeOQis of peptic ulcer disease, gasttk C&clooma, and primllry B cell gasttlc lymphoma ('.}). Peptic nlcer affecui approximately l!Yib of 1Ddividwtls in the Uoitcd States at sorne tim.e in Uicir fives (4). Treatmcnt of the lnfeetioo $hould be based on an accurate dillgooais of H. pylori infec:tion., aoo the large nwnberof individuals with symptomAtic: H. pylori infecrlon u~ the importance of simple, nomnvasivc methods ro d&:ct the p:rc.,ence at 8. pylori in the stomach. The initial gold standard for the d~ of H. pylori infecdon lws btt:n.hlstolog.ical t:Xam-- ill,llt,j_on_. cul111:re. or both of ~tric mucosa! biopuea obtained at the tinw of GI ~copy. The hiswparhokig.ist'a tat.k or identifying the ~ of H. pylori infection was greatly .runplified by mtroductiou of tbe Gema stain (a combination of hcmatoic:ylia and eiJSlIL. a1clan blue. and the Steine.r silver staln) to sinmtomeonsly identify the organism.md tbc in-flammru.lon (5). Toe inro:xlm:tion of :serological tests al-lowed fur ao.indirect assessmeot of H. pylori lfflittl3. The noniovMive Urell b=th ~st ls tho only noninv~ method that will detect the pl:'!Sence of acdve H, pylori infectil;lll. Since the initinl publir;:.;i.tioo jn 1987 (6), the 13C urea br~th test bas become a widely l.t'5o1 research f.e$t for the detection of ff. pylori infection. The te.'$1: is hued on the high urease activity of tbe org.mism, wblch re:ildily hydro~ urea to cMbon dioxide and ammonia. When the. urea is i3Qtopically Ja_b....kd wlth tt carbon isotope, the label is el)'" rlched ln respiratory COz and can be detcaec by appropmte 690 ~ ooa

07/H/97 MON 11:28 FAX 615 333 6202 AJG -April 1996 meas~nts. The urea ~ test has proved Io be re-m.arlarhly robust in the dr:.tenrunatlon of gastric urease ac* tivil:y notwitbswiding the IBigo nnmber of minor modificap tions that have~ pr<)pOSed oc Introduced (7-19). 1'be original desaiptioo of the tr.1t showed that it would cor-rectly categorize ll. pyfuri status independent of the use of, or oompositlon of, the test meal or the dosage of 13C urea (6). Although these oooe:n'ati~ hzt.ve. been conflm:ied re-peare.d)y, the urea \\J:rcath test baa remai:nt:d a research tool. The tem pcrfom1aace may be different for a research test and a test that IIJUSt function reliably in a bnsy cliI:iic21 practice. RigorotJ.$ evaluation of the factors that affect test WiC and perfot:/1l.llllet! in roch a clinical settina has nQt previously been done. We evaloated the use of a stmdaroized breath test kit to optuuize the ~ f!X genaa]. us:;lgC of the test for diagnoalS of active H. pylori infection oft.he stoJ:nacb before u well as a&r am:i.microbW therapy. MATERIALS AND ME1HODS l~c urea bre:sth test kits were ablained from ~ Dia_gno&tics, !nc., Houston. TX. They OOtU:aincd a pmesr meal consisting of a can of vanillit Eru!.uI& pudding (Rosii I...aboratorios, Columbus, OH), 125 ~ of ' 3c un:a (99% 1~ Tracer Teclmolop,&. Somerville., MA)., 90 mL of ster-ile water, a breath CQllectkni aod traosfer bag, three 20--mL evzicuab:d sample ttl.bes (Becton Dickinson. Rothc::t:foo;I, NJ), patient forms, and a :mmple tube mailer. Samples were remmed to Men:tek fur analysis oo an aul:m:llakld gas iso-tope ratio m8.!1S spi;:ctrometer systrm (Model 20'20 Em:opa Scientific Company. Manchestec, UK). All samples wcm: mea.smed agaimt reference standards of known isotopic composition versus tbr: limestone staodard, Pee Dee Bele:m-nhe (PDB). llepeatabillty of sample )I:.ICaS1.l{l::lllCnts was

!::0.14% (pee mil) with overall variability of 0.28%.

&tabtishmQII of 13C urea dosage aw cnt--0ff values Healthy iwfaidtwi were screened by EUSA test to eval-uate their H.. py/.ori status, and 60 infected and 60 nonfn-- fected VOOIOteers were recnmed. All subjects gave informed COll#llt, arid the protocol Wa.5 appt"01'£d by the ~ga-tional Review Board of Baylor College of Medlcino. On day 1, $1.lbjects widerwent upper GI endoscopy in wludl four large cup biopsies (Olympus FB-13K, Lab Snccess, NY or Radial faw Large Oipacity Il, Mi.a'ovi!Si'Ve Booton Scien-tific, Watertown. MA) were taken: one fu)m the anbUm oo tile lesser cu.rvawre at or near the iac:isur.l (llite A3), two from the ~ C\\lrvilhln', wil:hin 2 cm of the pylorl.ll'l (site 'A4) [one for' un:ase testing (CI...Otest. Delta. We,t., Western Australia}l, and one from the middle of the ooq:,os on the gream C'llrvainre (site M). H. pyl.orl. stato3 was detmmioed by h.Wology: the specimen.$ were fixed with lO'lli bnffr:red fonnalio, cut into 4-nun sect:ioll3, sniined with the Ge:nta litain (5), and examined by au ~ pathologist un-aware of 1he patient's condition or ondoscopic findio.gs. Each subject received a 13c urea breath test to which a MHRETEK DIAGNOSTICS, INC BREATH TEST FOR fl. PYLORI 691 125---mg or 250--mg do!.e was randomly msigned. In ellCh test, baseline, 30-, and 40--min p0$tdose brea!h saropJes WCie collected in tripl.kate using sep;mue breath collection bags. The following day, the breath t~ was repeated using a 250-mg or 115-mg dose of uc me.a as ;required to complete die croM-OVCr design. One-set of samples was anafyzEd for tlc abundance within 24 h; the other two ~ ww::re atored at room temperature for 10 days before analysis. All an.tl-yses were completed with the :respectiv~ labon.todes (pa-- thol.ogy, breath te1;t) bli.oded regarding the results of the other. u~ af the. l1c urea breath test fQI;' -diagnosis. mi ibllovr-up a&cr tre.atment of fl.pylori inf~on Urea breath ~ were incrnpomted into climctil lrlals of antimicrobw th.el'llpy of H. pylori tnfecti.on ia duod<<ia1 ulcer p.mcnts. Duodenal ulcer pa1ienta were atndied in 15 study Iocarlons in the Un.ited States.. Pali.,nt$ tt2tt'l'fug the S1JJdy bad a history cif peptil: ulcet' disease and UDderwcnt en.do$COpic examfuatioo with biopsy fur histology,.rapid 1.11:etiC testing, and cul~. and 13c 'lltea brulh test with 125 mg of.substrate. H. pylori status wu deretm.ined by Oe:;nta ~n as :ootcd above. All proced.u.reg ~ repeated afte.t-4 wk (2 wi: after rb.e completion of the b.linded il.dtimiciobial or p1act:bo therapy) t1f ttcannent: and then 4 wk later. Cum of H. pylori infectioa was defined~ absence of histolc),gical evidence of ll1feciian 4 or IOOie wk after endin& ~ bi.11 therapy. Because the pwpose of the study was to eval-uate the cffOCliveness of ~ nrea breath teat in clini.u1 practice and nor to evaluate specffic tbctlp'cs. the du:ratlon of the study was limited to 6 molllhs. The results of the. individual antim.icroblal WJTSUS placebo arms are not glvf;?l;l ~ it w.as not nece:&-ary to break the blinding ~ the goal of 11:us study Wll3 to eval:u41te whetbe:r th= tirea breath test w;:is able to detect the presence of H.. PJlori infection and not whether an indi.vidlllll reipmt:n WM.supc,- rl.or to another or to placebo. Calcul.a1ions The analytical results from the separate breath sample collection bags wen: compared for repeatahillty. In addi.tiWl,. analyses obtained wilhin 24 h were compared wUh those obtained aftu 10 days of storage to M:leS!, sample stability during stDntgo. The resnlt.s witb tbe two dil'ferent doses Qf uC urea were compared for correct cm:egocaation :ind for the effect of postdose collectioo time (30 vs 40 min). De-tamlnatioo of I.he appropriate cut-off points was obwn~ using Re<<i'vcr Opcrating Clwac:tcristk:8 (R.OC) ctn'VC5 fur the 125--Jng and 250--rng dowi (20). Fllr u gin::n ncea dose and. postdose time (Lg., 125 mg a.t 30 min), the cut-off pomt between negati-Yt and positive re5(llts fat: the rest wt:m evaluated by de.tc:rminiag 'lbi:: level at wbicb. the S1.IJil of uu, false.negatives plus the falst:~pos.itives were minimized, Sta* tisticsl comparl1i0ns were made by Sw.dc.nt.'s pai:tcd t teiit with signitb:nce at p ~ 0.0.5. T003C out-off value, we.re lg)oo.a

07 / 1_4/97 MON 11: ?9 FAX 6H 3.:,3 6202 692 ... 4--r--..,__--------~~ l, 0 . i'--------------- .. l J!

• ~*

t.1W'-'a.w~;.......JL.---J11---.Q..-1 141-------...... '-----I b o o 0 ~--......--....--0-,--...---"""'---I 10

at st_

40 A 60 Awnp delb pr sit: (Illar l + Bq t)IZ F:!o. 1. Blmch'Jtnum pk,t (24) << ba,-to big~ Whi. dr&J) ,lid !Cl-day~ 'N.1<<011 ("Pffl ~,r:/eiF, 95'1. ~.lloti:r.s 11m ~ then iiSCd to ~ me result1 of the <<Est when it wa,; Ull8lf in a huge multi-<:cntcc" trial. T~ SQelS 11::Sts were done l1ffl>I 13°'1-oootaining 2Q..oc: Va.ci:l.lai.Dcr tubes with ti:ttee lovda of~ The ~ and ~ tetted were c:brlptd to evahialt tbo6e tbat might OCQlt" mtrlq air or ground tranBit mid included ~ of -40°C 8Dli !i$°C and pres-- $Utt}3 of 10 and 14.7 pm.. RESill.TS Bi:wh samplOS collcored in dupl.lca:te bag! fur M:Omge lll1d tra:ilSfer yielded 1$CIKi;fly idcutical 111Sul.tl! ~ 1). Storage . for 10 da)'3 had.no effect oo the result$. The raw da1I. fQc the ina'ea&e. in ~ ahurtd.!bwe over the ba.sc1ine value (B pu-mil) ai:e mown in Pl~ 2 for the a:ame JIOt't1W.md H. pylcri-positi'\\IC individuals after 115 mg and m.'lu 250 mg of 1:iC"!ffl!Jll-Tbc cut-off poinb as detennined by R.OC curves fur dllC rwo do$CI of~ were high<< for the 2'0--.mg ~ of 13C nu:a compaced witb the 125-mj doac: 4.2% compared with 24W. f'OC' dxe 30--min colli:ctioo time. They were hip.l:'.r fat th$ 40-min fune. poi.at (4.4% compared with 2.84K, fur 250 mg aod 125 Wg OC 13(: urea, :respectively (1'1111!'! 1). Four hundred mxty-tlve patiellt.. with a WSLOiy of ulcer cliseue we.re sauned for the p~ of H. pyi,ori infection with the ute$. bt:eath test aud hilltol(lgy. At the end of the 6-n:mtll irtudy, 173 had rompleted the fullow-up 6 wk after the etJd oftllertpy (l'.ahle 2). UsinJ 12.S mg of UC urea Md a tt:it dciectioo limit of 2.4% at 30 min, tire accur.icy of the bteath test was 94.3 [95% Cl (confldimcc inh:rlal),;, 92-97%] before :antimicrobial tbctapy' 80d 95.4'11 (~ Cl ::::i 91-98'11) after. Six weeks afb.:r therapy. a time when ooc !bould be able to reliably dhtingwsh the results of the;rapy, the seor.itivity ;u:td specificity "\\YCRI eJCCl'ltlent (Table 2). Tht;se rcsulb, obtuncd outside: the highly :;killed I'CICat'cli cnrironment, rdlect the pcd~ of the USt in clinical. practice. Of inte;rett, 2 wk afteJ the end of 'thetapy, the re.81.lltt confirmed that mis is rhe dmt' wfren it.ls dif.ficnh or impo,r sibl.e to Idiabfy ~ s~l.on from t;tm: (21, 22). llERETEK DIAGNOSTICS. INC AJQ - Vol. 91. No. 4, J996 100 i, I ' I. I. 0 I I 0 D 0 0 Q tt1m&6lilt ---- U1 Fte.. 2. ~\\n ~~MMldl<n11:tbae>>nab.llomuil ("1/P cfn:fa}ud 1L ~ hidlvidllals ~ ri.rr:u3) JOmln afttt cifbd' J.l!i ar: ~ Dli of IJc 1IICL BQCd on tlie re.mlta of hbtokigy, the i;amitivfty, :spc:cificity, and positive and ocgative predictive values for the wi:a bn:atb test were 89.5%, 7o.6CJi, 74.3'1\\ and t:7.7%. ~ tivdy. The overall ICCUJ:'aCY of the test ~ed low (79.8'11) pr.i.m;u:ily dw:- to the iDcrea.s:c In "'f.we-posftive" ~ using hiitoJog:y BS the st.a.nilard. Eighty-m.n,: pcrceat of all "false-positive" results occurred at th.it v.is:it, ewpha- !lizing the importaru::e of Wlli.titte to datermh:le -whelh:r the .Infection ba'I rccstab.6$hcd it!eff. A ~ << fullow-np visit W'B.! aVill7Bbh! for 31 of the 43 stlbjecb; '25 ~ amfirmed to have bCCQ trac ~ at this 2-wfc after 1heo.py evalumicm point. The= :te:mltii fuffllcr comi:Im the necessity of waiting wuil 4 or.moo, wk a:i't<< ffllCM8 therapy toUst:ss~~ DISCUSSION Because tbe 1'c urea breath tat llOllUlW$lvely ea~Iisbes the preaep.ee of active H. pylori iJJfEctioo of !be stomach, it bu the. potelltial to be an imp,nant tool both m the dlag~ IlOSis of i.n!cictl.on and in pat:ullll ~ after a:alimi-crobial therapy. The studtea reported lieu: were dr.signed to evalu.a.te: the pe.rametc:! required ftlf l'll.CCeli8fi;i USC of t1J.1' test in genera.I clinical p11M:dce. Tho physicil oompollt!mi of tbe kit: a bretafh swnpllng b;ig for collcctkm and trBnsfcr of patient breath into evacuati::d test tubes. 11 bn'/.afh sa.mplo mailer for n,turn af the samples to the refeaocc analytical laboratocy, and cbe walyw:;al proa::n of,a,. Jaotopo.nuio mass spectrometty to detetmine 1>c abundance tn respiro--- tt'.l"Y CO2 proved to prcvidt:. highly reprodllet"ble :reswts. 1'.liese componenu and the ana1yticzl proc:eM inttoduee l!ti ll.DCeltainJy of less than 0.30% (1 SD) in the ahundancc ~ rcsu.lting in the ability to dctcnnine. the con-ce:ntradcm of u<:Oz ln bmtd:I to withln 2 J)SlrtS per roilllon. The oo.,a_ge of 1'c utea (12,5 mg_) and b tfme of Ample col.ieclioo {30 roin) chosen wiw1 cmibtned w:bh tb0 a.tt-off li1l 003

07/14/97 MON 11:31.1 PAX 615 333 8202 MRRE'rEK DIAGNOSTICS, INC AJG-April 1?96 BREAffl TEST FOR H. PYLORI TAJIUI 1 693 q<<1 of 0,,,. iu,,i ~ no-OIi ~ltic 0,1-0ff P.iW ~ }'t,rfooa-Do,c n-Cul.off' !elll S'pe,:i. PPV NPV ~!/ (mg) (Ill.In) (~) ('1,) (~) (';I,) ~) (S) l2S

31) u too 100 JOO 100 too 12' 40 28 100 100 100 100 100 2'()

30 4.2 100 91! 100 98 99 ~ AO 4.4 100 lCO 100 lOO 100 Sc:lls~ a:lllidTi1y; s~ ~ PM', ~ pnd,::il'ffl -r.aJne; Nli'V, ~ ~ -r.ilac. ]:Mt.e 2 ~ o/D~ P~ of Ura1.8n:IUl:1. t'c,t AgaiJu:t ~ F,itiod N Diqnostkt ~ ('Ii) 'l\\'uo fzke

Tiw, FaI,e

&:nm!Y.ity 8pc,a!!iaJ:y ~

• AI. ICIIS14 wk~

tbdapy. 4 l 19 63 val:De of a 24'1> ~ in 13c wea ahnoow:e prov~ to detect u. pre:sc:ncc or~ of H. pylcri in th, setting of.its

!nrttlded use: w assr.ss H. pylori status by medi£al pmoonel

-wilhourpcior ttSt:Xpencaiec. The t"."Ecellent paf0Jlll2IICC of tbe JeSt C0ll1inno:i that tbi3 ver:sl.oo of the UC urea breath tr:st il'ltl=:nded foc use in the cli.nb i! a &imp1e, robust, aod ~ re.,t in the: bands l:1f tuy htaltb cam~ Cun: of H. pflori infection has bcmx defined as tho ab-lcncc of it:l:fucd.on 4 or IJ1IX1:I wk aflct ending the.apy (21, 22). This criterion was cbolen after.recognitioo that unwo-cessfid therapy may merely suppress the infection and that telaJlrs of therapy are not app8X\\mt until the Infc0tiot1. bu had the opportnnity to rctum to itB full 'Vigor nnd be detected ~Unbly. 'I'M naninYllSiw: DCC8 btee.tb ten bas additional adVamages over biP>logy bl tb:&t il effectively.integnte:s the enzyme.activity of bectetia ()Ve,- the Cllllte aurfiu:e or the stotnacb aodcan deti!dagkm jn wbidJ. the organimtls still present ln auch iruJtmces. the patiml1 will ~y pn:se.nt M a tbllrapy firuure. 'Ibo ~ bet:M,cn the bl'Qth n=st sod~ i1 a visit 2 w:k afkir eiullng*tbcmpy illllsr:mes the ~ of timing of t.ostmg for H-pywrl sttuus. Wti do not recomroeud ihat tdthlg be dooe inµncdi-lddy l'lftet" tMrapy hccauac tllt:l:e are a IIIUDhct of studies con.firmins the ~ of !he 4--wt: role foi: e$tablishing H. pylori.stat.us after~ ('23). Toe dose.~ and dtff'en.1nt cnt.-Qff p::,nt3 QbtaiPcd wub. the d!ft'eR:nt cbcs, 125 am1 :?$0 mg a urea. and time po.trus (30 w 40 min) illuml.o:arc the ~ of i::ooc:lifying teat ~ rondltions (Titi!e 1). Wltb 1'25 mu, 1he lowest ~ avei ~ aht:Indance at which H. pyiD,{ c:ao be: detected is 24%, whkh is ~atcl.y 23 tll:11" ffie inlw:rcnt initnlmeDtal ~ fin:rlt. ~ ~ mich as iPh-red ~ Ol an -.,ociated l.nsb.1nntnt Cllm:dly have an aoolytical Umft of ;:t l %. Al pn-,:,cint, thls would prob-ably oot pe:rmit one to discrlmiuat= with ~ lllilQ'le ability as 20 5 &7.9 9$.S 'Mlh the 1U.i0 of gas isoo:,pe, J3tio 1llall$ ~* 1be. fad: that !be att-ol! Jnczeasc:d widi a bipc't' dose of mca ~ lb2ll 'th! reaction bu not adrltved fu.Il ~ of tho &a$bic lll'CR.'!t>~vity. The't18':'of oose.umall<< than 125 (e.g., 75 mg) (9, 13, 14) or mmmado dosCi'i as um:l :in ~ vmions of me WC urea breath test (15, 16) may~ the nm,ge ovs wmm. absetlcc of info::don wold be c:;tat.,lisbed widJ. a,.minty. am mca breath ~ tl!SUlg dif1irent d09BS or differcm t1m:::s m ~ 'flliII.a:.q_uir,:: a~ rt:&SPMtilllCllt of the or,dmum ~-Off ","B.hJe. ACKNOWLIIDOMENTS 'Ibe lllltbm!, thank ~ P'b.annaa:utica Products Division of Abbott.Labomtoriea for thm coopc;cadoo in tbis i;tudy. The :,tudy*wa& wpportro m -part by Mereret ~ Inc., Houston TX. Meretek Diagoosri~ is a campeny founded by Bii.ylor College of Medicine to commercialize lhc 1ac urea breath test. Drs. JQeiJ.). and Oniha:m 811: ~ hQ)den in Mmetck Diagno6tics. DI'. Martin is l1 comultMt to

Mare1:ck Diagnooic::s.

Repdnt ~ and ~ Darld Y. GI1UllllD., M.D~ V/.. Medical 0:nt.cr lAlS'.2. :ZOOZ Holoo.bt Bl"'-.~ 'J."X 71030. REFERENCES

1. NlH ~

eoor~ /ldH::O~ PJk!l'i m P'f4lc 'oUlllll" di,;.. euz:. NJU ~ De11'ft~ P.ux:I llll H~ J¢<<'f in Peptic m-~ JAMA J994;272:6S-9.

2. ~

PG. Gmtto lympbcma acd ~ pylori. N &.sl J Med 1~.13JO-l.

3. arar-PY. E'l'Oftltlooo of~ tqpitdlDg ~r

,,,,i,>>t: ~ II - of ga:strim to II~ '-lib~ Am. J ~ IIC1)I. 199-1,:89:469-7.Z.

4. Soll AH. Gutrie, duodca.iZ:, ill'Jd ~

tdc.i:T. In: Skma,er M. Paidlran J, eds. Gaslro~ disl:Na, Sdx ~ Pllil~*- WB Samide~ 199$: 580-679.

5. o..ia RM. ROOMOn 00. Qaham DY. ~

~ C.: fiil006 1 \\

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July 1, 1997 Rita Aldrich, Principal Radiophysicist Radiological Health Unit Div. of Safety & Health Building 12, Room 457 NY State Office Campus Albany, NY 12240

Dear Dr. Aldrich:

'JUL O 2 1997 RAD!OLOGlCt',L '.~E,\\LTH lJ~llT OFFICE OF SECRETARY DOCKETING & SERVICE BRANCH On behalf of MERETEKdiagnostics, Inc. I am writing to you to ensure you are aware of a recent proposed Nuclear Regulatory Commission rule that has significant implications for Agreement State authority over the use of radiopharmaceuticals. MERETEK is the manufacturer of a pharmaceutical containing Carbon-13 (a non-radioactive, stable isotope) used for the in vivo diagnosis of bacterium Helicobacter pylori (H pylori) - a cause of peptic ulcers. Because our product is a stable isotope, it poses no radiological risk and is unregulated by either the NRC or Agreement States. On June 16, 1997, the NRC published a proposed rule for comment that would exempt from NRC regulations the distribution and use of a product manufactured by one of our competitors, which employs a one microcurie dose of Carbon-I 4, also used for in vivo diagnostic testing for the presence of H pylori, 62 Fed. Reg. 32552. Comments are due by July 16, 1997. The effect of the proposed rule, if it is adopted in its present form, would be to allow any person otherwise authorized by federal or state law (including non-nuclear medicine physicians) to receive, possess, and administer this radiopharrnaceutical to patients under an NRC exemption without the need for either a general or specific license. MERETEK, of course, has a commercial interest in the outcome of this rulemaking, but we also believe it raises several significant policy and regulatory issues which we would like to call to your attention. Two such issues may be of particular importance from your agency's perspective. First, because the NRC is proposing to authorize the distribution and use of the 14c capsules by way of an exemption to its regulations, Agreement State agencies will be required to fully conform their requirements to the NRC' s, and will lose their existing authority to adopt more stringent standards or to continue to require specific licenses for the distribution and use of such materials. (Adoption of rules to pennit the manufacturing and distribution of the 14c capsules under a specific license to persons who are exempt would be a "Division 4" matter of compatibility. The exemption to allow persons to receive and administer the drug would be a "Division l" matter of compatibility). See 62 Fed. Reg. 32555. Therefore, by adopting an exemption, the NRC will deprive the Agreement States of any opportunity to establish regulatory policy different from that set by the NRC. Had the NRC instead simply proposed a general license, rather than an exemption, your agency, as well as other Agreement State agencies, would retain the authority to adopt the general license or continue to require spe'cific licensing.21 The second significant issue is the appropriateness of utilizing a radioactive drug when a non-radioactive alternative is available. A federal government decision to mandate that Agreement State agencies pennit exempt distribution and use of 14c, when a non-radiological alternative is available, may not be consistent with ALARA considerations. 21 In comments previously submitted to the NRC, six Agreement States favored the general licensing approach and only three suggested that an exemption was appropriate. Corporate Offices and Breath Test Center 618 Grassmere Park Dnve Sli1ce 20 NashV11le,Tennessee 37211 Phone 615*333*6336 Fax 615*333* 6202 Breath Test Center and Research Laboratory Med1calT<YWers Building 1709 Dryden Road Suite 1513 Houston.Texas 77030 Phone 713*799*1282 Fax 713*799*8395

MERETEK will be commenting on the proposed rule and will raise these issues as well as several others which we believe argue for an approach different from the one the NRC has proposed. We are providing, for your information, a brief point paper which will serve as the basis for our comments. If you have any questions, feel free to call me at (800) 945-8252. KCB:vw Enclosure

I. Point Paper Regarding "Exempt Distribution and DOCKETED USNRC Use of a Radioactive Dru Containin one Microcurie of Carbon-1 Summary' of Proposed NRC Rulemaking 21 Pl2 :52 OFFICE Of SECRETARY DOCKETING & SERVICE BRANCH On June 16, 1997, the NRC published a proposed rule that would entirely exempt from NRC regulation the distribution-and use of capsules containing one microcurie of Carbon-14 (1 4C) urea for in vivo diagnostic testing for the presence of bacterium Helicobacter pylori (H pylori), a cause of peptic ulcers. 62 Fed. Reg. 32558 (June 16, 1997). While the manufacture of the 14C capsules would continue.to require a specific NRC *licerise under 10 CFR Part 32, any person otherwise authorized by federal or state law to receive, possess or administer the capsules could do so under an NRC exemption. 1bis would eliminate all NRC or Agreement State regulation over the receipt, possession, and administration of the capsules. Physicians and non-physicians could receive and possess the capsules so long as they were authorized to do so under other federal or state laws. Relationship to Part 35 Reform Initiative The NRC has underway an initiative to reform 10 CFR Part 35 governing medical uses of byproduct material. The proposed 14C rule represents a piecemeal effort to respot¥1 to _a narrow rulemaking petition which addresses a single type of nuclear medicine diagnostic procedure. It does not take into account the many other nuclear medicine diagnostic procedures involving low risks of injury due to radiological exposure. Nor does it take into account the significant resources that have already been expended and the planned efforts by the NRC, the medical community, _and other stakeholders to achieve significant improvements in the existing 10 CFR Part 35 regulatory program.

ce While reduced regulation of the receipt, possession and use of the 14C capsules might be warranted, the same is true for virtually the entire range of radioisotopes used in nuclear medicine. All of these materials should be treated comparably and efforts to reduce the level of prescriptive regulation should be undertaken in a comprehensive and uniform manner. Indeed, the NRC Staff has already proposed to "subsume" various other specific rulemaking efforts into the overall initiative to revise Part 35, rather than continue to separately pursue those individual rulemakings. These include, among others, rulemakings on relief from requirements governing mobile nuclear medicine se0ces and revision ofbrachytherapy procedures. See SECY-97-062, March 14, 1997,

p. 3.

Furthermore, the medical community has strenuously sought widespread reform of the NRC's medical regulatory program, devoting substantial resources over the years to this effort. The NRC has now concluded (through its Direction Setting Issues (DSI) initiative), that revision of 10 CFR Part 35 to establish a risk-informed, performance-based regulatory program is a "very high priority." See Staff Requirements Memorandum "COMSECY-96-057 Materials/Medical Oversight (DSI 7)," March 20, 1997, pp. 1-2. It simply makes sense to address this single diagnostic procedure using 14C asp~ of the overall Part 35 revision effort. ~- The nuclear medicine community has consistently taken the position that nu~l~ar medicine diagnostic procedures present a very low health risk when they are administered by trained and qualified medical personnel. Under the proposed rule, any physician or allied health care personnel may administer the test regardless of their background or training in radiological health or nuclear medicine procedures. Indeed, physicians untrained in nuclear medicine would have full access to and could administer the test. A fundamental tenet of proposals by the nuclear medicine community for regulatory reform 2

is that an appropriate function of the regulatory regime is to assure that personnel handling and administering radiopharmaceuticals meet certain basic training and. qualification requirements. The proposed exemption for the 14C diagnostic procedure would impose IlQ training or qualification requirements on users. In her comments on DSI-7 relating to NRC regulation of medical uses of radioisotopes, NRC Commissioner Greta Dicus recommended that for low-risk diagnostic procedures, the NRC Staff should: consider alternative regulatory schemes that retain regulatory oversight but in a cost effective manner consistent with the lower overall'risk of these procedures. Memorandum, Commissioner Greta Joy Dicus "COMSECY-96-057 Materials/Medical Oversight DSI-7" (January 27, 1997), p. 1. Exemption of 14C is inconsistent with this recommendation in that it would eliminate all NRC regulatory oversight over the possession and administration of the product. Users of 14C under the proposed exemption would not be required to establish any radiation protection program or to comply with ALARA principles. Agreement State Issues _.:: Pursuant to Section 274(b) of the Atomic Energy Act, 42 U.S.C. § 2021, the l'{RC may relinquish responsibility for certain nuclear regulatory matters to states that have entered into an agreement with the NRC ("Agreement States"). In some instances, Agreement States have the authority to promulgate regulations that are more stringent than those of the NRC, provided they are "compatible" with NRC's regulations. Currently, possession and in vivo use of 14C requires a specific license from the NRC or from the appropriate Agreement State agency. If, however, the NRC promulgates the 3

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. As the NRC has stated: 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 without need for a license. 62 Fed. Reg. 32555.1 Thus, the Agreement States will be forced to accept the exemption and to authorize the unlicensed possession and administration of 14C. Exemption for In Vivo Use The exemption would be unprecedented in NR<:;'s regulation of byproduct material. Existing NRC regulations, exempting certain small concentrations of byproduct material from regulation, state: "[t]his exemption does not apply to the transfer of byproduct material contained in any food, beverage, cosmetic, drug, or other commodity or product designated for ingestion or inhalation by, or application to, a human being." 10 C.F.R. § 30.14(c) (emphasis added). Thus, NRC's policy in the past has been not to exempt byproduct material that is ingested, and any change in this policy would be a significant departure from existing NRC regulations. -~ Although, prior to 1986, the NRC granted general licenses for some medical uses (ill vivo use oflodine-125), it subsequently eliminated the in vivo general license and-required that "all medical use be authorized by a specific license." 51 Fed. Reg. 36932, It is interesting to note that although six Agreement States suggested the use of a general license and only three Agreement States favored promulgation of an exemption, the NRC Staff opted for an exemption. Oddly, the Staff now favors the exemption approach even though it recognizes that some of the Agreement State objections to the general license were founded in part on the erroneous assumption that an exemption would produce less administrative burden than a general ' license. SECY 97-031, pp. 2-3. 4

36935 (Oct. 16, 1986). Accordingly, complete exemption of the 14C product would represent a radical change in regulatory direction for the NRC. Basis for ACMUI Recommendations The Advisory Committee on Medical Uses of Radioisotopes (ACMUI) has concluded that either an exemption or general license is appropriate for the 14C. product. However, its judgment was based partially on the assumptions that: (1) the product may only be dispensed by prescription; (2) the product is approved and regulated by the Food and Drug Administration ("FDA); and (3) the office/facility using the product will ~e subject to Clinical Laboratory Improvement Amendments ("CLIA") regulation. These assumptions, however, do not address fundamental asp~cts of nuclear safety and, in at least one respect, are incorrect. First, physicians' offices will not be subject to CLIA requirements, if they are only collecting samples and sending them to outside laboratories for analysis. Only those offices that have liquid scintillation counters would be subject to CLIA. Additionally, even for those physicians' offices subject to CLIA, these requirements address quality assurance, not nuclear safety issues. Second, FDA approval of a drug indicates only that the Agency has determined that a product is safe and effective for use in patients; the FDJ\\ ~oes *not address nuclear safety issues affecting physicians' offices. Indeed, in its Statement of General Policy on the Regulation of the Medical Uses ofRadioisotopes,-the NRC stated that its "authority to regulate the medical uses of radioisotopes as necessary to provide for the radiation safety of workers and the general public... does not overlap with FDA's activities." 44 Fed. Reg. 8242, 8243 (Feb. 9, 1979). Finally, state prescription drug requirements provide only that the product must be prescribed by a 5

physician. These requirements also have no bearing on nuclear safety issues presented by the potential accumulation of 14C in physicians' offices. Disposal of Unused Product According to statements made by the NRC Staff to the NRC's ACMUI, an exemption does not provide the NRC with the flexibility to impose a limitation on the amount of 14C any one physician or physician practice group can possess in an office, notwithstanding the rulemaking petitioner's suggestion that possession be limited to 150 14C capsul~s. Consequently, in the event there is a recall of the product, or a large ~ount of product becomes unusable (because it is past its expiration date, damaged, in violation of Good Manufacturing Practices, or for some other ~on), the NRC will have no control over the disposal of the product. Toe manufacturer may request that the exempted material be returned to it for proper disposal, but it may not have control over this procedure if title to the goods has passed. Labeling of 14C Pursuant to NRC's proposed rule permitting 14C to be distributed to persons exempt from licensing, the immediate container of each capsule: 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." 62 Fed. Reg. at 32558 (to be codified at 30 C.F.R. § 32.21a(a)). Additionally, the regulation states that either the label affixed to the immediate container or an accompanying brochure must: 6

(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." Id. (to be promulgated at 30 C.F.R § 32.21a(b)). Regardless of the form of licensing ultimately imposed by the NRC, product labeling provides critical notice to end-users that the material is radioactive. Indeed, under the NRC's proposed unprecedented exemption from both federal and state regulation, the labeling would serve as the sole notice to users that the product contains radioactive material. Because 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, the labeling must be conspicuously and prominently placed. Existing labeling for the 14C product, for example, refers to the product's radioactivity only in small type in the second column of a lengthy package insert. It is important, therefore, that proposed section 32.2la(a) be revised as follows: (a) The immediate container of the capsule(s) must bear a durable, legible label which: (1) (2) Conspicuously and prominently bears the words "Radioactive Material." Additionally, because physicians and those that they supervise often refer to manufacturer-provided promotional brochures rather than package inserts as points of 7

reference and guidance, for consistency purposes, NRC should require that the radioactive material legend be included on these materials, as well as the immediate container label. Accordingly, it is recommended that section 32.21a(b) be redesignated as section 32.21a(c) and that a new section 32.21a(b) be added, as follows: "(b) All package inserts, brochures, hands-on training guidance, and other promotional materials that directly or indirectly accompany distribution of the capsules, must include in conspicuous type and in a prominent location the words "Radioactive Material." Conclusion Modifications to the present licensing and regulatory system for the 14C c!1-psules should be _undertaken as part of the overall effort to reform 10 CFR Part 35. Furthermore, such modifications, if adopted, should substitute a general license for the existing specific licensing requirements and should not remove all NRC and Agreement State controls - as an exemption would do. Proceeding in this manner would ensure a coordinated, coherent and uniform response to the overall issue of radio pharmaceutical regulation by the NRC, and would provide appropriate regulatory flexibility to Agreement States. 8

3255J f"ederal Register I Vol. 6Z1 No. 115 / Monday, June 16, 1997 I Proposed Rules 5 927.33 (Amlndod}

7. In§ 927.33. paragraph {a} ls amcndcid by remo"1:ng the word "ten" in the first sentenca and adding in its place the word "cine"; !Uld adding the WOTWI "telecopier or othet electtonJc mearu,"

and a comma after the word mall" in paragraph (b) first 1entonc:e, D11tod: JW!e ~. 1997, 1.AJa Ela t.am!7 ** Admlnlltftltt:ir. Asrf cultuml M~a &rvica, !FR Doc. 97-15863 FUed 15-13-97: 8:45 am) pllJ.n,l(I cooe; !Ml~ DEPARTMENT OF AGRICULTURE Rural UtlQtlea Serwlc:e li/JfFR Part 1753 .iJr0eep1anc;e Teat Pollc;y. - AG81CT: Rural Utlllrl$ Servtce, USDA. ACTIOPI: Propo:1ed rule. SUIOIA.RT: The Rural UtHitl.&5 Service (RUS) I.a proposing a minor an:uu1d.m11nt to 11:1 test acceptance procedures to con,,ct 7 CFR part 17 53.3 9, pll.X1lgrllp b (c], to reflect new acceptance tests gu!d.allnu co"'el'8d under RUS B,ill,mti. 1753E-Z01,.l\\ccept&lce Tests for Digit.al. Stored Program Controlled. Central Otflca Equipment. In the final ?llfes section of this Fisdenil Jlcgi:rmr, RUS ill publbhing tlws action u a direct final rule without prior propo11al becal.l!!e RUS views th1., as a noncontrovlll'lli;u :u:rt:ion and anli.c.ipatas no.a.d.vsne con:u:ri.enta. Uno Aadvsrsa cor.nmants am. l:'Cl!:alved In ~po~e lo the d.l.recl ru,.al rule. no further action will be taken on this propo.oed ru1e and the action "'111 become effective at tha time spec:Uled in the direct final :rulo. If RUS NCeivss adverse comments, a document will be published withdrll~ng the effective date of the cllrect fiiutl rule md all public: C1:lnunaots nieaived will be ad~ed in a 11ubaequanl fi.mtl rulo b:aad on this :i.clion. A:Jiy ptuti0e i.nte~ted in comm.anting en thla action should do 110 a.t thh t:ima.. CATE3: Com.menu on this :eropoaed .iclion mwit be ~ived July 16, 1097. ADDRESSEa: Written comments should be se1:1.t to Ormn E.. Cune:ron m *. Director, Te]ecom.municatlans Swuwds Division, R:ru:al Utilities ServJr;o, STOP 1159a, Unlted Statca Department of Ag:rlculhlhi, 1400 I:ndflpendence /\\Yl'J,, SW, Washlngtcm,.. DC, 202.50-1598. RUS :requ!.n,s, m hard copy, a algned otiglnal and three copies ofiill comments [7 CPR.part 1700.30(e)}. All comments :received will be avllllable fur public 1n.3pecUon at room 2835 (addreu as above) during :regular buainff!J hours (1 CFR part 1,37(b)). FOR FUATHM INF=ORMATION CONTACT: John J. Sc.hell, Chief, Central Oflico Eq_uipment Branch. Telecommun:icadc.n.s.Stmdarda Division, Runl UtiliUaa Ssrvico, Unitad States Department of Agriculture, STOP 15,98, 1400 Indepm:idimca Avanua, SW, Wesb.ingto.0., DC 20250-1598, telephone D.Ull:lber (202) 720-0671. S.UPPl..BtEHTARY INFORMATlOH: See the Suppleau,utary Information pt'Ovided in the direct flnal rule located In the fill.al roles section of thb Federal Jb=gi.sts.: for the applicable supplemen.wy inf'onnation on thi:J sec:tiou. °'1tad: JU'I\\O 9, 1110'1, Jlll Long Tbomp111m, Undtkl' Secn,uuy, :Ruml Dettalopm<t11L [FR Doc. lil7-l5758 Filad S-13.-Q:1: 3:45 am] ?IIL.L.INIJ a,i;,e.,.,o...,...... NUCLEAR REGULATORY COMM&ssiON 10 CFR Parts 30 and 32 RtN S150--i\\F70 Exampt 01.Strfbutlon at a ~loacUva Crug Oon'lalnh'lg One Mk:rocurie oi Carbon-14 Uraa -'GEHCY; Nuclear Regulatoi:y Com.mlssion. ACTION: Pmpcsad rule; request for eommenr.s. SUJDIARr. Tbe Nuclear Regulatcll:y r.ornrn laaion (NRCJ is (11:0p0.11ing lln smendme11t to lbs regwatlona that would perm.lt NRC Ucarueas to d.lsµibuta a radioactive cl.ug containing one mic:rocw:is of arbon*14 urea to. any peoon !or "in vlvo dlapowr; uae, The NRC has determined that the radloactlva component of such a drug in capiiulo form pressnts a mJnlCMl radiation :mk e.nd, thexelbre, regulatory CClltrol of the drug for radiation aa!Bty iB not n~. H ad.o~ted. thL, tut1end:mim.t.

• would J.11U8 the d.rUg mon, wldaly avail.ah]..., and red,ui;,,- CQ,sb tQ patient.a, insurera. end the hMllh CBllJ fndU5ttY
• Tbia action is hei.ug tahn in iespome to a petition for :rul8IllAking (i'RM-35-12)

$ubmitted. by Trl-Mcd Spm::i4ltlos, hi.e.. DATES: Submlt comments by July 16. 1997, Coxttmenu 1;'!JCOi-.l aft4:r (bu date, will be COllllida:red if it h pmdicahla to do aa. but the Commlssicm i* able to aJA1ll8 consideration only fol' comments received on-or befo:n, thL, data, * /. ADDRES8&8: Se.nd commsots tD: Secreta_n:. U.S. NuclearRegul.a.tDry/ Com.m!.ulon, Wuh.ington, IX.:: 20$55-0001. Attention: Rulsrneklng1 fllld hclfudiC11ti0na Staff. Hand dsllvar comments to: 11555 Rocmlle Pih, Rockville, Miuylmd, between 7:30 am and 4:15 pm on f.'edaral wod:d.ay

• 1"he public may examine CQmmcnts re<:aiv11d. tha 11.D.vironmantal a.uuamsnt and finding of no slgnifu;a:Dt lmpw:t, im.d the mgulatoi:y,m.itlysd.a at tu NRC Public Document Room, 21zo L 511'88t NW., (Lower Lllv111), Wuhington. DC.'

rCR FURTHER INFOAIIATJON co,rrACT: Dr. Ao.lhonyN. Tu, Office u!~ud.ear Regulatory Research. U.S. Nuclear R~a.tory Commisoioa, V(uldngtoD, OC Z0555-0001, telephone: (301.) 415-6233 or e-mail al ~.gov. SUPPI.EMEHTAIIY l,iifORM.1.TIOH: L 84C.kgiaUD.d II. Ducunlon

m. Sl.1l2Ul:IJl1'7 0£ P!,,opo&ed. A.m.ei:o..dm.el:>h rv. Agr!l'Olll.Ollt Stata CompUblllt:y V. Elearoo.lc: Acc!IU VI. F'md.mg o!No Sigp.lS=t Env!romnm:ital Impru:t; AYllilabWty VIL Ptlpmwork Reduction Act Sr.ate.m.ent VIll. il.egu]11tory Analyl'I.I IX. Regu!iit.ory FlaxtbUlty C:trtfflcatlr.i11 X. Baci:fit hnalysis XI. llit of Subjocla I. Backgrcnmd Ths Putition for RwcrmaJ:ing On October ct, 199-1, the Commb;51011 dod:et.ed a petition fot rul9II1aking (Docl:,,t No. PRM-35-lZ) from Tri-Med Spoc:ialtie.v, bu: {Tr.I-Med). In a lattsr dated Auguat 23, 1994, T.d.-Mod patitloned the NRC lO amend iu regulationa "to al!OW" fux-tlw 8','lnaral llcen.smg and/or exemptlim for the commercW distribution by 1ic:11Med pharmaceutia,.l manllUI.Cbl.ra,a of 11 capatile contain.Ing one mic:ro-Cw:ia (JJ.Gl) of 14C-lll"Ba for !.n vivo diagnoimc test:b:ig. The puq,oso of t1ws diaga.ostic teat is ti, dotoct the pn,:seilCt! of tho bacterium Helicobacter pylori {H.

pylori), a cause af pc,ptic ulcex-s: "Peptic: ulcar disease ii a chronic tnf]n.mm11t0:ty C9ndition ofdu, :nomac:h and duode.num. that a.ffoota as many u 10 parcenl al people In tbs U.olted Stat.al al scm.11 tiD::111 in their llva. The clLs-haa reLt.t:lv11ly lo-mortality, lrut It reaults !.n subsl8Iltlal human suffering .lllld high economic: COlrta," (Sotu-ce: Ard.cle 1nclud8'd as an_ appendix to the ~Hon, from JJU..f.A, Jtl.).y e. 1QC4, Val-- zn, No. 1, "H. pylo.rl in Paptk. Ulcar JluEIJUI~ 0:UlS&nStJ.S CQnfemnea"). In the petition; th.a petltlone.r lltated the follow.ing: R.acent.mad1caI ressari:h baa found that peptic; u1.c:::en a.n, commonly cawiad by a bai::tsrium called H. pjlort. 'I'hbl

Federal. Register / Vol. 62. No.. 11!5 I Monday, Jun0 _16, 1991 / Proposed Rules 3Z bac!.erltun livesa in th~ :Jlomach of l'.l'lO$t ulcer sulferers, By treating ulcer patients with antibiotica, doctors can no,.,. curo most ulcer P.robleIIl!I, It ii; theretora nece.uary to detect tho ptcscoca ofH. pylori bacteria l.n ulcer patients so that the na"' treatment can be given appropr!ataly. In tha past, thi., was done 1.iy a ga.111:::roantarologfat who took biopAy =plea of the stomach lining 11t tlndoscopy, a procedure which was uncomfortable and exp..nslve ($1,000}. With the new hist, H. pylori can be detected non-invi1Slvely using a °C-u.rea tracer. 14C-tiraa Is bro.ken down by H. pylori to form labeled CO2 which ts expired in the hrFlath. To do tho tc,t, a doc::tor a.slra lhe pr.itlent to swallow the capsule with 30 mls of"latcr. Altar 15 minute., tho patient bloW!I 2 liters of breath inro a collection bag (a mylar bo.lloan) which L. }nailed to ll testing biboratory, If 1"('.--CO:2 more than twice bad:.ground is preaent in the breath sample, lhen the patient must be lnf.eeted with 1-L pylori. This proposed rule,.l5hou.ld it become final, would grant the petition for rulamaktng (PRM-35-tZ) from Trl-Med* and complete action on the petition. Public 0:;mmMts on the Petition Following the receipt of the petition, the NRG publiahed for public comment a notice of receipt of petition for rulema.l.:ing in the Federal Regbtcr cm Der.ember 2, 1994 (59 FR 61831). Thc;i commant period dosed 011 Febru11IY Ui. 1995. The NRC rec0h1erl 315 public ~ commont letters, of...,hic:h 313 support the petition (they were mostly form letters) and 2 lelteni opposed th.a petition. The two lettAni opposing tho petition stated that the. product i;houlcl not rec:elva El.ll exempt.status becaui;e the uncontrolled distribution and application of thi:i product could lead to significant risk to the public and that the medical tltiCS should be restrlc;tad to short-lived isQtopes becaUJJe of disposal problc!n$ pl'f#entad by long-lived lsotop1,1s. The NRC has cog:sid.tm:,d the two opposing comments. and has detormhted the follcr-Ring: (lJ The I8511ltin2 radiation dose from the capsules to workers, ps.tlauts, and the public is very low (see Regulatory .Analyais). (2) The lmpact:s IIS$Ocia1ed with any

releases of 1'4C to the surrounding KD.vironmenl e.re e:;,;pe.ctod to be very small and the expected :rlsb are m.1.nimal (see Envirqnmeo.tal Assessment}. Similarly, the small dosa from naturally occ;u:rrlng 1"0 ate ofllttla

. rdgniflcance to human hoolth and th.e

• smd:roillllflnt. Aho, the.Comm.lsslon condudas that the poo::ntlal loni::-tcrm impacts from widgi:pread rolaasH of tho long-1111.,d 14C (5 1730-year nidiological half-life) from breath tegts are insign!flcant.

Commimts From Advisory Committse on the Medico? US8S of lt,otapes Thfo peUlfon wa, dl5cW1Sed with NRC's Advisory Commltlee on tha Medical Uses of Isotopes {ACMUI) at iu October 1995 meeting. ThE! ACMUI hidicatcd that it endorsed the wit.le avcilabllity of this diagnostic test and that tho rad.iMctive drug could be used under a general license or an exemption, whir:hevcr thtt NRC may determ!ue to be procedurally easier.

n. Discumon

&gulatory lssus Tha regulatory luu11 ~:, wh..:ther cap:Jules conminl.ng one mtr:rocurle of carbon-14 urea prllSent a suffideutly 11mall radiation ruk that they can be safgly distributed to B.IJ.Y pcuon (including physlclarui who ara not "authorized users" under Part 35]. C'uJ.Tent NRC Ragulatian6 for tht: Ma.nufacm11:e and Commercial Distribution of Radioactive Drugs Coiitajnlng Byproduct Material NRC reguletions in 10 CFR 32.72 addNss the manufacture, preparation, or tral:13fer for commercial dimlbution of rad.ioactlvg dmga containillg byproduct material. Th.ls regulation requ.lres manufactureN ot' propaters of radioactive drugs for commercial distribution to be.: (1) Registered or licensed with the U.S. Foori and Drug Administ::raliol'\\ [FDA) IU a drug mat:iuhctu.rar; (2} Reg.i5tm:Bd or Hcensed with a State agency aa a drug ma.nufecturer; (3) Licensed 8$ a phannacy by a S~e Board of Pha:r:macy; or U!'iA. The Agrooment State& have sim requiremcnui. Current Nfi.C Regulations on ExompU.ons From Licensing Existing oxemptlon.s from 11cens1n requirements for tho WI$ of byprodu, material Include exomptlons fat spei products (e.g.. time p_icces), exempti, for cl.uees of products (e.g.* gas and aerosol dGtectorsJ and broader m..at.er exemptions in§ J0.14, "Exempt concentrations," and§ 30.18, "Exem qua.nliti~." These two broad mated! exemptions specifically exdudo the tran,fer of byproduct material contai in any food. b~varog*o. coametic, d.rui aI1.Y product de:iig:ned for ingestion c inhalation by, or application to. a h,1man 'bBlng. (In the case of exempt qulilltiHes, this prohtb1tion ta contaii in§ 32.16, "Manufacture, dilrtrlbutlc aud U"an5fer or exem-pt quantltle.s of byprocluct materiel: Reqwn;ment.5 fc license," § 32.16(b)). Capsule, containing one microcur carbon-14 urea would not qu3.lify a.s "exempt quantity" in accocd.ance wt § 30. 18 because of their lntended us, a clnlg) even thoui;;h they contain a smaller quantity tlian that set forth f* S 30.71, Schedule E. This use i., outs lhe intent of the exemption curra\\'ltl; § 30.18. It would introduce needle$5 complexity to !.ha regulations ao.d confusiOll to accor:nmodata this uni9 Ulla under the aforemcntlonad.sec:Ua Howe,ror, becau:se the cap,ul~ prasant an insignificant radiological lo the public a.ad the en.vl.ronment, t. NE.C beliens they could ba cUstrlbut to persons axempt from licoW1ing !or vivo d!agnostlc ws. Proposed Amern:fments for Permlttin the Dia:tribution of tJ111 Capsult:tS to Pr.rsans Exempt From Ucen$ing Proposed Amsndment to 10 CFR Par (4) Operating as a.nuclearpbru:macy within a Federal medical institution. The regulations in 10 CFR Pan 32 These facllities have a specific license would bo amended to add a new with tho NRC. Unclcr Uia i,ped.f!.c § 32.21., to provide req_wrements fer 1 licen:ie, the manufacru:rec OT pharmacy specific licem:e to n::i.anufac:turc, p?QF can distribute l'l!ldioactiv.. dnig5 only to proce:111, produc-e, par;kaga. repackag, persoDS authorized pursuant. to Pa.rt 35, tnmsm fer commarcial clictribution "M~w Use cf BYF,duct Material" capsules contll.l.nlng one microcu.rle < Current Nfi.C Regul~t!ons for dte carbon-14 urea, as a radioactive drug Medical Use o*Radioaer::iVE1Dro,n,

• be cll5trlbuted ttl =Y pen,c:c. for "in

~ o-vivo" diagnostic use. Tholl.8 ConJaln.ing Byproduct Material

i,r;,quiremen~ are con.,i3tent with the Curralltly, 10 CFR Pan 35 only 8':ld8ting requirements on other Ue.clS penirlti physicians who ll:I'9 authorlz.ed under ths hoad.ing "E.:icllmpl:ioDB" 1n u.sers.fc.g.* phpid.a.ns whc meet. cartain CFR Fil.It. 30. The propoi.ed regul.atio*

• training and e:xpw:i8IlC9 crlbn:ilol would include a reminder that Uceru regarding the safe we. oh:ad!oactive distributing the radioactive drug to drugs) or peISOUS wo.rki.Dg unqilt the
• penons 6:Xetnpt from lli::el115b:l.g woul supervWo;o. of an 11.utho.dzed. user to not be taliaved from other applicablE

. administer radioactlve cl:ru~lor tnodfoal F$dernl 1c.g.., FDA) or St.ate

32554 Ff:deral Register / Vol. 62, No, '115 / Monday, June 16, 1997 / Propo5ed Rules req_ui:remcnts govoming the manu&cture and dlstriburton of drugs. The NRC has decided th.at the manufacture or preparation of capsules cont:i.in!ng ona mkrocurte of ca.rbon-14 urea 5hould continue lo be p~parod by persons who meet the currenr NRC regulations to ma..u.factul"!I IUld commercially dilitrlbute radioactive rirug.1,. Thi'! NRC believas ragulatoi:y control Ls oeedeti lo provide Wgb con.fidem:e that the drug cont11i~ only one microcuric of carbon-14 u:rea and does net contain any oth..lr r-o.dioaclivo contarnioants. Proposed Amsndmsnt for Exempting "Any Pr:r5an" From Licen5ing Requirements To Rect1IVli the Drug Proposed Amendment to 10 CPR Part 30 he NRC ha.s determined that the g 1n cap~lo form pr11:51,nr., no gniffcant radiologicul s;ifoty er environmental ti:d,, and thtit it 1.:5 net n11ce::sary to :rogul:i.te th'1 use of this drug for Its radioactive component. Therefore, the NRC can not ju,tlfy

• ll'tl"-iri.ng phy,klans, or =y other person,,o meet NRC training and axperience criteria directed llt the Hnl usg of radio:u::tivg drugs, or to become a.o. "authorized user. Hence, the capsules can be distributed tn any person. However, other Fcdcral or Sbat..

aecncie!I m:,y Hmlt tbt'I recefpt 1md use c! the cnpsu}c:, in ac:cordn11c:c with thcl..t own requirements. The rcgul:stlons in l O CFR Pm 30 would be amended to add a new § 30.21, lo permit any person to receive. sse:s:s, lac, tra.o.,fer, own, or 11.cqulre r "in vivo" diagnor:tic w;e, capi:ulgi: ntainlng one mlcrocurle of c:arbon-14 urt!a without a license. The proposed regulation would include a reminder 1h31 parsons receivfng°Th~ cepsule:s would not b., rAliavod from other Federal or State law governing drugs, Further, in accordance with the NRC's provisions for rescarcli invqlving human i,ubjecl.3 (10 CFR 35.B}t 1h11 m:emption permitting ~ceipt angu:sa of the c:ap!1.ule11 for "m vivo'~ diiignostic use doe;, not extend to we of the capID!es for rasean:h involving human subjects. Any person desl.rio.g lO use the capsules for human resaa:r:t:h. would still ht, required to submit an application for a sped fie Heenw uuditt Part 35 fa o~

• to protect human subjeoctB, The phrase "in vivo diagnostic use" is being used in§ 30.Zl wtead of "medical w:e" for two reasons. Flnt, the tcxm "medical u.,e" has a.speclfl.c:

meaning and Is defined In§ 35.2 to mean "the intentional internal or extern.al adminlsti:-atlon ofbJProdUct material or the,:adiation therefrom to p.QUgnts or human I'QS'1atch 1.ubjects under the supervision of an authorized user." This term would be inappropr'!Rte. because: (1) "Medical 11.'!a" limits adminbtn:.tloo. to authorized uscn.; use of this drug would not be so Umlterl; .i.nd (2) "Medical we" includes the udm.ln!strntJoc of the drng to a human research,ubject, which would be prohibited by lh1s rulemak!.ng. Effects of the Propotsed Amendmenu Tho offoct of these proposed amendments would bll to m.a.ka the drug available lo aJ:J.Y peuon, for "in vivo" cih1gnostic: u~e, without need for an NRG or AgNement Stata liccnso. Boc:.nu&o tho receipt and use of the drug would be exempt from NRC licen~ing. Agreement States would need to make appropriate provi.ion.s in their regulations to recognize the exempt di3a:ibutlon of tho drus. for "in vivo" diagnostic use. Thw:, after the manufacture a11d distrlbudon or the drug, the NRC and Iha Agreement Stata:s woult.l not rei;ulate thou.so of the drug a; long as !ts us0 was far "In vivo" diagnostic; ustJ. Thi:!; moons that, ulld.er NRC and Agreement State regulations, primary*care physkian:s would not need to be "authon,:.ad ui;P.rs" in order to admimst!ll' the drug, and would not neccs:sarlly need to refer their patients to nuclet1r IOadicino physicians. This should result In cost savings to patlenl!i. Othtir Federal and State orge.ni.zatlons with responslbU1t1os for regu.laciilg drugs would be left to detennice and regulate who could receive and we the drug for "in vivo di:i.gno,tic U.JE!. NRC would ~ate the u11e of the drug for researc:h Involving hum.an subjects W1d111r a apeci!lc Part 35 license.

m. Summary of P.roposed Am.endiutn>.ts Manu[actu~r and DJ11r.riburrm A new section would be added to 10 CPR Patt 32 to p;mnll the distribution of the capsules to persons wbo ara e:.c:empt from lic,msing.

Section a2.21 Ra.dioc.ctr:rr:-Vrug: Manufacture. Preparation. or Transfer for Commercial Diirtributfon ref Carbon-14 Urea Capsules Not Exceilding One Wr::rocurie Each for "In Vivo 11 Dfagnostfc USB for Hamaru. to Persaru Exempt Pn:,m, Li.etIUJU1f5; ~ulremenkl for a License Pan;igraph (a] This paragraph would establish tha requb:ti:menu for appn;rvsl of a lice:tise application to manufactura, prepare, process, produce, pac:htge, repacbge/ox-traruf'ar for commercial dhtrlbution cw:bon:14 un,a t:apsulais not exceeding one mlcrocurie ear,:h fcir "In vivo" diagnostic USe, to per!!OllZ5 !1X8mpt from lk1:mJ1lng. Paragraph (a)(1J Thi11 f):aragraph would limit issuanea of an "exempt di.1tribut1on Hcen,e.. fur di,tribution of the capsulu to parao= exempt from licensing to only those who possess either a NRC or AgreQJD.1Jllt State "specific 1iC1Jnsc" Co.t possession and use of byproduct material. Pa:rag:raph (11.)(2) To as:n.U'e th"t the o,.piruls. contain no more than one mlci:oe1.1rh, of carbon-14 and present no other r'!2diologit:l!ll rlsk,, this paragraph would rsquimtha.t tbe per::ions ml'ni;f11clu~in5,md.10'f commerctally dbtrtbuUng the capsules for "in vivo" diagnostic use must also meet the requirements of§ 32.72.(a)(Z). Sped.fl cal ly, these {,lA~on."' mu.st be: (l) Regi:st.ered wiih or licensed by the .FDA" a drug manufacturer; or (Z) Registered with or lkens~ by 11 state agency as a drug manufucturer, or (3) Licensed u a pharmacy by a Stale Boanl of Pharmacy; or (4) Opamting ;i.; a nuclear phn:rmacy within a Federal medical 1.rutltutlon. Porflgraph (,i)(3) This paragraph wottld require applicants to provide evidtmee that AJach carbon* 14 11rnA r.apsu le will not exceed one mkrocu.ric. The NRC':. cvali..ation that tl:!e capsules would not rerult in a!gnifica.nt ndiation risks wus bu:sc,l on the capsules containing one m.lcrocu.ria of =rboo-14. u.re.:i. TherefoN, applicanta must dem0ll3trate that the activity of each =hon-14 c:11psule will not,;xceed ODB mlc;ro =I. e:. Paragraph (a)(4) This paragraph would-prohibit carbon-14. urea Eron:i b.ai.ng cont.ai.nad in any food, be'lerage. cosmetic, drug or othar commodity dM!gned fot ingestion or inhalation by, or topical applkatioll to. a hum.an oafng axeapt for Iha Qp:sules as de:11:rlbed in thi!, section, becausa exempt distribution ofthh: drug has only bl,en evaluated far "In vlvo" die.g:nostic 1..1.Ba m tha fo= of a capcule containing one m.lcroc:urtq of carbon*l4 l.1.t9a. Becaus~ of the capsule's "in vivo** d~stic 1.138, there 1.5 no prohibition ngiunst the capsule being co:m!:iinad with food or bev-erage at Iha time of'

• adminlstmtion so that tho cap.,ule can be ingested by the padant.

Pa..ragrnph (a)(!S) Because the exempt distribution cf this drug hu only been 9valU11.ted for "in vivo" diagnostic use In the form of a =psul1:1 i:ontain.tng cna mic;rccuris of

Federal Register / VoL

• 62, No. 115 / Monday, JUl'le 16, 191'.17 * / PropQsed Rules 3255f cubon-14 urea., thb pa.ragrapb would prohibU Incorporation of ths capsules Into aD. y rnanu!n.ctu:.eci or as.s,,m bled commodity, product. Qr dev1c" intended

!o\\' comxnsrcal di:st.rlbution. Further, althotlih the drug is being cllitrlbuted to person5 exempt £rem licell.5'ing, this paragraph would require the ca:rbon-14 Ul'llll to b. idimtified a.a radioac:tlv" becall!I~ tho drug is helng wed for Its rad.io~ctiva =tent: lher~fore, lha and user must be provided with Information that the drug contains a radioactive lll.Qterlal. Paragraph (a)[6) /\\S with any product approved for distribution to persons r;;r;empt from Hcensini. tlili paragraph would requfn:J pia?Son& who apply for a llc:,,,,;isw to manufilcrure or commerclally d.istributG thef:e cap,rul~ to au'bmH copim. of protocype labels or brochures for NRC approval. This will aliow the NRC to confirm that the labeb or brochures meet the raquiremont.s of§ 32.21a (al acid (bJ. Paragraph (b} Thi$ paragr..ph dec:lams that the regulatioil.11 do not rclhrve licenseea or license eppUcimts from ccimplytng with applicable FDA, other Fedoral, llll.d Smur

requlremenui governing the manufacture and distribution of drugs.

Section 3:Z,21a Same: CondiUons Qf License

• Th.ls section would ei.tablfsb thg condition. required for a Ucense ta commercially distribute the capsules to persillg Hl.lmllll Subjects, and Mu.st Not Ba Jnll'Oduc:8d into Foods, Buvaragu, Coato.!'JtiCB, or Other Drugs or Medklnals, or in1o Product; M.anu.!actu.red for Coi:nm1nclal Di:rcr!. bu tion."

The intont of the requlrcamsnt.set out in (b)(i) is ta make clei,r mat the CZIJ?llllle mu.st remain In the form of a capsule and is not to be combined with one of the lhtad Hems such u food or beveragea which would rMUlt In. a mdfoactlve product other than in the form of a caps.Jo for CQ,tlUD.erclal dlstrlbutlon. Became of the caprule'a 0 in vivo" diagn0.1Uc use, there is no prohibition a&afnst the capsule belng c:onibinod with food or beverage at tho time of Cldmmiatration so that the capsula can be ingQStad by the pa.Uaot. "In Vl1t1::>" Dlagriostlc U11t1 by Pt'/l':SODS E:rempt From Licensing A naw section would be 11.dd~d to 10 CFR Patt 30 to oxampt my person from NRC or thn.l\\greement Statet n:gu)atlons to receive th.a drug for "in vivo" dlag.no11Uc use for hll.IIUlWI, Secdon 3D,2Z Radioactive Drug: Capsules Containing Ona Microcu..dr::: of Carbon-I-! Urea for "In Vfvo" Diagnostic Use for Humans: Would Be 11.ddacl To Perm!, any Person To Receive the Capsul~!: Paragn1ph (a) This paragraph would provide an exe.i::aption tD a:ay pernon f.rom the mquirernents for a lic:aiue to :i:,:,eeive, po:ueu, U5S, U'llilS!cr, OW'll, or acquire capsules containing one :in.ic::rocurle of caibon*14 urea for "in vivo d!agn011tic ~oses. It :should be noted that the 'tra:c.af11r in th.a parugraph d0$$ not lnclude.. transfer !or cammen:W dlstribu.Uon, which-is covered In pa.ragraph (c:J below. Paragraph (b} Thls paragraph would Qltlllb\\ish that per.semi nxempt ftom l!caming would be prohibited from u.s!.ng the drug for rue.a:rcb ln.volviDg humans sublects. A specific Part 35 llcens11 would bo nooded lo use the dn1g in my research Jnvolv1.ng human subject.It. Pa:ragm.ph(cl This paragraph would apeeify thnt a specific liC9Ma la needed to manufacture. prepaie, p.roc:Ga&, pr6duce, package, repackage er tnm11fer 11ui:h. cap.rules for commercial diatrib\\t'tion.. Parngra~h (d) This pantgraph d.aolues lrult the regulations do not relieve end usaa ftom complying v-rilh._pplicable FDA, other Federal, or Sta.ta reqummients governing the receipt, ad.m!n.tatration,

md use of drugs.

IV *.l\\ireement Stale Compa.tih.llily Under tbR Atomlc Enargy Act, certain n.,gulatory functions arc ra11111Yed to the NRC. Among ~ a.re the distn'bution of products tc _rlil.l:SOns exempt from licensing, as r:l11lC\\lSSed in 10 CFR Part 150. Honea, the proposed rule, if .adopted, would be a DMsion 4 ltm of compatibility, with regaxd to th. man'Ul'a.cnJrc and i::om~etelal distribution of the capsules (10 CPR Par 32), Because of the need for natlonwide consis~nay 1..n the we of products which ere widely disll'ibuted, the proposed rule, if a.doptad, would be a Division 1 item cf compatlbillty wich regard tO po1m,1ssion and use (10 CFR Put 30}, Therefore, ths hgreement States will need to m.ili appropriate provisions in their regulations to allow any parson to receive capsules contain.In~ one m1crccu.rie of carbon-14 urea for "Ill viva" diagnostic use without D.Btld lo-r a llceDJle, V. E1ect:run.h; Ac:a::ss Commcnu may be :rubmlued el8Ctro?!kally, i:r:i. either A.'-:CU text or WordPc.rfeict !onnat (veniion 5.1 or lat,u], by c:tll:lng ilia NRC Eleet.ronlc Bulletin Bcatd on FeidWorld or connac:ting to the NRC lnl<n-ac:tivo rulemald.ng web site, "Rulan:u:u::ing Foruni." The bulletin board may be 11cccsaad usi.D.g a. ~,oi:i.121 comy1.tlfir, e. modem, and one of the commonly a.vnilahle cammu..nicatioDJJ software pacl:.ager;, or directly via Intemet. I! uaiag a pe:r:son.al computer and modem, the NRC :iub3y5tem 011. FedWorld c::::i.n be 11cci:i11sad diroclly hy dial.i.0.g the toll free oumbcr: 1-eoo-303-9872. Communic.ri.tion aoftwm-e parameters should be set 84 follows: paricy to none, data bits tD 8, and stop bit_s to 1 (N,s,1). Using hNSI or vr-100 teiminal emulation, the NRC NUR.ECa and Reg Guides Car Comment subsyatez:r: can then be accessed by salacting the "RuiCll Menu" option from the "NR.C Mein Menu.." For further Information nh.;,ut options '!,vailable for NRG al FedWorld, comult tho "Help/ Info.o:xu,,tion Cent.et" from the "NRC Ma.1.D. M@lL" Users \\\\rill find the "PedWotld Online User's Gu.Idea" particulm::ly helpful. Many NRG ~bsystems and databases aho bAvo a "Help/Information Center" optlon that is b:tllornd to the pan!i:ular iru.b:lysmm..

32558 Federal Register / Vol. 62, No. 115 / Monday, )une 16,

• 1997 I Ptoposod Rule&

The NRC,ubsystem on FedWorld CIU1 also be accessed by a dl.raa.-dlal tale~hone number for the main Fed World BBS, 703-3Z1-S339, ot by using Tohuit via lntcmct. fodwodd.gov. If using 703-321-3339 to contl!Ct Fcid.World, the NRC aub&ystam will be accessed trom the mm FadWorld menu by selecting the "Regulatory, Government hdmin!11t:radon IUld State Systems." then selecting "R.egul1t0ry Information Mall. At that point. a menu w-111 be di.splayed that ha an option "U.S, Nt1cli:ar Regulatory Coill.llll!lllion" th.at will tal::.e you to the NRG Online main menu. The NRC Online llJ:'C?l al.so= be accc.s~ directly by typing "/go nrc" at a FedWorld eor:nm.a.nd line. If you ai::cesa NRC from Fed.World'! Ol.B.in DlCilu, you A:.:y rvh2.r:r:L to l?cdWorld 'by aelactms the 9'.ietum to F'edWorld" option from. the NRC Online M~n Menu. However, if you access NRG at FedWorld by using N:RC's toll-free number, you wfll have full acceu to all NRC,ystems but you will nol have ac:i:cs* lo the main FedWorld system. If you contact Fed World u,i:ng Telnet. you will see the NRC a.re.a and meulll, including the Rules menu. Aliliaugh you will be able to download documents and leave massages, you will not be ahlo to -write comment.. or uplQ4d files (commanb). lfyou contact FedWorld using FTP, all files C!1U be acces:sed and downloaded hut uploads i,re not allo...-ed; all you will see is a lii:t of ftles without de.,crtptlon., (normal Gopher look). An. f:o.d11x file listing all A files within a subdl.r-ectoxy, With ., descriptions, is lncludod. Th0.t'D is a 15-milluta tima limit for rtP acce1111.. AlthoUAA Fud.World c:.m be llCC:OMed through tiia World Wide W11b, 1ika FrP that mode only provides a.c::cess for downloading files and dogs not display the NRC Rula:s meu,u. You may aho ~~the-~** interactive rulemaldng web site through the NRC hol'Xl.C p~s (http.1/ www.nrc.gov}. This site provides the same ac:=s a, tho FedWorld bulloUn board, illclud.lng the facillty lo upload cox:om.nbi iu £.ltcG (aJ:ty format), 1£ yew: web browser supports that functlpn. For mare informat:loa on NRG bulletin hoards c:all Mr. Arthur Oe.vi11. SyataJll.lll Integration IUtd Development Bnmch, U.S. Nuclear Ragula.lory Commualou, Wa.sbl.ngton. rx:: Z055:S, telephone (301) 415-5780; e-mail AXD3@mc.gov. For information about the lnteractive rulemaling site, can bid Ma. D.uol Gallagher, (301) 415--6215: e:mBil CAG@m,;;.gov. VLFindingofNoSfgnificmt Etrri:ronmental Impact Aviill.abillly The Ctimmi~iou hu determlned tmdar the National Environmental Pelley Act of 1969, 8.5 lmll!lllded, at1d the Comm!si:ion'i: rogufatio~ f:o. Subpart A of 10 CFR Pan 51, iliat the proposed amendments, if adopted, would not be a major Fader,d action 1igni.Bcantly affecting the quality of tha human environment; the~fore, a:ci 11nvfronmental Impact statement ls not n,q~d. The prop3ad ruli, would establish requirelnents for the n:utnu.facture and commercial d!stributlon of 14 C-urea capsules ro petsons exempt from licen.:sing and establish regulatfoD.i to permit any psraon to rccslva tha capsu.11116 without an NRC llceJl!le. The Com.mls:iion believes t.h:it th0 radio11.c:ti"c componcnt of this dru~ presents no slgni1'.amt radiaUon nalc and, thercifote, 1'1!:gulalory conrrol o!the "in vivo" d.1agnost1c use of the capsulea.fur radiation saf'.aty ia not neci=sary, It l:i ~octcd that !his proposed rule. if adopted, would not ca.\\.Ue any :significant 1l::u:::rcasc in

• t.l.dlation. exposut"Q to th1;1 public 01' radiation releas1ot to tha environmant beyond the expasurea or releesu rQlilult.ing from I.he use of the Carbon-14 cap.sules under the cw:nmt regulal:iom.

Abo, it is expectad that there would be no non-radiological impacts if the propoaed rule is adopted, The draft environmental assassment and finding of no aigi:uficant impact an which thJs determ1nar.lon 15 based 15 available for inspection at th. NRC Public Document Room, 2120 L Stnrat NW.* (Lower Leval). Washington. DC. Single copie11 of the draft ~virollilllltlW assessment nt1d th111 finding of no 11lgwfltau1.t i.tqpact III!! aVllllii b le from Dr. Anthony N. Tse, Office of Nuclear Regulatory Research, U.S. Nuclear Regulatory Commission, Wa.sbington. DC Z0!!i!55-0D01. tel1!1phana (30l.) *'15-6233 or e-mail at ANT@DJ:c,gov. VII. Paperwork lb!duction Act Stahl.m.ant This proposed mle aJill;!?lds infor.maUon collection requirements that are :ru.bject to the Paperwork Reduction Act of 1995 (44, U.S.C. 3501 et aeq.). Thia rule hu been aubmitt.ed to the Office of Management and Budget for review and atip.roval of thtt information coll~tian requlremants-Thc public rcportlng hw:don !or l:hh collection of 1nformat!on is estl.tnated to average lB hours per rmpon.se, Including the tl.ma for raviewing imtructlons, 1n1atching 11xis!ing data I .sou:rcc:r, gathmi.ng md matnt.alnf:o.g the. data needed. and completing IUld

• re11'!8'Wing the collection of in.fom:i.ation.

The NuclelU' Regulatory Commission la sooldng public commant on the potential impact of the collSt:tio.o. of lc!ormation containad ill tha proposed

ru.lc lltl.d on the f'ollowing l:,:nu;a;

1. Is the propoi&d collection of to.formation n~essary for the p.toper performance of the func:tfous of tha NRC, includio.g whgthor the.lnio.n:a.a.tion will have practical util.Ity?

2. Li ths atim.ate of th.a bu.rd.au conect?

3. Is thet11 a way to enhance the quality, utility, and the cla:qty of tho information to be collected1.

4. How C!lll tho burden of the collactfon of in.formation b'ii rnluimlz11d.

locluding the use ohutomiued collection techniques? Sond com.mcnls on m:1y ~ac:t of thla proposed ioformatlcn collectlon, including ausse.at:iona for ~~ucring th. burden, to tha In!ormatlon and Records Management Br.inch (T-6 F:Ja), U.S. Nuclear Reogu]atory Com.mis.non, WashingtOit. DC 20555--000'l, orby Intun:u:rt elect:roclc miill at BJS1@NRC.GOV: and to the Desl: Officer, Office of lnf'ormadon and Regulatory Affuirs, NEOB-10202, (3150-0001, ats~o11, 1md 3150-0120), Officlil of Managemumt and Budget, Washington. DC 20503, Comments to 0MB on the information colllilctions or on th* above iuuu should be submitted by July 16, 1997. Commlilnts r11ceived e.ft.ar thia data will be coll!lidered if it Is practical to do 10, but assut1u11:e of co%1${cleratiot1. c:mnot be g1ven to c:ommenf.3 received after this date. Public Prot.Rr.tion NaUficatlon Th.a NRC may not conduct or aponsor, and a peI:!lon is not requued to respond to, a collecUon of Wo.rm.a.tion unleu it displa;13 a cunently valid 0MB control nu.mbc.r. vm. Rsgulatory Analy,lia The NRC has propartad a rogulatory analysis far the prnposed rule. The analyels examinea the ~neftb IIJld impeu:t, considered by the N.RC. l'ho regulatnry analyaia ia available for inspection 11t the NRG f"ublJc Document Room, 2120 L Street NW. (Lower Laval), Washington, OC. 51.agla :n!:L of the nigulatoty ~yais a.rs a le fto?A D,:,.t\\nthony N. T:se, Office of Nuclear Rogulatory Rasea.rch, U.S. Nuclear Regulatory Go:i:omlaston, WMblngton, DC 20SSS--0001, telepbo11a (301) 415-6233 or e-mail at ANT@n.rc.gov, IX, R.egnlatory Flexibilily Certification. As. raquirad by tbs Regulatory Fle.xibllit:y Act o! 11'.lB0, 5 U.S.0. B0S(b),

Federal Register / VoL 62, No. 115 / Monday. June 16, 1997 / Proposed Rules 3255 PART ~RULES OF GENERAL APPLICABILITY TO DOMESTIC LICENSING OF BYPRODUCT MATERIAL PART ~z......5PfCIAC DOMESTIC LICENSES TO MANUFACTUR2 OR TRANSFEA CERTAIN ITEMS CONT A.JNINQ BYPRODUCT MATERIA the Commls:ilon certifies that this rule clor.s not hava a signiflew1t economic Impact upon a substantial number of .ll1'1Jll\\ entitiH. The pro.po5<11d rule would pennH physicians and 0th.et health care providers to uso llll additional 1, The auihorlty citation V>r Part so diagnostic test without h~ving to obtatn c:oru.l.Quas to read as follows;

4. Tbe authority citation for Part 3Z continues to read as follows:

a.a. NRC llCl!Wie. thus, would ptov1do cost Hvings to patients, Insurers, and tha health cars tndustry. Any small entity subject to this regulation which determ.in1111 that, hocauH ofits slze, It is lilcaly to boar II dl:sproportionate adverse economic Imp.act should notify tho Commission of this.in a comment that l.o.cllc:aw; thafollowing: (a) Tha llcc.t1.5a1;1's size a.nd how the re'1,l].ation would result in a significant economic: burdan upon the licensee u compared to~" economic burden on a larger Uconaae. Amhorlty: S.:a. 81, l!Z, 161, 182, 183, 186. .08 Stat g35, 948, 953, 9M, GSS, u 1.1:xun:td~. 1111c. :z311, 83 Stat. <<-<<. u u11undllli (-42 u.s.c. 2111. 2112, 2201. 2232, :123:S, 2238, 2282]: aao. 201, as amancied, 202, 20s. 88 SblL 1242, " =ended, 1244, 1246 [42 U.S.C. S841, 584:.1, 5M!S). Scct.!on ao. 7 al:ig L,sued undar Pub. L 9!-eo1,,ec.10, 512 Stal 2051 u amended by Pub. L, 102-too, sec:. 290:Z, 106 Stat. :nz:s, (42 U,S.C. 51.1:!l). Sectlnn S0.34[b] aho l11Sued under sec. 184, 68 Stat. g54, u =ruiad. [42 U.S.C. :223.. ). Sactlc,n so.at al..::, 1"wtd ~ .. t.:,r ~ 187, !SB Stat. 9!!.5 (42 U.S,C. :ZZ37).

2. In § 30.8, paragraph (bl ls revised to read M follows:

1!.11thorlt:y: Sa:s. 81, 151, 1B2, 183, 88 Stat 035, 948, QS3, 05-1, u amended (42 U.S.C, a111, 2201, 22321 22:13); slljj, 201, lffl Stat. 1242. a, =da:ii (42 U.S.C. 5841).

5. In § 3Z.8, paragraph (b) ii; revised I rea.d a.JI follow.ll;

§ 32...B Information c.ollfl'C110n requirements: 0MB app.roval. (b] How the re~ons cou1d ba modifi"d to tal::o mto account tha lken5ee'a Jiffenng.necds or Cllpabllities, § 90.B lnformst}Q" colle-c.tlon (c) The benefits 1hat would accruo, or reqUll'llmenJS: 0MB ilJ'Pl"Q'wal. (b} The Approved i;iformation collocU011 requireme.o.l'J contained in this pa.rt appear in §§'32,11, 32.12, 32,14, 32,1!5, 3Z,1tS, 32.17, 3Z.18, 3Z.19 32.20, 32.21, 32,21:i, 32.22, 32.2!1, 92.2 32,28, 32,27 1 32.29, 3Z,!51, 3Z.S1~, 3Z,5 32.53, 32.54. 32,ss. 32..56, 32.57, a:z.sa 32,61, 32.62, 32,71, 3Z.7Z, 32,74, and 32.210. ths detriments that -would bo avoided., U the regulations were m.odiflan as (b) The oppcoved informaUon suggeatecl by tho Ucensee. collection Nqui:emcnts contained l.n (d) How the regulation, as modified. thl.s pa.rt appear 1.n §§ 30.9, 30.ll. 30,15,

6. A new § 32.21 Ill added to teAd u

!ollow.s: would more closely equ:ili.ze the impact 30.18, 30.lg_ 30.20, 30.21, 30.32, 30.34, of ntgulations or create more eqwtl

JCl.35, 30,36, 30.37, so.ius, 30,41, 30.50,

§32.Zl Rac:ncar.t!Ye drug: Manu1acture, accasii to the benefits of Federal 30,51, 30.55, append lees A and C to this preparation, at transfer for cammerolal ..,o,.. dlstrlbuilon of C!ll'bon-14.urea cap-,;ules m" progr,mui as opposed to prcv1dl.o.g r-~ ez=-dlng one mlcnx:utleeach for"ln special advantages to any individual or --lvo" dl-n--'"c ***- f,.. u-*- t........,., 3, A new§ 30,21 is added uuder the ..., """u - e 11 ""'"* 0 r-*-1 group. exempt from llcenJ1ln9; Aequlremi,nta ror i (e) ttow ~e ~1at1on. as modified, undesignated center headl.D.g llcense. Would at!ll *dequa*-ly p....... *--t public "Exem.ption.5" to read u folfoW3: ( ) A_ U ~ = a n..o app *cation.for a ispecific health and safety. § 30,21 Radl081.'dve drug: capsules license to manufacture. prep~. X. Bacldit A.nal)'1is containing one n,lcmeuJlg of ca.rbcn-14 proceas, produc*, pac~c, n,packagc,, Tue NRG has det1mnined that the Utea for In,.+.,.," d~gnotdfc uae Tor !.rall.1fer for cam.mercta 1 rustrlbutioo tiumam,.. carbon-14 mea cap,ule11 uot excood.lng badfit rule, 10 CFR !50, 1o9, dcea 110t (a) Except as provided in paragraphs one microcurie each !or "in vivo" apply to thl,; rule. and thlill,lfore, a (b) and {c) o[thts section, any p8Dcn Ii diagnostic use, to persona n;empt from ~t analyais is not n,quired. bccau5e axampt from the ~ui:rumsnta £or ta licolll!ing under§ 30.Zl or the these amendment! do not Involve any llccnsa set fonh [n Section 81 of the Act equivalent regul*tion.s of an Agreemc.a1 provbions fu.at would Impose bc,_ckfiu; and frora tha ?9g\\llations in this part and. Sta.ta will bo approved If: as deftned 1n 10 CFR 50.109(a)(l).

• pan 35 of thu chapter pl"Ovlded thst (1) The applka:o.t "-tuiIH tha gelll!lra Li.It of Subjects 10 CFR.Pa.rt JD Byproduct materl_a.I. Crhninal penalUcs, Govm:nm.e:at contri,.cts, futergovemm~ relations, hotopes,
• Nuclear materials, Radiation protection, Reporting and r,.cord ~i.rtg

?O<J.l.lirem.entll. 1 o CFR.Pcm :,z Byproduct material, Gl'iminal pllna.Uiff, La.b8ling, Nuc:laa.r mat.ni"*ls, Radiiltion protectlon, Repon:l.ng and

record.keeping rcqw,emea.b.

For the rauons set out.in tho pramnble and tm.r the authority of the Ato0:1{c Energy Act. of 1954, 8J Blllil'Ilded, th.c Energy Reorganization Act c;,f 1974, u amandeid, and 5 tr.S.C. 553, the NRC

b. proposing to adopt the followiog

.AJ:r.umdmentB to 10 CFR Parts 30 imd 32. mch per,on rooetves. poase1111es, uses, requ1.rc.ml!lllts.:speciB.ad in §30.~3 o!thi f:ra:r:1sfurs, owru:, or acqulrea CUDOD-14 chapter, provided that the requirement 1.II1!l8. capsules, not exceeding one of§ 30,33{a) (2).and (3) of this chnptat microcuris each, for "in viva do nae apply to an appllcatio11 fo? a dii;gn.05tlc we for hum"Sl1L licei:ue to l:ra.tulfer byproduct aiatma.l [b} Any p11rraon who* desires to use the manufactured, p.tepamd, procesMld, capsules for :research h1volving human producad, packaged, or"'rapacbgsd. subjects ah.ell apply for 1Wcl t'IICC!vs.. put!!Uan.t to a license inned by an speclflc license punn.lllllt to pa.:rc 35 of A~nt State; this chaptsr. {Z) The applicant maets the (c} Any per1SOD. who dmue, to requirem11nts unclar § 32.72{1il)(2)1 manufuc:ture, prepare, pro=. p:t,:iduce, l3) Tho applicaDt p~vid~ evidence. p11.cl::.age, x,:,packags, or a,mzfer for that sach carbon-14 u.tea capsula will commetclal disu:ibutlon such capaulas-

• not ~eel ono microcu.rie; shiill apply ibr md receive a specilic (4) The ca.rbon-14 urea h tiot I.iceD.;a p~uant to § ai.21 of this conWx:i11d In any food, beveragv, cha:etcr, cosmetic, drug (except as dmcrlbed ln

[d) Nothlng in rhls sat:lion NllE!VBS th.bi section} or ol.hel' commodity persons from complying with applicable de1igri.ed (or !oge.stion or lnhalatfon by, FDA, other Federal, alld State / or top!cal 11.pplicaUon to, a hume.n bein: raquiramm:its go"Vemlng.teceipt; (S) The carbon-14 urea ia_in the fQrm 11.dml.n!stratlo:Q, and 1:115e of~- C!f a capaula, identified as radioaativa,

32558 .Federal Register I Vol 62, No. 115 / Monday, J\\IM 16, 1997 / Proposed Rule:i and to be uaed for its mdioacttve properties, but u not. incarporatecl into any manufactured or 1153embled commodity, product, or device lnlaadad fOE commercial distribution; ud (S) The applicant,u'bmib copies of prototype Jabel.s and brochures and the NRC approves these labels iu,d b.roch u:res. (b) Nothing in this 111etlon raliBvcs tho liceosee from complying with applicable FDA, othsr Fedaral, and Stata req~ governing ~-

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

§ 32.21 a Same! Condltfons of llo!mailil. Eachlicenselssued Uildcr§3Z,Zl 1s aubjecl to tha following conditions: (a) The immediate conta.tnei o! the c:apsuh:(s) must rte:11" a t:h.1.rable, lagi."'ble abel which: (1) Idantif!.8!1 ths ra.d.iei.lotope, tho physical and chemical form, the quantity ofndioactivity of each caprullil at a specific: date; a.nu. (2) Baa.rs tha words "Radioactive Material." tb) In add.ition. to thg labiillng tnformaUon required by ~g:nsph (a) of this r.actlon, the label affixed to the imm1o1diar. conlalner, or 8.l:1 accompanying b:rochure also must: [1) State that the contents are exempt rrom NRG or J\\greemcnt State Ucrm:sing requi~menb; lll.tld {ZJ Bear thi, words Rad1oact1vc Material. For 'In Vivo' Di.ignostic Use Ooly. Tbh Material Is Not To Be Used for Rc,oo.rch Involving H~ Subjeclb and Must Not Be Introduced into Foods, A fJeveragell, Co,mal:ica, or Othar Drugs ar Medicinals, Of lllto Ptodw:u Manufac:tumd fer Commercial DatribuU01+," Dated at Roc:l;villa, Maryland. thb 10th cloy 0U1.mlf, 1997. For the Nudaar 8cgulatocy Co~!ol\\. Joru:i c. Royi.,

f.

s<<rcr.ary of the: Cammisslim. (FR Doc. 97-1!5(197 jiled 6-13-9!1': a:45 aml lllU.lN(] COOi!! l"!llll-lll.... DEPARTMEN1' OF STA~ Bureau or Consular Atfafrs 22 CFR Pan 22 [Public Natic::a 2555) Schedule of Fees for Consulat Senrlcea, Depertment c,f $tata and OVerseD Embassies anG OOnsulate:s,. Diversity Lottery ~ AGENCYt B~u of Coi:au!ar A.ffalra. Stale. ACllOH: Proposed rule. SUMMA.RY: On Septamber 30, Hl96, the Immlgrotlon and Nationality t,,ct ON.t\\1 war; amended by !!llC!tlon 636 of tho lllcg111 lmmfiiation Reform and Immfgrs.nt R.esporuibility Act of 1996, (llRIRA) to authorize the collection of a foe for adn:iinliiteting th11 divimdty tmm!grimt visa lottery. The DspartmcJlt IA, th1m1fore, amending their regulations a.ccordmgly by in.rtitut.ing a $75.00 Caa, in the namra of a su.rch.arga, to be paid by applicant, issued diversity immigrant visas. Collectlon of the fe.-i would con:u:i:11,nce as of Octobet 1, Ul97. DATES: Written comments 1hould ~ no,lved by July 10, 1997, The anticipated affsdive date of the final rule ls October 1, 1997, ,6.DDRi.SSES: lntensal"d pet.o.tl.S arc invited to submit comments to: Office cf the B.xecutlvo Director, Bureat1 of Can:sular Affa.In, Room 4820.1\\, Depa.rtolant of Stat~. Wasb.lngton, D.C.

Z05ZD, FOFl FURTHER tHFORMAT10"11 CONTACT!*

Sally Llght, Office o! the Executive Director, Bureau of CoDSUlu AHaln, telephone lZOZ] 617-1145; telefax (202) 647-36,17. SUPPLEMENTARYIHFORMATION:Tbe Departm.anl is fn.sUtuling a new fee, in. the nature o! a 81.U'Charge, to be paid by app licat1 ts fur di venity im.rnlgrant vis.u:. Thu additional fee wJll recover the full coRl:Js of the visa lolliuy conducted pllfflu.a.nt to INA zo3 and zaz, 6 u.s.c. 1153, 1202. from thMe SUCC8l!Sful lotte.ry entnmts who actually apply !or divers(cy visa,g, The tiw was authorized by !!eCtion 631:1 0£ the DI~ UlllD1gllld011 R11forrn 11nd Imml~nt Rallponsibility Act of 1996, Pub. L 104:-:z.oa, 110 Stat. l00S-703-704 (Sepl 30. 1996). A aingla fee imposed on actual divvuity visa aa~~e-!.:ill ensure that th.a costs of 11

• g the lottcty and allOC4tlng di"lef3ity visa.a aie recovered from actual w;ors of the lottery, while avoidlng th.a Impracticable impo:rltion ofa fee on all v:iu lottary @!:rants (technically. visa "petitioners"). Tho lmposll:ion of a fe-e on all entmnu rather th11u actnal applicants is not feasible, given the millions of entrant!!, the problem.a of ccllm:tlng a uniform fee from individual., all over tho world (who will have: Var:riilK accesa to U.S. orothar int.a%nal:l.cu::ual cu:min.cy ). and the bwden of having to collect and accou:nt fw what would bes. vary amall foo.&om. 11.

Iatgo number of pe:r10n.,, Roughly seven million ent:m.nts have ent8?8d tho 1998 divlS.tl.lity lottery. Appro:dmately 100,000 of tho,e i.will b8 invitad to iipply for a vi11a, and of those, appt"O:d.mately 87,000 will apply and pay the fee/l'be Department's projected coot to adminlster the 1998 dlvarr.ity lottery is about.sa,sao,ooo, wblch will ba cuvered by the diversity visa surcharge of S75,00 ProvisioI). hu already been i:i:w:le in the visa regulaUons (ZZ CFR 42,33(1)) governing the diveui.t;y vi.u. lol:ta:ry !or a. fee of this natUie. (St:!8 61 FR 1523,) Thus no regulatory amendments other than an ada1t1on of the Schedule of Fe-83 for Consular Servlces published at 22 CFR z2.1 are required to establish this fee. The new f4HI is bairlR added as item 11 umber 19 011 the Sc:hccfule of Fee:s. This will locate it lnnnediataly b"font the other fees for immigrant vlsu, which diversity visa applip:lnt.s: will ilio be ~uired to pay (i.e., before the :f'fla for immlgrant viSJi appli~tion and wuaru:e}, With the exc:eptlon of nonimmlgrant VlH. rec:iprod.ty fees, which arei est.abllwd bn.sed Oll the pi;actlCC3 of other count:riaa, all coruiular faaa are establishetl on a basts of cost recovery and in a lnlll:lller consii:tent with general u6sr charges pncc1ples, regardlees of the specific !ltatutory Alltborlty und8l' which they are promulg11.ted. The proposed fee, Is con11isumt wjth f.hesg principles and the gwcumce in 0MB Ci.rc=uw-~s, which addres,ed th.et establlahmsnt of user charges. The fee la bUlld on a cost* of-service study U6i.ag fiscal year 199S data Huit documanuid and pref ecuid into fucal year 1998 the ciliect and Indirect coi:ts associated with administration of the dive111ity viM lottery, so aa to capture the full cost of service. Proposed R.ule This rule is not consid~d to be a major tule for purposes of E.O. 12291, neil:' la it wc:pacted to hav11 a siillilicant impact on a substantial 1:mmbar of small entities under tha c.rirerla of the regulatory Flexibility Act, s U.S.C. BOS(b). This rnJe does not impose information collac::tion rnqulromonb u.nder rhe provisions of the Pnperwork Reduction.Act, 44 U.S.C. Chapter 35. This rule halibeen reviawad as required by E.O. 12988 and determined to be In compliance the;rewith. Thia rule lb exempt from review under E.O. 12866, but has been :i:ev:iewed intemally by the Depara:i:,,ant to en.auni consiatan.cy with the objectives thsniof. List or Sllbjecbl In Z2 GfK Part zz F'ees. Foreign SSIV.lce, :rusports a:ad ' vi:sa5, Seheduls of feaa for C10ii.sular servio:=s. In view, of tha foregoing, 22 CFR 1s propoa~d tci l:?a a.m~ded a., icillows: PART 22-{AMEHDED}

1. Tha authoricy c.ita.tiou £tll' Pan 22 is 1"8vi&ed ta ~:

DOCKETED USNRC 1~~t~IMERETEI "97 JUL 16 P 3 :58 The Breath Test Company OFFICE OF SECRFTARY DOCKET !~ Gs~.,f H *icE BRA, CH DOCKET NUMBER July 16, 1997 Secretary U.S. Nuclear Regulatory Commission Washington, D.C. 20555-0001 PROPOSED RULE 30 J32; ( 1o utn :i.ss:i.) @ Attention: Rulemakings and Adjudications Staff Re: Comments on Proposed Rule Regarding "Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea" 62 Fed. Reg 32552 Qune 16, 1997)

Dear Mr. Secretary:

MERETEKdiagnostics, Inc. (MERETEK) appreciates the opportunity to submit comments to the Nuclear Regulatory Commission (NRC) on the proposed rulemaking referenced above. MERETEK is a privately-held Company formed in 1993 by BCM Technologies, Inc., the technology transfer subsidiary of the Baylor College of Medicine. For the reasons discussed in the attached comments, we encourage the NRC not to promulgate the proposed rule in its present form, but instead to address the regulation of this particular diagnostic procedure as part of the overall effort to reform 10 CFR Part 3 5. If you have any questions, I can be reached at 615-333-6336. S inz:, ) ____ _ Kerry C. Bush Chief Operating Officer Corporate Offices and Breath Test Center 618 Grassmere Park Drive Suite 20 Nashville,Tennessee 37211 Phone 615*333*6336 Fax 615*333*6202 Breath Test Center and Research Laboratory Medical Towers Building 1709 Dryden Road Suite 1513 Houston.Texas 77030 Phone 713* 799*1282 Fax 7 I 3

• 799* 8395

J.S. NUCLEAR REGULATORY C0MM1~10<, DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSION Document Statistics Postmark Date H D trn 1 fa '6 / CJ 1 r I Copies Received __ ___:/ ___ _ ,\\dd'I Copie~ Rep7oduccd __._..__ __ Special Distributio;i_:fse1 TM, 'P_I DS_

I. MERETEKdiagnostics, Inc. Comments on Proposed Rule Regarding "Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea," 62 Fed. Re1:, 32552 (June 16, 1997) Summary of Proposed NRC Rulemakini On June 16, 1997, the NRC published a proposed rule that would entirely exempt from NRC regulation the distribution and use of capsules containing one micro curie of Carbon-14 (14C) urea for in :yiyQ diagnostic testing for the presence of bacterium Helicobacter pylori (H. pylori), a cause of peptic ulcers. 62 ~- ~- 32552 (June 16, 1997). While the manufacture of the 14C capsules would continue to require a specific NRC license under 10 CFRPart 32, any person otherwise authorized by federal or state law to receive, possess or administer the capsules could do so under an NRC exemption. Physicians and non-physicians could receive and possess the capsules so long as they were authorized to do so under other federal or state laws. In addition, all NRC or Agreement State regulation over the receipt, possession, and administration of the capsules would be eliminated. MERETEK has a number of significant concerns with the proposed rule and recommends that the NRC not issue the rule in its present form_ll Our specific comments are provided below. 1/ MERETEK is the manufacturer of a pharmaceutical containing Carbon-13 (a stable isotope) also used for the in yjyQ. diagnosis of H. pylori. Because our product is a stable isotope, it poses no radiological risk and is unregulated by either the NRC or Agreement States. MERETEK has a commercial interest in the outcome of this rulemaking. However, we believe that there are a number of significant technical and policy grounds for not issuing the rule in its present form, which are independent from our particular corporate interest.

II. Relationship to Part 3 5 Refonn Initiative The NRC has undeiway an initiative to reform 10 CFR Part 3 5 governing medical uses of byproduct material. The proposed 14C rule represents a piecemeal effort to respond to a narrow rulemaking petition which addresses a single type of nuclear medicine diagnostic procedure. It does not take into account the many other nuclear medicine diagnostic procedures involving low risks of injury due to radiological exposure. Nor does it take into account the significant resources that have already been expended and the planned efforts by the NRC, the medical community, and other stakeholders to achieve significant improvements in the existing 10 CFR Part 35 regulatory program. The issue of reduced regulation of the receipt, possession and use of the 14C capsules is applicable to the same extent for virtually the entire range of diagnostic radioisotopes used in nuclear medicine. All of these materials should be treated comparably and efforts to reduce the level of prescriptive regulation should be undertaken in a comprehensive and uniform manner. Indeed, the NRC Staff has already proposed to "subsume" various other specific rulemak:ing efforts into the overall initiative to revise Part 35, rather than continue to separately pursue those individual rulemakings. These include, among others, rulemak:ings on relief from requirements governing mobile nuclear medicine services and revision of brachytherapy procedures. See SECY-97-062, March 14, 1997, p. 3. Furthermore, the medical community has strenuously sought widespread reform of the NRC's medical regulatory program, devoting substantial resources over the years to this effort. 2

The NRC has now concluded (through its Direction Setting Issues (DSI) initiative), that revision of 10 CFR Part 3 5 to establish a risk-informed, performance-based regulatory program is a "very high priority." See Staff Requirements Memorandum "COMSECY-96-057 Materials/Medical Oversight (DSI 7)," March 20, 1997, pp. 1-2. It simply makes sense to address this single diagnostic procedure using 14C as part of the overall Part 3 5 revision effort. ill. Absence of Any Training or Qua)jfication Requirements The nuclear medicine community has consistently taken the position that nuclear medicine diagnostic procedures present a very low health risk when they are administered by trained and qualified medical personnel. Under the proposed rule, any physician or allied health care personnel may administer the test regardless of their background or training in radiological health or nuclear medicine procedures. Indeed, physicians untrained in nuclear medicine would have full access to and could administer the test. A fundamental tenet of proposals by the nuclear medicine community for regulatory reform is that an appropriate function of the regulatory regime is to assure that personnel handling and administering radiopharmaceuticals meet certain basic training and qualification requirements. The proposed exemption for the 14C diagnostic procedure would impose oo training or qualification requirements on users. In her comments on DSI-7 relating to NRC regulation of medical uses of radioisotopes, NRC Commissioner Greta Dicus recommended that for low-risk diagnostic procedures, the NRC Staff should: 3

consider alternative regulatory schemes that retain reID,Ilatoiy oversight but in a cost effective manner consistent with the lower overall risk of these procedures. Memorandum, Commissioner Greta Joy Dicus "COMSECY-96-057 Materials/Medical Oversight DSI-7 11 (January 27, 1997), p. 1. Exemption of 14C is inconsistent with this recommendation in that it would eliminate all NRC regulatory oversight over the possession and administration of the product. Users of 14C under the proposed exemption would not be required to establish~ radiation protection program or to comply with ALARA principles. IV. Agreement State Issues Pursuant to Section 274(b) of the Atomic Energy Act, 42 U.S.C. § 2021, the NRC may relinquish responsibility for certain nuclear regulatory matters to states that have entered into an agreement with the NRC ("Agreement States"). In some instances, Agreement States have the authority to promulgate regulations that are more stringent than those of the NRC, provided they are "compatible" with NRC's regulations. Currently, possession and in YiYQ use of uc requires a specific license from the NRC or from the appropriate Agreement State agency. It: however, 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. Because the NRC is proposing to authorize the administration of the 14C capsules by way of an exemption to its regulations, Agreement State agencies will be required to fully 4

conform their requirements to the NRC's, and will lose their existing authority to adopt more stringent standards or to continue to require specific licenses for the administration of such materials. (Adoption of rules to permit the manufacture and distribution of the 14C capsules under a specific license to persons who are exempt would be a Division 4" matter of compatibility. The exemption to allow persons to receive and administer the drug would be a Division l " matter of compatibility). See 62 Fed. Reg. 32555. Therefore, by adopting an exemption, the NRC will deprive the Agreement States of any opportunity to establish regulatory policy different from that set by the NRC. Had the NRC instead simply proposed a general license, rather than an exemption, Agreement State agencies would retain the authority to adopt the general license or continue to require specific licensing. As the NRC has stated: 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 yjyQ" diagnostic use without need for a license. 62 Fed. Reg. at 32555.~ Thus, the Agreement States will be forced to accept the exemption and to authorize the unlicensed possession and administration of 14C. It is interesting to note that although six Agreement States suggested the use of a general license and only three Agreement States favored promulgation of an exemption, the NRC Staff opted for an exemption. Oddly, the Staff now favors the exemption approach even though it recognizes that some of the Agreement State objections to the general license were founded in part on the erroneous assumption that an exemption would produce less administrative burden than a general license. SECY 97-031, pp. 2-3. 5

V. Failure to Consider Non-Radiological Alternatives in the Environmental Assessment The NRC's environmental assessment (EA) in support of the rulemaking only briefly discusses the "need" for the proposed action. It states that the proposed rulemaking "would allow physicians, who do not have an NRC license... to also receive and use this product.... [providing] greater flexibility to test for and monitor the presence ofH. pylori.... " It also notes that the "new noninvasive test... has a potential to eliminate the need for many gastroendoscopies... [ which are] expensive and uncomfortable to patients." See "Environmental Assessment for the Use of 14C Urea Breath Test" (May 1996) at p. 2. However, the EA fails to consider the fact that another equally noninvasive, but nonradiological, diagnostic procedure is available and provides a comparable alternative to the 14C test. (Materials describing MERETEK's 13C diagnostic test are attached to these comments). The apparent assumption underlying the EA is that in the absence of the 14C test, the only alternative for the detection ofH. pylori is invasive gastroendoscopy. That assumption is not correct. VI. Exemption for In Vzyo Use The exemption would be unprecedented in NRC's regulation of byproduct material. Existing NRC regulations, exempting certain small concentrations of byproduct material from regulation, state: "[t]his exemption does not apply to the transfer of byproduct material contained in any food, beverage, cosmetic, drug, or other commodity or product desi~ed for ingestion or 6

inhalation by, or application to, a human being." 10 C.F.R. § 30.14(c) (emphasis added). Thus, NRC's policy in the past has been not to exempt byproduct material that is ingested, and any change in this policy would be a significant departure from existing NRC regulations. Although, prior to 1986, the NRC granted ienera1 licenses for some medical uses (in Yim. use oflodine-125), it subsequently eliminated the in Yi,yQ general license and required that "all medical use be authorized by a specific license." 51 M. Reg. 36932, 36935 (Oct. 16, 1986). Accordingly, complete exemption of the uc product would represent a radical change in regulatory direction for the NRC. VII. Basis for ACMUI Recommendations The Advisory Committee on Medical Uses of Radioisotopes (ACMUI) has concluded that either an exemption or general license is appropriate for the 14C product. However, its judgment was based partially on the assumptions that: (1) the product may only be dispensed by prescription; (2) the product is approved and regulated by the Food and Drug Administration (FDA"); and (3) the office/facility using the product will be subject to Clinical Laboratory Improvement Amendments ("CLIA") regulation. These assumptions, however, do not address fundamental aspects of nuclear safety and, in at least one respect, are incorrect. First, physicians' offices will nQt be subject to CLIA requirements, if they are only collecting samples and sending them to outside laboratories for analysis. Only those offices that 7

have liquid scintillation counters would be subject to CLIA. Additionally, even for those physicians' offices subject to CLIA, these requirements address quality assurance, not nuclear safety issues. Moreover, there is active interest currently being expressed in Congress to reform CLIA to exempt physician offices from any and all quality assurance and training requirements. Senator Hutchinson (R-TX) intends to introduce such a bill sometime in July or August, and Congressman Archer (R-TX) has indicated that a companion House bill should issue soon thereafter. Second, FDA approval of a drug indicates only that the Agency has determined that a product is safe and effective for use in patients; the FDA does not address nuclear safety issues affecting physicians' offices. Indeed, in its Statement of General Policy on the Regulation of the Medical Uses of Radioisotopes, the NRC stated that its "authority to regulate the medical uses of radioisotopes as necessary to provide for the radiation safety of workers and the general public.. . does not overlap with FDA's activities." 44 M. ~- 8242, 8243 (Feb. 9, 1979). Finally, state prescription drug requirements provide only that the product must be prescribed by a physician. These requirements also have no bearing on nuclear safety issues presented by the potential accumulation of 14C in physicians' offices. vm. Disposal of Unused Product According to statements made by the NRC Staff to the NRC's ACMUI, an exemption does not provide the NRC with the flexibility to impose a limitation on the amount of 14C any one 8

physician or physician practice group can possess in an office, notwithstanding the rulemaking petitioner's suggestion that possession be limited to 150 14C capsules. Consequently, in the event there is a recall of the product, or a large amount of product becomes unusable (because it is past its expiration date, damaged, in violation of Good Manufacturing Practices, or for some other reason), the NRC will have no control over the disposal of the product. The manufacturer may request that the exempted material be returned to it for proper disposa~ but it may not have control over this procedure if title to the goods has passed. IX. Labeling of 14C Under the proposed rule the immediate container of each capsule must bear a durable, legible label which: (I) 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." 62 m ~ at 32558. Additionally, the regulation states that either the label affixed to the immediate container QI an accompanying brochure must: 9

(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 Distnlmtion." Regardless of the form of licensing ultimately established by the NRC, product labeling provides critical notice to end-users that the material is radioactive. Indeed, under the NRC's proposed exemption, the labeling would serve as the m notice to users that the product contains radioactive material. Because 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, the labeling must be conspicuously and prominently placed. Existing labeling for the 14C product, for example, refers to the product's radioactivity only in small type in the second column of a lengthy package insert. It is important, therefore, that proposed section 32.21a(a) be revised as follows: 10

(a) The immediate container of the capsule(s) must bear a durable, legible label which: (1)... (2) Conspicuously and prominently bears the words Radioactive Material." Additionally, because physicians and those that they supervise often refer to manufacturer-provided promotional brochures rather than package inserts as points of reference and guidance, for consistency purposes, the NRC should require that the radioactive material legend be included on these materials, as well as the immediate container label. Accordingly, it is recommended that section 32.21a(b) be redesignated as section 32.21a(c) and that a new section 32.21a(b) be added, as follows: "(b) All package inserts, brochures, hands-on training guidance, and other promotional materials that directly or indirectly accompany distribution of the capsules, must include in conspicuous type and in a prominent location the words Radioactive Material." 11

X. Conclusion Modifications to the present licensing and regulatory system for the 14C capsules should be undertaken as part of the overall effort to reform 10 CFR Part 3 5. Furthermore, such modifications, if adopted, should substitute a general license for the existing specific licensing requirements and should not remove all NRC and Agreement State controls -- as an exemption would do. Proceeding in this manner would ensure a coordinated, coherent and uniform response to the overall issue of radiopharmaceutical regulation by the NRC, and would provide appropriate regulatory flexibility to Agreement States. 12

Meretek Diagnostics, Inc. Meretek Diagnoaties;,Inc. ('"Merete);' or the "Company") has developed a breath test technology with is non-invasive and non--radioactive. The technology platform incorporates the use of new diagnostic drugs fur breath tests to diagnose Htllccbacter pylori (u H. pylori") infection associated with the development of peptic ulcer disease; liver disease; and gastric emptyin~ disorders. Additional drugs for breath test appliutions are currently wder evaluation. The Company is privately held and ww. formed in 1993 by BCM T ech.nologies, I11c., the technology transfer subsidiary of Baylor College of Medicine. The oompanrs main objective is to establish breath tests as convenient and cost e:ffi:ctivc: diagnostic tools. desianed to serve as altmnatives to tho traditional invasive methods of en~y and radiology.

• Meretck.'3 initiativt.S have been directed towards obtaining approval and clearance

~tivdy for its combination product, Pranaotin ' diagnostic drug and the Meretek UBT' Breath Tc:st Collection Kit ("UBT"') for di.aguosis of H. pylori bacteria. The Company received FDA approval and cl.em.nee for the UBT in September 1996 and is. eurrently working toward full commercial distribution in 1997. The Company', product! m-e targeted for large markets with a critical need foe oott:e;r diaposti~ products. For example, H pylori is now considered to be thb world's most common chronic bacterlaI infection in human beings, affecting m csfunated 78 m.illioo people in the United States, with a higher incidence abroad. ~aticnt aceeptance for the other available diagnostics has been limited. due to either mi~ towanb the invasiveness of the method, a Jade. of accur:acy., or both. Aocordingly, the Compm1y believes that thcR! is a pat need in the primary care and managed care marlcets for a safe, precise a:od easy-to-use diagnostic tool Mcretek's breeib. test technology offei1 compelling advantages over traditional diagnostics. It is entirely non-ra.dioa:cti.ve>> non-invasive, user-friendly. safe and eccura~ It is also much less expensive than the "gold standard" endoscopy-based procedu.rei. The Company 1w taken steps t.o establia.h breath tests as the etandard replacement diagnastie procedure in these markets. The results received from the pbaanw:.eutical clinical trials have been very favorable. Many of the largest pe.ym in the Uni~ Staws have: approved ooveraee of the UBT fo-r claims submitted by providers. Meretek will continue to evaluate additional breath tests as diagncstics for diseases whk.h affect large DUIJlbers of people. This,trategy is consistent with trends in the health care sector favoring prevcmi~ non-invasiv~ diagnostic~ cost-contaimneclt and simple office procedures.

FDA TALK PAP.ER t=ood and Drug Admini&ttatlon U.S. O.partmant or Healtl'I and Humen Services Puolfc: Healln Service 5600 Ftliltra t.ane Roekvf1111 MO 10851 FDA Talk Papers are prepared by the Press Office to guide FOA personnel In 111spondlng with cansJstency and accuracy to questions from the public on subjects of current interest. Talk Papers art subJe.c;t to change as more Information bec.omu available. Talk Papers are not tntentfed for general diatr'ibutlon outside FDA, but all information in them 1$ publlc, and full texts are releuab1e upon 111qua.st. T9tS-72 Nov. l, 1996 5haz:on Snidet: (301) 443-3285 Broadc.a.st Media: (301) 827*3t34 Coc,~u: Xotlina: (800) S32-4(t0 a:eath Teat fo: H, pylori Th* FDA hu ~**c ~*c*iving inq~irie1 about a a.uapie, ne1,* br*ath test to help detect & b&ct*ri1.m1. tbAt is the majo% cause of peptic ulc:e i:-s. The follotd.ng c:.n b* used to auwt'lr quea t1.oiu. The fi~st Qf it'-4 'kind teat is the Me~ac*k U~~ B~*ath T*tc collection Kit made by Mer~tek niagnoatica, Inc., ot Washv1lla, Tenn. It:. wa11 clea.r;ed fat :marketing by FDA t:ci detect the H. pylo:1 b~~t*~i\\lfll, Whic~ 11 a1s0ciat4d with ulcers. P.i:eviou~ly, the only way t.o acc\\u:ately dia(jfl\\o** H. 1,110.tl infection waa by endo,eopy with 1to1.U.ch blcpay -- & pEoc*dw:e in which the patient 1, sedated, then a t\\lbt! 1a in.t*~tad into th* stomach through the mouth and a aamph of 1:.he at.cmach llru.nc; ii remav.-d fo;r; analyaia. Bloc:>d. tut* h&ve c1ho beea u.aed. to ct.tect H. pylori, but with less depecdable results. With the new bi:aath test, the. patient. d~inM a new-n0n-rz1.1:li011.cti ve diagnoistic:. drug.soluti0n and then e~loa into the coll*ction ki~. ~* p~oc*du.ce ia pe.c!oi::med 1n a doctor'* offic* aqd take* a.bout 36 minutu. The dru;, P.:canactin(ftt), wie., ca.cl>on 13 enriched w:ea, =i natw:ally occurring, nan-radioactive ~ompound, t:.o datemina the preuncl!I or abi:1ence of iln.active H. pylod infect:io:i.. 'l'h* breath kit b 1ent to Mc:etelc fo:: an&ly,i1. rtasults u:e availal:>~111 1n ~ d.&y Ol: two. FDA' s cl.ear&no* of the teit: WI.IS based c>>n dat4 f.z:;am.stUdl.e.s of 499 adults with duodenal ulcer disease at 7! sitea in tbe United State.a and Canada, 'rhe paticut:s were exud.ri.ed. witn endo*eopr and atomach biopay and we:e al.5o 9ivcn the b~ea~ teat, The ruu ts ah<,Wed tlu.t the breath ta1t was al:>l* to detect th~ presence Qf H. pylori in 95 p~cent of the ~asea -- ffl&kin9 it** good an endo~~opy with blopay in dat*ct:ing the infeatLon in pat:.1.anta with ul.cera. H. pylori 1* a co1t1m0n bacte:iwa. which u thou.qht to infect the atom.acha of 35 p*:eent of kn:ican adults, about 10 P*~c.n.c of whom develop peptic 1.1lcus. Th* ot;he~a ~Y not. dew~op ui..cen but have chronic g~:it~iti:1, \\.fhi~ can cat;,s~ i~(J~*~_t.1ort,.. ~nal p&i?\\~* qluslaess, XUIUH& a~ o,t!ier stamac:li prohl"~.. The_ ~u!o:msn::e ot the test'has'not been eatacli*hed*in ~cients with chronic qaat~itia. The b~eath test w~5 elearecl for ma.cketing Sepe. 17, 1996. Ult# 11~Z3-1

O)l;l..~104~ 1'.XW Tul ~ Joil0.w. 0, (;~ ('.'9'pyrl&b& C 1996 by Am. Col~ ol ~~&.* Val 91, No *._ 19911 l'~laU.5.A. Noninvasive Detection of Helicobacter pylori Infection in Clinical Practice: The 13C Urea Breath Test Peter D. IClein,. Ph.D., Hoda M. Mn1$ty, M.D., Ph.D., Robert 'F. Mamo, Pb.D, Katbleen S. Graham. M.O., Robffl M. Gen.ta, MJ>., F.A.C.G*, and. David Y, Gndwn, M.D, M.A.C.G* ~ a/ M/IQICUltt and V,uraH ).jfal,1 JI~ Cffll<<r. Bayk,, Colh~ of MeclkiJtt, aild JdlZ/'Cltem Auociat,-d. 1111*., CrHICQfd. Mt:Ustl.duums Objteti,u: To n11idate the "'C urea bt"eath test tor the dateedon ot B~ nlorl tnfld:lon both baton and a.rte:r treamLeDt. Mlflhadl: 0 c urea ln:mth tats with 125-mg and 2!0-ma dosa were carried out on each of 60 infeded and. 60 aonia.tected subj~. RMUltl were com-p.ared with histoloaicaJ exarnlolill:ion r,t patr.lc biop&ia to estahlbh detection Umits. The best cut-ottpolntwas UICd in a cUnlw trial of the lfflcac:y of the bra.th test In dllOden.al nicer y.ltlerttl before md after antirnlc:!l'Olllal therapy. The incnmeu!al increuc (percentage, 3 over basellnt la U of &'miJ) ID ~pirstory °C01 abundance wu l.8!!0Citlted with blstolop<:ll mdem:e of H.1Jlorl. Outpatimt, tertiary care medkal omter, awl scamda:r:, and prlmary care tadlltlcs we.re lndud.ed. One hundred twenty healthy asymptomatic subjects and 465 pedent.s "1th duodenal ul.i:et' dbauie were studied, Tho test kit au!S91!d repeatabJ11ty of breath sample colec:flon and storap a.ad stability of sb:ind nmplca. Test perfor-mance was analyzed by eompuiaoa ot 125-mg and 2SO-mg ~c l.ll'ea with mcanircments at 30 ud 4(1 mm p<lStdoJe. The test w&1 med to diQlll)llle ClCtive H. nlorl infection ad pup mccus of antiraicrabial therapy. Ralllis: The teat kit results I were ldply.reprodndble. The cut-off -ralae:, ~ hfcber wttb 250-ma compared 'llrith 12.S~mg dw o( uc urea aucl 40 r;aJq compared with 30 min. Using a 1.25-m& '-'C urea and hist: deiection llmlt of l.A4Kt at 30 mbl, Ole *CCVICJ' wa, '4.8 ('59', con.ftdeaet Jnterr:al 111,:z..,711,) herore antlmlcrobbl therapy aud ~4ft (JS,. cooDdoce latcrTal

• 91-98") aft.er. Ao Increase ol 2,A,&, tn the abundance~

breath 13CO, mfm'Ot'fld 30 mlD aft.e:l-a US-mg dote of uc urea reliably indicated the praeuce or active B. p11or1 lafcctlon e&ther Wore Ol' dbl' andmicroblal thff* apy. The c urea breath hist provides a aimple aud reliable and nonlnva.live method of ~ H. p;yblrl status. 6,t1 INTRODUCTION ln Pebntary 1994. a National Inlti.tu.tel of Health Coc-KMI.I Deve!opmont O:,o~ eoaoluded that Hillco-l>atttr pylori wu lbe l:IU.SO of moa cues o( pcptl.c u!c:cr disease and that all patituts with H. p.vlorl ln&:ctlon and ~ ulcr::r abould receive anti.mic:robill.l thc-rapy (1). Ia. June, iM huemationa? At,e:tC11ot ~ on emcee Wodl:iDi Oroup of the World Health Org:mi2:11.tion. dct'ined H. pylori u a Group I, or definite, human cari..inogen. The role oC H. pylori in cancer has broadened slni-e the rec:og-nitlon !bat c1.m, of H. P]lari l.nfccdon resulU in remiALOn of many. if Mt most, cues of priawy B cell gastri<: tysnpboma (2). H. p:jlori inf ecticm w thetefore tvolv.d from an ob-seute emu: of gastrim to, pcvom.l role in r11e ~is of peptic ulcer dLseas,e., pstric e:e.rcltioma, and primary B ce1J gastric lymphoma (3). Peptic ulcer affcctJ approximately 10$ of individuals in the United States at aoms time i11 tbcit lives (4). Trca.anen: of !be infection should be bued on an a.ccurm dillgllON a: H. pylart ia!ection. and tho Jar;e nu.mbet of lndl.viduals with sympt~ H. pylQrl inkd:lon undmcom t11e lmpart1nce of nmpJ.c. nomnvuive method.I to dco!ct the pte&eru:e o1. H. P1lori in tho ~ The laJll.al fOld 1tm1da:n:l for the diagn,ocis ot H. pylori infedion has been lwtoJoglcaJ. exam-ination. cu.lwn!. QI:' bQth of gasulc mui;oAl biopsies obb.incd at tbs time of GI endoscopy. The !w.10paU1.0l(l&lst's ~skol idec.tifyurg th~ pmiimr::c of H. pylori Infection wu.greatly slmplif Led. 'by inttoduaton of tho Oen!& stBin (>> combiruuion ofht:matoxylin sod eoiin. alciart blue. and the Stemor silver stain) to si1t11.1~Ully ldwlfy dJe orpmsm llDd the Lil* fwnmation (5).. Tho introdw:tioa or scrolo~ cests al-lowed for 11.D i.ndin:<< w.eumem of H. py/Qri stal:u.L The nonlmui.vc urea breadl tell: ls the only n.oni.ovasi.vo modtod that will detEct the presence of active H. pyicirl infection. Since the initial p,.iblication in l 987 (6). the 13C ut'H ~ IOS.C has become a widely used rcaearcta teat fgr the detection of Ji. pylori inf'ection. The test i& ba&id on the high ureu,g activity or the orpnlsm. wluch readily hydrolvfe!f un:& to carbon d1o,cid,c ~ ammonia. '\\Vt1et1 the UTEll is i~l)' labeled with u c:11rbon isotope. the label is ~- rlched in mpirttory C01 and can be de~ hy appropriat.e

AJG - April 199( ~menu. The wu breath test bas proved lO be re* markably robu,t io the detmnination of gutric urease ac-ti vit.y notw\\ th&tanding mo large number o! IIllII01' Q'lOdmea,- tions that have bun propoaed ~ lntrodu=i (7-19). Too ongillal deacr:lptioa of the tc:&1: showed that it wowd cor* l'llCtl.y catepize H. pylori m.tus independent of !be use Qf. or cogipo4icion of, the teal m*;il er the dosage of 13C urea (6). Althwgh these obaervatiotls bavc been cmifim:iod re-peatedly, li:lc urea breach tw has remained & 1'1$W'Cll tool The te:ll ped'O[TOance rnay be dlf'f'ereftt for I reSCICQb tBU and 11 ~ that mu.st ~ reliably in a busy eUnk:al practice. lUiorous cvalu.atl.on of the fOCIOtS mat aff'l:l:t tl:!lt use anc. perfor:mancc in such a clinical,ettiog has nl)( pnmow1y been dooo. We evaluated the u.se of a standardized. bmtb te$l kit to opUmhe the param<<ten tor ionmral usap of the test for d.ia8fl0Sis of active H. pylori infectioo of the stoD'UICh before aa well u after andmk:robial therapy. MATERIALS AND METHODS 13c urea breath test Ide were obtained from Men:tck Di.apostioa, Jne.. Homtoa, TIC. Th.-y oontained a. ptt(est meal comistmg of a can of vanilla ~ padding {Roa Lllbocatoriel, Colmnbu:I, OH). 12' mg of Ile w-ca (99CJ, 13C, Tracer Teclmolo&iea. ~ MA), 90 mL of atcr,. ilc water, t breath col.ledkl11 and tlUdcr bq, thtee :!0-mL evacua.ccd nmplo tubes {Beet.oft Di.ckfnsaa. Rulhcrf0rd. NJ). patient forms, and a l8Dlple tube mailer. Sample$ wcro remmad to Mcreli'.k for :malysis OR att automated gas ito-- tope ratio man spectromM aystem (Model. 20f20 Buropa Scientific Company. Manc:hcttcr, UK). All sampln were meil.WrEd against rcfenmoe sranda:rd& ot known uotDpic CQlnllositioa YCT1U8 tho limeatooe.swtdard, Pee Dee Bdcm-nue (PO:B). Rtpeatabillty tJf sample meaurcmenu wa

!:0.1411 (per m.iQ with overall variability of 0.lS~.

l!m:lbli.lluMn.t of 13C urea ~ and e.t-off' va.lD1$ Healthy illdlviduals were moencd by ELISA test to eval-uate mm H. pyu,ri status. and 60 illfeoltd and 60 oonm-fccted. volunta:rs wore rcci:uited. All aubjects pve informed consent. and the pco<<K:ol wu approved by the mvemga.. tiona.l. Roview Bovd ot &ylor College olMcdclne. On day 1, subje.cta underwent upper OI eodogcopy In wbic.b foi.ir 1arp cup blopsics (Olympu fB..l'.31(. Lake~. NY or Radial Juw tarp Capacity ll, :Micm'tlulwi BostDa Scifl'l\\- t.ific, WlltertOWn, MA) weta taken: ooc from lbc anu:um oa the lcseer curvaw.re at cr near me lndtua (lite Al), two from the grtat<< eurvamn, within 2 an of tbe pylorus (fite

• A4) [one for urca,e: leatu\\l (CLOtest, Delea Wat, Wcatem Awtralit)}, and one from tha amdd1e ot tbci CQ1P11S on. the pmiCr CUIVallU'e (lite B6), H. J11/crl $tatl.UJ WU dctcmlined by hi.to~ the speci.rneos were futcd with 1~ buffered formalin. cut into 4-mm aecti.o:ns.. atained. with th, Genta Jta.ia (~). and examined by an cxpeneaced pachologl.fl uu--

rwan: of the piltit:nt' s condition or ettdolcopic fia.diogs.

Each siibjc:ct received i 13C u.n=a hRath ~ to wmdl a SR.EA TH TBS1' FOR H. PYWR!

69.

125--mg or 250-m, dose wu rmdoatly usip.d. 1n each tr.st. buelino. 30-. and 40-Dl.in postdo&c ~ u.mpl= were collected in aiplieate utins.epamc breath collei::tf.0t1 bag£. The fQllowinJ day. the breath test wll$ repca= ~ a 2$0-mg or 1~ dose oC 13c urea as requiffil. ti> eomplete the CroA-Ovct dc::aign. One &er of aampJ.eo WlllS udyz.td fer 13C abundance wi.thlD 24 h; the ochet two sets wen: ltoi"ed iu fOOl1l tcmpttarure for 10 days b&fon: analyli:i. All ana'.- ysos w<<l!l completed with the re:spcotive I.a.ooratori.cs (p:i.. tholoa;y. brci.til tu.) blinded regatdfni: tm1 rcswt>> ot tho othtt. Uu rf tha uc urea breath test for -diaallOlia arid foUi:,w. up after tR\\atmen[ en ff.pylori int'cctioo Urea breath tceit wue ~ into clmica.l trials of antiml.Ct'Oblal WU'IPY of H.. pywrl. i.nfectKll'I in duode11al ulcer piidents. Duodeoal ulcer pa.ticntl were studied in 75 ltl,idJ loc:atloos in me Ullited Statcl6. Patititts r.Dfaing the study but a. hlucxy of peptic ulcer disease and UDdorwent endolcx,pic cumioatlon with blop,ry for biatolo3y, rapid uteUa msd111, and outnm:, and 13c urea breath tuit wi1h 12.:!i mg of ~ H. pylori &bltu.& WU ~d 'by Gefltl sr.am as noted above. All procc:dllm wem reputa:1 aflu 4 wk ('Z wk aft<<' the completion of the blinded antimicrobial or pi,Kebo thcnpy) of l:l"eatnllmt aod Ulieu 4 wl later. Cure ot H. pJlori lmection wu defiried u abscoce en bittological cvidanco o/. iPftcdoo 4 ot more wk attar en.din,1t a.ntimJcro. 'oial tberapy. 8ecaWJC tbe i;iwposc of the.wdy WM to cmll-lWC the dfcdiVCAe.lS of the urea btearh tM1 in elinkal practice a.ad not to cvahWe specific tb.npic:1, tho dUR.riQll of the m,dy WU limited to 6 moathA. Tho n<<ilta of the indivldlltll and:mk::11'bill vcr.au placd>o arms nrc not givea bec:al;qe it WU 1101: ncccsw:y to beak the blimting because die Soll of tlWi 5tDliy was to en1uam wllelh<< the Uta bn!lth teat was abae to dotoct tile~ or H. pytort inf<<t1on and nat whclber an mdt:vldual rea£mi.iu wu 511!)&- rior to 1D.Otber Cit' to plact:bo. Coku!atU1'tU Tho analytiea1. results from lbe sep.um: breath sampte coUoc:tion ~ were compattd t'or rwputabillty. 111 tddiaon. anlliyles obbaincd witJtin 24

• w= cornpart'.d with thole oblllaed.net 10 days ol ~

to 11S1NJU sample stability durinl ~ 1be reswtJ with the two difi'ereol doles of 1JC \\!tu were compared for correct c:atcgcriz.uioo and fot Ibo effect of ~c l;Qllcctlon time (:30..., ~ rnio). Dc-tmminulion of the appt"Qpri&l6 c:ut-off' poim wu obtained asiJ1g Receiver Opemrlaa ~ (Rex..') c:um:s for the l~C aad 2.10-mg do5e6 (2(1). Par A given urea dOIC wt postdole time ( ** 8.. 125 me a130 mm>, ttiii c:ut-off' point between neptive and positiwi M&Ulu fbr tbc teat were evnkwm by ~ the level &t which the sum or tho f'a.lsc.neptivea plu& m. flbc>-polltive:a we:e mmimiz.cd. Stz.- tlaµcal compuisona were made by Student':-. paln:d t ~ with sJ~ alp,. 0.05. These cut..-oft VMW!S -were

692 KLEIN et al ~*-------------, J3 0

2.

ilt--~~-----..--.....__, ! 0 i-1 fO. 141--------------; l o Q o a., Q ~~-t---.--.-----r---...--i 0 lt 1,0 30 40 ff AY'Ol'a&t dllta JIG' mil: <Bl41 + liq :i)l'l J!ro. l. :.81.mrJ-,tJIIlllUI plt!C (24) ot~ bq dtttaMm (M,IW nl'Ol&r) 111Mi lQ-41.y ~ vahlcl (DjHII CU"dn); "4' cooftd&lll:C lin:i.iia _. ab.on. then used to as1~ the teSUlts of tbo tcet whell it was used il1 a larse multkenter trial T~ Streu testl~da:>ewlng 130Jr containing 2Q..cc: V11CUtainer t\\lbmJI with mr= lcvr:Lt of CO2* Tbe tempemturel and pP$SUrCl8 tested were ~ to evalna.te those that might ocwr dlltt.Dg air or grow:id lnDllt and iocludcd tempmtu:res of -40"C all.d -"'"C allld pra-sun:t or 10 and 14.7 ptil. RESULTS Breath eatnplascan.cted in. dcpllcate bags for Storq."e aid tra.nJfer yielded eaeat1ally fdeotk:al rcsolts (FlK-l). Storap for 1 O d.a.ys had go effl!Ct oa the nnults. Tho raw d.m. fer the incn:aao In 13coz.buudancc avu tho bac1ioo valao (Spa-mil) are shown in fi_eun, 2 (Ot the AD'IO normal and H. pylorl-posum b:K\\iv.iduals after 125 mg ud after 250 en& of uC ureii. The cut--Ofi' points as determined by R.OC CW'W.S for mo. two dCilCS of urea W'CrC hi&hcr fQi.- the 250-Jlll don of nc urea C0111parcd with the 125-mg dole: 4,.2ci, compaml wltb 2.4~ for the 30-miD collediOl.1 time. They were hieher fa-the 40-ml.D time pcrl!U (4.3 compared with 2.8~ fot 250 !'08 and 1zs mg of 13C w-.. reapeetivd.y ('I'ahle 1). Four hundred.ixry-nve patiacl with

• hiS!Ol'1 of ulcer disease wwe ecreencd fr1t me JX9AllCC of H. pylori intc:ctlon witb the urea bttsth tart ud mstolo17. Al. me end of the 6-month study, 173 bad..:ompleD,d tbl t'ol.low-up 6 wl: af\\a' the cad of therapy (Table 2). tJllnc 125 ma ol "'C meJ ml a test detection Jlmit of 1.41' at 30 mi4. the lCCIU1IC)' of tho breath test waa 94.8 {95~ Cl (contlde.:occ i.DletVll) ""92-979"1 bel0te andmk:n:lb.ial thenpy and ~.4<1, (95111 CI
• 91-98':l,) after. Sil' weeks afwz' therapy, 1 timB when ono should be able to reliably dlstlnpiah the resultl of tbonlpy.

tho M!P$itivity wt :speci.&ity W11rC excellent (T:lble 2). These reaulu. obtained outside the higbly skilled nl$C8tC:b ~lroll.ffllltt. n:.t1oct tlPJ ptd'onmnoc of tho teat in diaietl practice. Of !ntmat, 2 wk aftet tho end of thenpy. the results confirmed thilt thi$ I.! tho time when it is difficult or impos-sible to reliably scpu.rate supprwion from ~ (21. 22). AJG - Vol 91, No. 4, 1996 lff I I I 0 I § I

• I I

0 0 0 C, ,...,~ u.-,-. Ul PIQ. l. IOO'IIUI! hi ~ apalad

• Mnll ovi:ir bui:Um far IIOl'Il'lal.

(o,fftwr:ia) alld H. ""°'1-bl!letcd lsldhidual& ("°"4dlclu) 30 min Lflcr

• IIIIN' 1 U or l!IO *1 ol '1C IIRIL Based 00. the n:.sult& of hiatolO&,'Y, If>> sensitivity, specifictt;y
• and positi'N'J.nd DOgarive pn:dictive valuca for the u.r-e.

bream tell wm 89.5-., 70.6~. 74.3~. a 87.7~. resp<<:* tiwly. 'the o~ accuracy of tbc test llf)peued low (79.8%) prhnarlly due to tbe ia.crcacle in '"labc>poaid.vo" .resu1tJ ual.q histology as l:b8 atandud. EiJlhty nine percw Qf all false-poaitive" rcsulta OCllUCl'ed at this vl&lt. *mph:a-sizina the *~ of waiting to detetm.l.oe whecher tht infectloa bas "CCitlblilbed itself. A caltun, or follow-up mt wu availlble t'or 31 of tbc 43 subjo.;t.T. 25 were C0llfirmtd to have been trt1e positiYCS at this 2-wk after therapy evaluation point. Thcac results furtbE!r OQnfltm the necc:aity of waitiug uun 4 or more wk afmr = Kling the.nlP}' to.,_, ovttall dfectivei1ca.. DISCUSSION Bccauac tho 13C mea lxutb tatnoniaYui"nly establishes tbe pn:sc:nc:c of active H. pylori intt.ctkm ot' die,cg~ it hu thct pote1'lfial ro be im important wo1 bo1h in 1he dias-nos1, of i~ and in patient~ &fter utimi-c:robial th:rlpy. The studic& reported hen: were designed to evaluate the pa.ramctm zeqwred for !IUCCMful UM of tb.i& tc:at in pocral aUnJcal practke. Tho physical comp011e11ti r;,I the lcir: a bream camplin1 bq tor ~llectkm and transfer of !:Jadem bn,ath l.nto micuaro:t tea tubes., a llRlll\\h Ample .mailei' for retmn ol the: sampfts to lhe refenmce malytical laborator.,'. and the autyucal procea of sas isotope ratio mm ~ ro deairml.ne 13c abundance in rcspl.tia.- tw, C0:i proved to pro'Vidc: biabJy.repioduciblc rua.lts. 1beae comporil!lll:I aitd the analytical p.roooi,;s int:rod11ee an uncmtainly of 1c.sa tll8ll 0.30,, () SD) bl the ll.bwlda.noo DUWl~ment, raul.ting ia. tho ability ro de:erm.lne the coa-ccru:radon of 13CO,, ia breath ro wlcbln 2 pmu per milllo;n. The dosage of UC urea (12' ma> alld the !trne of samp1e cotlection (30 roio) cl1l.')Cffl whlsl combined with ti:,,; cur.-<<r

AJG - ApriJ 1996 BR.BA TH TSST FOR H. PYLOJ<I 'tMU I 693

• ' "'~ i:wJ c~ nm, QJI ~

o.u-ofl Pf}btt Diqricsd; ~ Dou nm. Qu-01f $ml. Spc,:. PPV l'fP",I AccutlllC;' {aq) (ll'WI) ('\\I,) (')\\) (1,) (~) (.. ) ('I,) l~ 30 2.-4 100 100 100 100 100 12.S AO U 100 100 LOO 100 100 2!!0 JO ,.1 LOO 91 100 98 99 ~ 40

• 4 100 100 JOO 100 too

]lt&a 2 Cd/ftparilfJfl a/~ Pl~ a{ r./rr.it 8NtJIII T*tr A,.. Eiitto/,,CJ P'addve PIS&:)d. N ToM ITaiM Tm. Pdoc '4i5 4U 4 lP ~ 173 1(12 3 6l "N. lwt '4 w); ~I dieapy value of ~ 2.4~ iuc:reeH io UC urea al:lmldance plOVed to dea!d: the p:~ or absence of 1:1. pfo:,rl m tho aea.tng of i1s lntendcid UN: to... H. pylori sta&u by a1Cl:b1 pemmmel w:bhow;pclor tell~ Tbo~ pcr.fotmanco oflbo lClt ooAfimvd tbac this vcaloo of be &Jc wn bc£ll1b a:st intended for uae in the c&ic:I lJ a slmp1c, robust. and Itlfabjf; test in the ha.ads of buay he.um CUC p.ubsional,. Cun, of H. nlori lnftlctian has been defined Ill the ab- ,ence of intecd 4 cc l1l.Qrt; wk llf<at endiaa therapy (21. 22). '11m oritedon WU cboaeG l1ftEr n,cogmtion mat \\lfl£UC-ce.ssful tbempy r4Kf tJXmY ~ t!:1.£ inf=tiOll and tbtt results of tbe:rzpy are aot lpplrCllt ui.1dl the wectkm hu bad the oppommi.ty to mum to 1tl full vlp and. be dett:ctea rel.iably. Tbo ncainvasive UNI brtatb test has addluoul advantages over bist<Jloay in~ it dtocdwlty intopun die eozyme aaivlty ol bacwi& ovet b ~ IUl'face of du: stomach Md C1J1 doted.~ in wbkb mo orpoimn 1.1 still ~ In &171C:h ia.itanoea, the padelK will suhsequeutly pre:tent U I therapy.failun.. The disco1dance 'betweal tlJi: bmth test and billtol01Y at a viffl 2 wt &ft<< tadlllg"~ illllSl1'3.tC1 the hDport.anc,o ol dmiq of IMlina for 1/. p'Jlori stams. We do not rccoanni:eott tb,t ~ ba done iJmMdl.. ab:lly ;titer therapy bemlSe tltsn aro,a ffllCllber of StDdiet contirmiaa the mctuh1ou ot lbe +-wt. nue tu ~, H. pylarl S11b.U afmr thccapy (D). The dQ.,e rc1p:Pl8 and diifel'entalkJff po(ntl ob<<lw1ed with rhe di.ffen:nt d.m:ea, 12' and lSO u,g of 11m1. and timt pdnts (30 ~ 40 mm,) illmn.inam tho ~ of DXldifying llcSt pafa;JllaDec conditbla {Tablo 1). With 1~ mg. th= lowat increaN over basPJme abuDdll:a at wblcb H. szylori cu be de1cctl:d is 2A'I, whlcll ii app;ox.tmate1y 25 lim:8 ttic inhll'cnt i.natn1mtullal deteetlon limit. Al1enlate ~ auch as infrH'cd ~ tr an ~ i.mtru.mcnt cumm:ty ha-vo an analyciQJ limit o! :!: 19&. Al~ this would pl'Ob-ably 00t pennit one to discrinllDarc Wllh 11¢ same ab.tTuy

• Napd~

~¢ l"r.ri'ormanca ('ll,) Fmsc ~ ~ A.ccua,cy

21) 95-4 17 9 94.I

.5 ~.3 95.!I !1.5,l wflb - ~ of pl ilotDpO l:IIOO.num spc01:l'(JnJeQ;y. The fact lhal tho cut-off~ witb a hip do&& of urea MJgpltl nw tbe rea,.'lllon ha DO'C achieved Ml saturadoo Ql lhJ gau:lc un:a.tuctlvlty. n.: UN'ol ~ mnalle[ man 12S (c.,-. 75 mg} (9, 13, l4) or~ doses as \\1'Cd In,oms veta!.om ol the 14c utca lm:.ildi CIA (lS. 16) may reduce the ral13C ova-which lbalce of infection a'lOld be ~ with ccrtaimy. and \\ltU breath ltJSII lllUJI clffa:eot dosee 01 diflemtt t1mm of colll:cdon will n:qwtC a ~ J."l'IISSUl-\\lmalt of !be ~ aLt--<Xf valu,:.. ACKNOWI..EOOMENTS The nthorl thank me ~tical Prod.ucu Divislor. of Abbcn Ltboratoricl t'or theh' cooperation in this study. ThB study wu suppoc:tt:d in pt.rt by M<<ctr-Jc n~ !De.. llamtoa TX. MeR.tek Diaposdc& ls a. COfflP&n:' fi.xmdcd by Btylot Collqe oC Medk:mo to ~ tho C W'el bluth tea. Dn. Kiwi and Grnluun a.rt lbare-boklc:d in~ Diapmtlcs. Dr *.Manin l~ a ct)l15Wtaal to Meretek Dil3Dostics. Jtip:mt NilqlMltf Ud eoffl~ Jlmd Y. <lamm, Jlf-D~ VA Mmfk:11 C.-, J,\\3$2,, :ml Hakombc Blvd.. ao.-. TI( 77030. RBFERBNCBS

t. 1'flH ~

Co~ Hdi~ pytr,n ia pcpllc Wl.lltdll,, ta1n. NJJ< ~ 0.-.ui.-mi Pilw oa H.*~ nlfNi In ~ (Jl=tl)J,aiu.1~ 1994:2,1l:5'-9.

l. 1Wc1m lG. Ci:u1Ek l)'mpbomt >>cl HII~ '-"'1ri. N Ellll 1 ModJ~mo-1.

3. Orallul DY. EYOIUDOO. QI COllllallU repd!oJ Fl~ Jl'Prt Fn:a, _.. otpPrkil ID a pablla b.n.l1h ~-. Ani J Gllll'OOl!-

11:tOl J994;1,.M!l-71,

4. SoU AH. Cuuio, dllodi:cd. imd arm ufoer, llll !I~

M. }'1-Qrdft. I. * ~ disalc, 3121 ec1. l'Di!adtl~ wa s~ 1993: 581)..ffl, S. OGG RM, Robuoc1 GO. Gcwnl DY *.!ll:amilalCOUS ~ cl 1 I i

694 Kl.EN,t al. lff/il:t,aact,r pylcnmd s:mlM ~: A acw ~ HwnJ'lllbal 199'1-:.1,:.?21-6. I'S. Grw.m I>Y. Jami PI), 1hw OJ Ir, ce aL ~r ,,,zorl dela:ted nolll:wuivdy by Ille 13C lla'la bn:llh lll:lt. LallOCt 1987:J; U74-7

7. Gnilwn D¥. lClmrt PO. Wlm Yoll lllo.ild know abou, the mcdlodl.

prgbleoii. uic.paawlw.l., Uld - ol. \\I.I'll bR:ath lmtt. Am J Gulr-o-wen,I 1991;16: 11111-21.

8. S.U GO Wail J, H,.rrisiia C, et al l4C am 1:Hum lllllysis.,

ncm-invul~ ttat fim, ~r p:,,k,ri In th& tt.l.lnKh. l..aocet I 9'1; 1: 1367-II (loUct),

9. BndN11l, ~

LP, Cupay WP, t& al.~ c~ IJC llffll bmlb 11t1 JJIOIW.&:atiom &till me<< t!MI csllm'la far YIW d.iapalil ol H~ nlari Wtcl!Qa. Z O~ul 19k:32:1Sl8-'20:%.

10. Coon:mmM.~Kr.ItrampWP.tell. J3CW'lllbnellalt*

1 noa-1ovmn INDOd !at 01&1 ~ or n.J~, (C"'"lr.r ~ nltJn. Dmclt Med Wochtmi:br 1990:11':5:367-71. 11, DUI S, ~ Jl, Ml.lln4cz D, ct IL 8vlll.lliioll of 13'.: wa bmUI atm mtdacctlono!H~pJldfi m:l!.11 ~ hl tdrtii:1 ol a:lpo1.u1111111 dWb:aroblrmm,,,,111 m a.on-11lccr d)'liplPlia. Ovl 1990-.31:l?.\\7-41.

12. Glupmyllllti Y, lklmdellm. l,, Verlac M, U 1I. tl111al I lll'la math._.

Wfflll' m'iSltlw inetboda to dewmiac tbe prenlmloit or If~ p-Jlo,t Ill Zoim. &I I Oia M~ latta Dis lffl;t l:322-7.

13. l..oi&D RP, Poban RI, Mllliewlt:a JJ, Cl IL Siffl£'Jitied m.i,.,ample t:!Cmo1 arm br&am u l\\lr H~r f1JWi: C0lllpllboa wiM\\

hllitt!Jcay, Clllam!. &ad EU.SA...ology, a<< 199l:l2:146J-4.. L-4. ~ E.* bn1ur J. LDdlD P!!. n AL nm simpli.Tltd 13C ma bNlll.tl !At OIM-pt!at IIIW,)'ftl foe ~ ot l11lko""'1tr n1<<1 ~ Z Oatroeal&al 199109'4P0-4. AJG - VoL 91, No. 4, 1996 15, Manla.tU BJ, P11ftlusy MW, HoCrm:m SJ." &I. A 20-nuaiite blMlh tui: tot e~r~r f/1loti. Am 1 ~ l991;i6:'4JB--45.

16. Mfflblll BJ, !uffiyw t Carboa-1.. \\in:11 bcaf1I '"1 ftr tlws ditlp01tl DI O:m,pyi,,:Jt,,JcJ,u pylon~ pttltl1. I Nilcl Med l9U,29:

11-6. 17, NoYII BB, Cldliay 0, l.eidifnla1111 G, ct al. Two-polnt -.tym 1.i-ta!atlllle l4C 11m1. txuUl a:,t. foc otnp:,,lni H~ n{<<i ialc:- tlOCI. Dlc,asdoo 1991;!!0:16-ZL 1 L l.aju OS, Slmlb MJ. Morto4 0. at 11. Mhl!..40M (l-auc111CI) UC ma bn:::ll.l:I iac foe the diwlci1on ol Htllcob<<J.v pylgri. Am J ~ ]~;!9:to.27-.Jl.

19. Sllffl)'QC I. Cloodwio CS, Mlll1lm BP. a. IL Tbo 14C W1la bt1oCHa1 h'lhaddediaa of l,uaiD ~nlori inllcdoa. Med! AIIII l919:l5l:-4ls-9.

20. :zwcla MH. Campbell G. ~.

~ (R0C) ploCII A. ~ <MIUlatlo11 mol io cliJMcal r:ncdldnc. C!ia Cbcm l993:39:~1-T7. 2L S&sch IJM, Gr:uaia DY. fl~ nlori. Ia: Cclllc~ MJ. ~ [,1IJllft D. Olb, ~ ol. pcp&k ~,,...__Ill* lwtdbook ot ~~.Yd~-.BcOa: Sprtop--Varla,. 1991: tCJJ-48. U. GabUI l)Y, Genta lM. Pdn6::c<.ioa 'llldl N. J'1l,,ri. 1111 Hl1lll RH. T)'till ONJ, -. ~ /l'Yf/#'I. Baio IIIIIIMl>>l1ll t0 eltMc:al =rc. DordrelCllc,0...,.. ~ Mfi.tben. 1~ 11J..:o.

23. Onblm DY. DltczmbllDU ol ~

~ ia H. ~ pa,llll. ID: Hunt 1Uf, T)ip,; ON2, cida. H~ JJ1fffl. B&ac ~ io Wllical can:. Donb:tK: !Ou..-h:adcuuc Nitldia:iQ. l!ISl4; SJ 1-7. l4. llllld JM. AJtnun CO. SC¥lldcll 1111ma41 for ~ ~ ~ two IMlmr'II cl cllni#al ~ LQca 1 l)t!S;L:'N1*l0.

• NEN LIFE SCIENCE PRODUCTS, INC.

DOCKET NUMBER DOCKETED US RC "97 JUL 14 A11 :4 7 PROPOSED RULE PB 30 J-3 ~ ( Ip~ F~ ~:l.SS~) (j) July 8, 1997 OFFICE OF SECRET1\\RY DOCKET' *1' fl ,-;:-1,

• 1 ci:-

Secretary U.S. Nuclear Regulatory Commission Washington, DC 20555-0001 Attention: Rulemakings and Adjudications Staff

Reference:

Federal Register, Vol. 62, No. 115, p. 32552, June 16, 1997, Proposed Rule: Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea , ~u \\_;(...... L- \\ JL-iiMiCH These comments are submitted by NEN Life Science Products, Inc. (NEN), a major manufacturer of 14C-labelled compounds. Although NEN does not manufacture radiopharmaceuticals we do have considerable experience with manufacturing and handling 14C-labelled compounds including 14C-labelled Urea. We fully agree with the Nuclear Regulatory Commission's (NRC) analysis of the safety of the proposed product and recognize the immense potential benefit to society. We therefore support the proposed rule and urge that NRC and Agreement States promulgate the necessary regulatory changes as soon as practicable. Detailed comments on this proposed rule are attached. We appreciate the opportunity to comment on this proposed rule. Please call the undersigned at 617-350-9111 if you need any further information or clarification. Sincerely yours, Leonard R. Smith, CHP Radiation Protection Consultant 'JU[ 1 7 1997 ~cknowledged by card... --... m*-- 549 Albany Street, Boston, Massachusetts 02118 Telephone 617-482-9595 Fax (617) 542-8468 Ls-97-006

i>.S. NUCLEAR REGULATORY COMM1S::,10n DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSION Document Statistics Postmark Date 7 / 'f / '! 1 Coples Received ______ ;?=------ ,\\dd'I Copies Reproduced ~ 3.....__ __ _ Special Dlstribution_-Ts), P~ R_~

NEN COMMENTS ON EXEMPT DISTRIBUTION OF CARBON-14 LABELLED UREA

1.

Page 32553, column 2, paragraph 2: NEN agrees with the Advisory Committee on the Medical Uses of Isotopes that the radioactive drug is safe to use under a general license or exemption.

2.

Page 32555, column 3, paragraph 3: ".... 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 without need for a license". NEN 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. NEN urges that the NRC take action to promote rapid expedition of the necessary NRC and Agreement State regulatory changes.

3.

Page 32556, column 2, paragraph 1:

4.

"The Commission believes that the radioactive component of this drug presents no significant radiation diagnostic use of the capsules for radiation safety is not necessary." NEN agrees that the risk of handling microcurie quantities of carbon-14 urea in any form presents an insignificant risk. Page 32556, column 2, paragraph 1: ".. this proposed rule,...., would not cause any significant increase in radiation exposure to the public or radiation release to the environment beyond the exposures or releases resulting form the use of carbon-14 capsules under the current regulations". NEN agrees with this assessment. NEN has many years of experience in handling multi mil~icurie quantities of carbon-14 urea in liquid forms and confirms that the labelled chemical can be routinely controlled with negligible personnel or environmental exposure. Ls-97-006

Georgia Department of Natural Resources 4244 International Parkway, Suite 114, Atlanta, Georgia 30354 ,._ Lo.Ri~Barrett, Commissioner 0 0 I.Ei\\llkool:i:iehtal Protection Division USNROiarold F. Reheis, Director (404) 362-2675 DOCKET NUMBER PROPOSED RULE PR Jo.1-3 ~ 0 "97 JJL 14 All :46 OFF ICE OF SECRET~ Y DOCKET! G & SL \\CE 8RANCH ( &~ Fl<3 :iss-:i..) Secretary U. S. Nuclear Regulatory Commission Washington, D. C. 20555-0001 Attention: Rulemakings and Adjudications Staff July 7, 1997 This letter is provided as comment for proposed rulemaking published in 62 Federal Register 32552 concerning the exemption of one-microcurie capsules of carbon 14 for in vivo use. Our program supports the proposed rule. We provided comments to the draft rule plan supporting the now proposed rule. A copy of our earlier comments are attached. The proposed rule reduces the regulatory and financial burden on the medical community. We do not foresee a radiological health risk associated with the capsules. Considering the amount and type of radiation from the capsules, we do not see any ALARA issues. We support adoption of the proposed rule. Sincerely, ~,.,c:,Od TEH:ELD:klc Enclosure Thomas E. Hill, Manager Radioactive Materials Program ~cknowledged by card JUL 1 7 1997 ................ "... ~

lS. NUCLEAR REGULA TORY COMM1~::>1ur, DOCKETING & SERVICE SECTION OFFICE OF THE SECRET ARY OF THE COMMISSION Docorr:s t Statistics Postmark Date _ 1+/"'""1 /,._.9'"-'1'------ Coples Received. ___, ____ _ .\\dd'I Copiei; Reproduced ____ 3 ___ Special Distribution...:15~ 11>0 'R.I ~£. ~

~tat.e of ~ £fn W£rs£~ DOCt\\ETED US 'RC Christine Todd Whitman Governor Department of Environmental Protection'97 JUL 11 Al 1 :~bert C. Shinn, Jr. Division of Environmental :::iah;t *, Hea lth and Ana l ti ca l Programs Commissioner Radiation Protection Programs CN 41 5 Trenton, NJ 08625-0415 Tel (609) 984-5462 Fax (609) 633-2210 July 3, 1997 U.S. Nuclear Regulatory Commission Washington, D.C. 20555-0001 ATTN: Rulemakings and Adjudications Staff

Dear Sir:

OFFIC F SECRETARY OOCKE n.. G & SERV!r.E BRA, CH DOCKET NUMBER PROPOSED RULE PR 30 J 3 ~ ( (pP, Fte 3:?55:l.) This is in response to the request for comment on the proposed rule published in the Federal Register, Vol 62, No. 115, Monday, June 16, 1997 regarding "Exempt Distribution of a Radioactive Drug Containing One*Microcurie ofCarbon-14 Urea". We recommend that 10 CFR 32.2la(b)(2) regarding product labels be modified to also include the statement: "Due to the small quantity of radioactive material in this product, it is exempt from disposal requirements and may be disposed of in the general trash". Considering the anticipated wide use of this product by physicians and other health care workers who would not have a background in radiation protection, containers of this product will most likely be stored in unrestricted areas with very little control. This could lead to containers of this product getting into the public domain. By labeling the product as containing small quantities of radioactive materiais and expioring that the materiai may be disposed of in the general trash, you will avoid unnecessary concern for health risks and how to dispose of the item. This will be helpful to local, county, state and federal radiation response personnel who would normally be called when products labeled radioactive are found in the public domain. c: Thank you for taking the time to consider these recommendations. Jill Lipoti Bob Stem Sincerely, ~~z dministrator Radioactive Materials Section New Jersey is an Equal Opportunity Employer Recycled Paper ~ - 1 7 1997 -\\cknowledged by card.... --..... _.~;.,.

.,5. NUCLEAR REGULATORY COMMI8ti1Qr. DOCKETING & SERVICE SECTION OFFICE OF THE SECRETARY OF THE COMMISSION Document Statistics Postmark Date ----=1~ 1,,-/..:..'l...:;1 ___ _,, Copies Received. __

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UNIVERSITY OF CALIFORNIA, LOS ANGELES OOCKETED..... *******---- Rc ...,,,_~ UCLA ll~H !t BERKELEY

• DAVIS
• IRVINE
• WS ANGELES
• RIVERSIDE
• SAN DIEGO
• SAN FRANCISCO SANTABARBARA
• SANTACRUZ July 1, 1997 John Hoyle, Secretary us Nuclear Regulatory 11555 Rockville Pike Rockville, MD 20852 "97 UCLA SCHOOL OF MEDICINE HARBOR - UCLA MEDICAL CENTER DEPARTMENT OF RADIOLOGY 1000 CARSON STREET TORRANCE, CALIFORNIA 90509 PHONE:

(310) 222-2845 FAX: (310) 533-7159 EMAIL: MARCUS@AFP76.HUMC.EDU RE: RIN 3150-AF70; Fed. Reg.:62(115)32552-32558, 16 June 97: Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea DOCKET NUMBER

Dear Secretary Hoyle:

PROPOSED RULE PR 30 "' 3 :U ( (p,2 F~ 3:J5St2) I wish to offer some comments on the above Proposed Rule. First, I agree with the Commission that "..... the potential long-term impact from widespread releases of the long-lived C-14 (5730-year radiological half-life) from breath tests are insignificant." That being the case, why is NRC forbidding research use of this drug to the same physicians who may use it clinically? A gastroenterologist still has to put his research protocol through his institutional review board (IRB). The IRB will probably ask him to put it through the Radiation Safety Committee (RSC) even if it is an exempt radioactive drug. That is an ample review process and there is no reason why this activity should be forbidden. Why is NRC suddenly inserting itself into a regulatory process in which it has no business? Medical research is in the hands of FDA and OPRR, and NRC has absolutely no l egitimate role here. NRC's lack of scientifically and medically valid thinking is conspicuous by its absence. Please remove this part of the Proposed Rule. I strongly recommend, therefore, that clinical and research activities take place with exempt C-14-urea capsules. Second, I cannot fathom the naivete of NRC in the area of radi opharmaceutical manufacturing, an area of regulatory responsibility that belongs to FDA, with drug standar ds being determined by the USP. If a manufacturer sets out to make 1 µCi capsules, he will make capsules of 1 µCi+/- some percent, let us say a standard deviation of 10%. That means that about 95% of h i s capsules will be+/- 20%, and about 99% will be+/- 30%. With your proposed regulation limiting every single capsule to 1 µCi (32.2 (a)), fully half of each batch will represent a regulatory violation! Whether this was purposeful viciousness or plain incompetence on the part of NRC I can only surmise, but I recommend that this requirement be eliminated completely. The USP wi ll set the standard, the FDA will oversee manufacturing pr actices, and NRC's j ob is to get out of the way and do HYLDUT.Cat ,. k JUL 1 1 1997 --,c nowtedqed bv r.a~ri

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• ,5. NUCLEAR REGULATORY COMMr~

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July 1, 1997 John Hoyle, Secretary Page virtually nothing. Stop trying to usurp the statutory authority of the FDA and the USP. NRC has absolutely nothing to contribute here but harm. Third, it has taken four months short of three years to publish a poor quality proposed rule regarding this insignificant radiation risk. It should not have taken more than 30 days, and the decision should not have taken more than 30 minutes. I recommend that NRC review its personnel, management, and procedures to find out why such a trivial petition became maximally bureaucratized with nasty portions sneaked in. Fourth, I see that NRC has again permitted only 30 days for public comment. As NRC has been told many times before, it is impossible to obtain broad-based public comment in such a short time frame. Has FDA already approved an impending hostile takeover of part of its regulatory authority by NRC? Has OPRR? It appears that this JO-day comment limit is merely a trick to whisk through dangerous precedents. There isn't that big a hurry; it took the staff almost three years to produce this decision, and the manufacturer of C-14-urea is already in trouble. Another manufacturer got C-13-urea capsules through FDA recently, and NRC can't touch that product, so the NRC lurch to closure is of doubtful importance. Patients will get their urea breath tests. It is most unfortunate that NRC is doing everything in its power to destroy the C-14 alternative, however. Fifth, I wish to compare the ionizing radiation burden from the expected use of C-14-urea to that of Tc-99m and I-131, the principal byproduct radionuclides of nuclear medicine. If, as stated in NRC's Federal Register article, 10% of Americans can be expected to undergo testing for ulcers at some time in their lives, we have 26,500,000 people over, say, 50 years, or 530,000 workups/year. If half of these use C-14-urea breath tests, that is 265,000 tests/year. The total energy released from the complete decay of 1 µCi is as follows: C-14: 4.7 x 10W Mev Tc-99m:

1. 63 x 108 Mev Tc-99m incl. Tc-99: 2.8 x 108 Mev I-131:

2.1 X 1010 Mev 4.7 X 1014 = 2.9 X 106 1.63 X 108 417 :K 1014 = 1.7 X 106 2.8 X 108 41Z X 1014 = 2.2 X 104 2.1 X 1010 BTLDUT.CSM

July 1, 1997 John Hoyle, Secretary Page Therefore, in terms of total ionizing radiation released, 1 µCi C-14 = 2.9 Ci Tc-99m, 1.7 Ci Tc-99m + Tc-99, or 22 mci I-131. Assuming 265,000 C-14-urea breath tests per year, this is equivalent to 450,500 Ci Tc-99m + Tc-99, or 5830 Ci I-131. In nuclear medicine in the United States each year we perform about a,000,000 procedures a year using Tc-99m. If the average administered activity is, say, 15 mci, that is 120 million mCi/year. Figuring an equal activity lost to decay, we have 240 mil lion mCi/year or 240,000 Ci in nuclear medicine departments, approximately half of the C-14-urea eguivalent. Our I-131 patient administrations total about 1250 Ci/year; with decay losses, say 1500 Ci/year. This is 26% of the C-14-urea eguivalent. This means that the total ionizing radiation debt incurred with a year's worth of Tc-99m and I-131 in nuclear medicine is about 80% of that which would be incurred with a year's worth of C-14-urea breath tests. Even if we include the rest of byproduct nuclear medicine and all of accelerator nuclear medicine, we see that the C-14-urea breath test ionizing radiation energy release is about equal to that of all of nuclear medicine combined. If the radiation risks from C-14-urea breath tests are "insignificant", well, so are those of diagnostic and therapeutic nuclear medicine. As the Commission purports to now base regulation on risk, it would appear that a large paradigm shift is necessary in nuclear medicine regulation, because the risks of nuclear medicine have now been finally recognized by NRC as being insignificant. While fewer people have the potential to be exposed to higher levels of radiation in nuclear medicine than in C-14-urea breath tests, the simple requirement that all authorized user physicians and pharmacists be wel l qualified in basic nuclear and radiation sciences, and that all technologists be sufficiently trained to work effectively under the supervision of qualified authorized users, should be all that is required for safety. Thank you for your attention and consideration. s~ Carols. Marcus, Ph.D., M.D. Director, Nuclear Med. Outpt. Clinic and Professor of Radiological Sciences, UCLA BYLDRP'r.CSM

July 1, 1997 John Hoyle, Secretary Page cc: Chairman Shi rley Ann Jackson Commissioner Greta J. Dicus Commissioner Nils J. Diaz Commissioner James McGaffigan Joseph Callan, EDO Hugh L. Thompson, Jr., Deputy EDO Edward Jordan, Deputy EDO Carl Paperiello, Ph.D. Donald Cool, Ph.D. CSM:sfd BYLDUT.CIM

DOCKETED USN 9590-01-PJ

• 97 NUCLEAR REGULATORY COMMISSION JU 11 P 2 :Q3 10 CFR Parts 30 and 32 RIN: 3150-AF70 OFFI CE OF SECRETARY DOCKET IH,_J &. ~E <'II,E BF<A NC,i Exempt Distribution of a Radioactive Drug Containing One Microcurie of Carbon-14 Urea AGENCY: Nuclear Regulatory Commission.

DOCKET NUMBER PR PROPOSED RULE 3 o.J-3 -:i. ( "1 a Ft< 3 a.s5a) ACTION: Proposed rule; request for comments.

SUMMARY

The Nuclear Regulatory Commission (NRC) is proposing an amendment to its regulations that would 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 a minimal radiation risk and, therefore, regulatory control of the drug for radiation safety is not necessary. If adopted, this amendment would make the drug more widely available, and reduce costs to patients, insurers, and the health care industry. This action is being taken in response to a petition for rulemaking (PRM-35-12) submitted by Tri-Med Specialties, Inc.

~ II, I /'111 OATES: Submit comments by (IMert date 30 days attec publicetioo date) Comments received after this date will be considered if it is practicable to do so, but the Commission is able to assure consideration only for comments received on or before this date.

ADDRESSES: Send comments to: Secretary, U.S. Nuclear Regulatory Commission, Washington, DC 20555-0001, Attention: Rulemakings and Adjudications Staff. Hand deliver comments to: 11555 Rockville Pike, Rockville, Maryland, between 7:30 am and 4: 15 pm on Federal workdays. The public may examine comments received, the environmental assessment and finding of no significant impact, and the regulatory analysis at the NRC Public Document Room, 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 ANT@nrc.gov. SUPPLEMENT ARY INFORMATION: I. Background. II. Discussion. Ill. Summary of Proposed Amendments. IV. Agreement State Compatibility. V. Electronic Access. VI. Finding of No Significant Environmental Impact: Availability. VII. Paperwork Reduction Act Statement. VIII. Regulatory Analysis. IX. Regulatory Flexibility Certification.

x.

Backfit Analysis. XI. List of Subjects 2

I. Background 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 (JJCi) of 14C-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~ "Peptic ulcer disease is a chronic inflammatory condition of the stomach and duodenum that affects as many as 10 percent of people in the United States at some time in their lives. The disease has relatively low mortality, but it results in substantial human suffering and high e_conomic costs." (Source: Article included as an appendix to the petition, from JAMA, July 6, 1994, Vol-272, No. 1, "H.* pylori in Peptic Ulcer Disease-NIH Consensus Conference"). In the petition, the petitioner stated the following: Recent medical research has found that peptic ulcers are commonly caused by a bacterium called H. pylori. This bacterium lives in the stomach of most ulcer sufferers. By treating ulcer patients with antibiotics, doctors can now cure most ulcer problems. 3

It is therefore necessary to detect the pre~ence of H. pylori bacteria in ulcer patients so that the new treatment can be given appropriately. In the pa_st, this was done by a gastroenterologist who took biopsy samples of the stomach lining at endoscopy, a procedure which was uncomfortable and expensive ($1000). With the new test, H. pylori can be detected non-invasively using a 14C-urea tracer. 14C-urea is broken down by H. pylori to form labeled CO2 which is expired in the breath. To do the test, a doctor asks the patient to swallow the capsule with 30 mis of water. After 15 minutes the patient blows 2 liters of breath into a collection bag (a mylar balloon) which is mailed to a testing laboratory. If 14C-COLi:nore than twice background is present in the breath s~mple, then the patient. must be infected with H. pylori. This proposed rule, should it become final, would grant the petition for rulemaking (PRM-35-12) from Tri-Med and complete action on the petition. Public Comments on the Petition 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 61 831 ). The comment period closed on February 1 5, 1995. The NRC received 315 public comment letters, of which 313 su~port the petition (they were mostly form letters} and 2 letters opposed the petition. The two letters opposing the petition stated that the product 4

should not receive an exempt status because the uncontrolled distribution and application of this product could lead to significant risk to the public end that the medical uses should be restricted to short-lived isotopes because of disposal problems presented by long-liv-ed isotopes. The NRC has considered the two opposing comments and has determined the following: (1) The resulting radiation dose from the capsules to workers, patients, and the public is very low (see Regulatory Analysis). (2) The impacts associated with any releases of 14C to the surrounding environment are expected to be very small and the expected risks are minimal (see Environmental Assessment). Similarly, the small doses from naturally occurring 14C are of little significance to human health and the environment. Also, the Commission concludes that the potential long-term impacts from widespread releases of the long-lived 14C (5,730-year radiological half-life) from breath tests are insignificant. Comments from Advisory Committee on the Medical Uses of Isotopes This petition was discussed with NRC's Advisory Committee on the Medical Uses of Isotopes (ACMUI) at its October 1996 meeting. The ACMUI indicated that it endorsed the wide availability of this diagnostic test and that the radioactive drug could be used under a I general license or en exemption, whichever the NRC rnay determine to be procedurally easier. 5

11. Discussion Regulatory Issue The regulatory issue is whether capsules containing one microcurie of carbon-14 urea present a sufficiently small radiation risk that they can be safely distributed to any person (including physicians who are not *authorized users" under Part 35).

Current NRC Regulations for the Manufacture and Commercial Distribution of Radioactive Drugs Containing Byproduct Material NRC_regula:tions*in 10 CFR 32.72 address the manufacture, preparation, or transfer for commercial distribution of radioactive drugs containing byproduct material. This regulation requires manufacturers or preparers of radioactive drugs for commercial distribution to be: (1) Registered or licensed wit,h the U.S. Food and Drug Administration (FDA) as a drug manufacturer; (2) Registered or licensed with a state agency as a.drug manufacturer; (3) Licensed as a pharmacy by a State Board of Pharmacy; or (4) Operating as a nuclear pharmacy within a Federal medical institution. These facilities have a specific license with the NRC. Under the specific license, the manufacturer or pharmacy can distribute radioactive drugs only to persons authorized pursuant to Part 35, "Medical Use of Byproduct Material." 6

Current NRC Regulations for the Medical Use of Radioactive Drugs Containing Byproduct Material Currently, 10 CFR Part 35 only permits physicians who are authorized users (e.g., physicians who meet certain training and experience criteria regarding the safe use of radioactive drugs) or persons working under the supervision of an authorized user to administer radioactive drugs for medical use. The Agreement States have similar requirements. Current NRC Regulations on Exemptions from Licensing Existing exemptions from licensing requirements for the use of byproduct material include exemptions for specific products (e.g., time pieces), exemption for classes of products (e.g., gas and aerosol detectors) and broader materials exemptions in § 30.14, "Exempt concentrations," and § 30.18, "Exempt quantities." These two broad materials exemptions specifically exclude the transfer of byproduct material contained in any food, beverage, cosmetic, drug, or any product designed for ingestion or inhalation by, or application to, a human being. (In the case of exempt quantities, this prohibition is contained in § 32.18, "Manufacture, distribution and transfer of exempt quantities of byproduct material; Requirements for a license," § 32.1 S(b)). Capsules containing one microcurie of carbon-14* urea would not qualify as an "exempt quantity" in accordance with § 30.18 because of their intended use (as a drug) even though they contain a smaller quantity than that set forth in § 30.71, Schedule B. This use is outside the intent of the exemption currently in § 30.18. It would introduce 7

needless complexity to the regulations and confusion to accommodate this unique use under the aforementioned sections. However, because the capsules present an insignificant radiological risk to the public and the environment, the NRC believes they could be distributed to persons exempt from licensing for "in vivo" diagnostic use. Proposed Amendments for Permitting the Distribution of the Capsules to Persons Exempt from Licensing Proposed Amendment to 10 CFR Part 32 The regulations in 10 CFR Part 32 would be amended to add a new§ 32.21, to provide requirements for a specific license to manufacture, prepare, process, produce, package, repackage, or transfer for commercial distribution capsules containing one microcurie of carbon-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 proposed regulation would include 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 NRC has decided that the manufacture or preparation of capsules containing one microcurie of carbon-14 urea should continue to 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 8

contains only one microcurie of carbon-14 urea and does not contain any other radioactive contaminants. Proposed Amendment for Exempting "Any Person" from Licensing Requirements to Receive the Drug Proposed Amendment to 10 CFR Part 30 The NRC has determined that the drug in capsule form presents no significant radiological safety or environmental risk, and that it is not necessary to regulate the use of this drug for its radioactive component. Therefore, the ~RC can not justify requiring physicians, or any other person, to ~eet 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 would be amended to add a new § 30.21, to permit any person to receive, possess, use, transfer, own, or acquire for "in vivo" diagnostic use, capsules containing one microcurie of carbpn-14 urea without a license. The proposed regulation would include 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 9

person desiring to use the capsules for human research would still be required to submit an application for a specific license under Part 35 in order to protect human subjects. The phrase "in vivo diagnostic use" is being used in § 30.21 instead of "medical use" for two reasons. First, the term "medical use" has a specific meaning and is defined in § 36.2 to mean "the intentional internal or external administration of byproduct material or the radiation therefrom to patients or human research subjects under the supervision of an authorized user." This term would be inappropriate 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 be prohibited by this rulemaking. Effects of the Proposed Amendments The effect of these proposed amendments would be to 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 would be exempt from NRC licensing, Agreement States would need to make appropriate provisions in their regulations to r-ecognize 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 would not regulate the use of the drug as long es its use was for "in vivo" diagnostic use. This means that, under NRC end Agreement State regulations, primary-care physi'cians would not need to be *authorized users" In order to administer the drug, and would not necessarily need to refer their patients to nuclear medicine physicians. This should result 10

in cost savings to patients. Other Federal and State organizations with responsibilities for regulating drugs would be left to determine and regulate who could receive and use the drug for "in vivo" diagnostic use. NRC would regulate the use of the drug for research involving human subjects under a specific Part 36 license. Ill. Summary of Proposed Amendments Manufacturer and Distributors A new section would be added to 10 CFR Part 32 to permit the distribution of the \\ capsules to persons who are exempt from licensing. § 32.21 Radioactive drug; Manufacture. preparation. or transfer for commercial djstrjbution of carbon-14 urea capsules not exceedjng one mjcrocurie each for "in vivo" diagnostic use for humans to persons exempt from licensing; Reauirements for a license Paragraph (a) This paragraph would establish the requirements for approval of a license application to manufacture, prepare, process, produce, package, repackage, or transfer for commercial distribution carbon-14 urea capsules not exceeding one microcurie each for "in vivo" diagnostic use, to persons exempt from licensing. Paragraph (aH 1 > This paragraph would limit issuance of an "exempt distribution license" for distribution of the capsules to persons exempt from licensing to only those who possess 11

either a NRC or Agreement State "specific license" for possession and use of byproduct material. Paragraph (a}(2} To assure that the capsules contain no more than one microcurie of carbon-14 and present no other radiological risks, this paragraph would require that the persons manufacturing and/or commercially distributing the capsules for "in vivo" diagnostic use must also meet the requirements of § 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 (aH3) ( This paragraph would require applicants to provide evidence that each carbon-14 urea capsule will not exceed one microcurie. The NRC's evaluation that the capsules would not result in significant radiation risks was based on the capsules containing one microcu*rie of carbon-14 urea. Therefore, applicants must demonstrate that the activity of each carbon-'J4 capsule will not exceed one microcurie. Paragraph fa)(4) This paragraph would prohibit carbon-14 urea from being contained in any food, beverage, cosmetic, drug or other commodity designed for ingestion or inhalation by, or topical application to, a human being except for the capsules as described in this section, 12

I 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. Because of the capsule's "in vivo" diagnostic use, 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 {aH5) Because the exempt distribution of this drug 'has o*nly been evaluated for "in vivo" diagnostic use in the form of a capsule containing one microcurie of carbon-14 urea, this paragraph would prohibit 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 would require 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 would require persons who apply for a license to manufacture or commercially distribute these capsules to submit copies of prototype l~bels or brochures for NRC approval. This will allow the NRC to confirm that the labels or brochures meet the requirements of§ 32.21a (a) and (b). 13

Paragraph (bl This paragraph declares that the regulations do not relieve licensees or license applicants from complying with applicable FDA, other Federal, and State requirements governing the manufacture and distribution of drugs. Section 32.21 a Same; Conditions of license This section would establish the conditions required for a license 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 cnemical form, and the dosage of radioactivity, this paragraph would establish 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 tb) This paragraph would establish that, consistent with the intended use of the capsules, the label affixed to the immediate container, or an accompanying brochure, must: 14

(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." The intent of the requirement set out *in (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. Because of the capsule's "in vivo" diagnostic use, 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. "In vivo" diagnostic use bv persons exempt from licensing A new section would be 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 mjcrocurie of carbon-14 urea for "in vivo" diagnostic use for humans would be added to permit any person to receive the capsules. 15

Paragraph (al This paragraph would provide 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) below. Paragraph (bl This paragraph would establish that persons exempt from licensing would be prohibited from using the drug for research involving humans subjects. A specific Part 35 license would be needed to use the drug in any research involving human subjects. Paragraph (cl This paragraph would specify 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. 16

IV. 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, the proposed rule, if adopted, would be a Division 4 item of compatibility, with regard to the manufacture and commercial distribution of the capsules (10 CFR Part 32). Because of the need for nationwide consistency in the use of products which are widely distributed, the proposed rule, if adopted, would be a Division 1 item of compatibility with regard to possession and use (10 CFR Part 30). 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 without need for a license. V. Electronic Access Comments may be submitted electronically, in either ASCII text or WordPerfect format (version 5.1 or later), by calling the NRC Electronic Bulletin Board on FedWorld or connecting to the NRC interactive rulemaking web site,.,Rulemaking Forum." The bulletin board may be accessed using a personal computer, a modem, and one of the commonly available communications software packages, or directly via Internet. If using a personal computer and modem, the NRC subsystem on FedWorld can be accessed directly by dialing the toll free number: 1-800-303-9672. Communication software parameters should be set as follows: parity to none, data bits to 8, and stop bits to 1 (N,8, 1). Using ANSI or VT-100 terminal emulation, the NRC NUREGs and Reg Guides 17

for Comment subsystem can then be accessed by selecting the "Rules Menu" option from the "NRC Main Menu." For further information about options available for NRC at FedWorld, consult the "Help/Information Center" from the "NRC Main Menu." Users will find the "FedWorld Online User's Guides" particularly helpful. Many NRC subsystems and databases also have a "Help/Information Center" option that is tailored to the particular subsystem. The NRC subsystem on FedWorld can also be accessed by a direct-dial telephone number for the main FedWorld BBS, 7O3-321-3339,or by using Telnet via Internet, fedworld.gov. If using 7O3-321-3339to contact FedWorld, the NRC subsystem will be accessed from the main FedWorld menu by selecting the "Regulatory, Government Administration and State Systems," then selecting "Regulatory Information Mall." At that point, a menu will be displayed that has an option "U.S. Nuclear Regulatory Commission" that will take you to the NRC Online main menu. The NRC Online area also can be accessed directly by typing "/go nrc" at a FedWorld command line. If you access NRC from FedWorld's main menu, you may return to FedWorld by selecting the "Return to FedWorld" option from the NRC Online Main Menu. However, if you access NRC at FedWorld by using NRC's toll-free number, you will have full access to all NRC systems but you will not have access to the main FedWorld system. If you contact FedWorld using Telnet, you will see the NRC area and menus, including the Rules menu. Although you will be able to download documents and leave messages, you will not be able to write comments or upload files (comments). If you contact FedWorld using FTP, all files can be accessed and downloaded but uploads are not allowed; all you will see is a list of files without descriptions (normal Gopher look). An 18

index file listing all files within a subdirectory, with descriptions, is included. There is a 15-minute time limit for FTP access. Although FedWorld can be accessed through the World Wide Web, like FTP that mode only provides access for downloading files and does not display the NRC Rules menu. You may also access the NRC's interactive rulemaking web site through the NRC home page (http://www.nrc.gov). This site provides the same access as the FedWorld bulletin board, including the facility to upload comments as files (any format), if your web browser supports that function. For more information on NRC bulletin boards call Mr. Arthur Davis, Systems Integration ~nd Development Branch, U.S. Nuclear Regulatory Commission, Washington, DC 20555, telephone (301) 415-5780; e-mail AXD3@nrc.gov. For information about the interactive rulemaking site, contact Ms. Carol Gallagher, (301) 415 6215; e-mail CAG@nrc.gov. 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 proposed amendments, if adopted, would not be a major Federal action significantly affecting the quality of the human environment; therefore, an environmental impact statement is not required. The proposed rule would establish requirements for the manufacture and commercial distribution of 14C-urea capsules to persons exempt from licensing and establish regulations to permit any person to receive the capsules without an 19

NRC license. The Commission believes that the radioactive component of this drug presents no significant 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 proposed rule, if adopted, would 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 would be no non-radiological impacts if the proposed rule is adopted. The draft 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 draft environmental assessment and the finding of no significant impact are available from Or. 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. VII. Paperwork Reduction Act Statement This proposed rule amends information collection requirements that are subject to the Paperwork Reduction Act of 1995 (44 U.S.C. 3501 et seq.). This rule has been submitted to the Office of Management and Budget for review and approval of tlie information collection requirements. 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, end completing and reviewing 20

the collection of information. The Nuclear Regulatory Commission is seeking public comment on the potential impact of the collection of information contained in the proposed rule and on the following issues: 1. Is the proposed collection of information necessary for the proper performance of the functions of the NRC, including whether the information will have practical utility?

2. Is the estimate of the burden correct?

3. Is there a way to enhance the quality, utility, and the clarity of the information to be collected?

4. How can the burden of the collection of information be minimized, including the use of automated collection techniques?

Send comments on any aspect of this proposed information collection, including suggestions for reducing the ~urden, 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, (3160-0001, 3150--0017, and 3150-0120), Office of Management and Budget, Washington, DC 20603. Comments to 0MB on the information collections or on the above issues should be submitted by (insert date 30 days after publication in the Federal Register). Comments received after this date will be considered if it is practical to do so, but assurance of consideration cannot be given to comments received after this date. 21

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 0MB control number. VIII. Regulatory Analysis The NRC has prepared a regulatory analysis for the proposed rule. The analysis examines the benefits and impacts considered by the NRC. 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 ANT@nrc.gov. 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 proposed rule would permit physicians and other health care providers to use an additional diagnostic test without having to obtain en NRC license, thus, would provide cost savings to patients, insurers, and the health care industry. Any small entity subject to this regulation which determines that, because of its size, it is likely to bear a disproportionate adverse economic impact should notify the 22

Commission of this in a comment that indicates the following: (a) The licensee's size and how the regulation would result in a significant economic burden upon the licensee as compared to the economic burden on a larger licensee. (b) How the regulations could be modified to take into account the licensee's differing needs or capabilities. (c) The benefits that would accrue, or the detriments that would be avoided, if the regulations were modified as suggested by the licensee. (d) How the regulation, as modified, would more closely equalize the impact of regulations or create more equal access to the benefits of Federal programs as opposed to providing special advantages to any individual or group. (e) How the regulation, as modified, would still adequately protect public health and safety. X. 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). 23

XI. 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. 553, the NRC is proposing to adopt 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). 24

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 § 30.8, paragraph (b) is revised to read as follows:

§ 30.8 lnformatjon collection reayirements: 0MB approval. (b) The approved information collection requirements contained in this part appear in § §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 § 30.21 is added under the undesignated center heading "Exemptions" to read as follows:

§ 30.21 Radioactjye drug: Capsules containing one microcurie of carbon-14 urea for "in vivo" djagnostic 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 carbon-14 urea capsules, not exceeding one microcurie 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. 25

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

§ 32.8 lnformatjon collection requirements: 0MB approval. (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. 26

J

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

§ 32.21 Radioactive drug: Manufacture, preparation. or transfer for commercial ~ djstrjbution of carbon-14 urea capsules not exceeding one microcurie each for "in vivo" diagnostic use for humans to persons exempt from licensing: Reauirements for a license. (a) An application for a specific license to manufacture, prepare, process, produce, package, repackage, or transfer for commercial distribution carbon-14 urea capsules not exceeding one microcurie each for "in vivo" diagnostic use, to persons exempt from licensing under § 30.21 or the equivalent regulations of an Agreement State will be approved if: (1) The applicant satisfies the general requirements specified in § 30.33 of this chapter, provided that the requirements of § 30.33(a)(2) and (3) of this chapter do not apply to an application for a license to transfer byproduct materiel manufactured, prepared, processed, produced, packaged, or repackaged pursuant to a license issued by an Agreement State; (2) The applicant meets the requirements under § 32. 72{a)(2); (3) The applicant provides evidence that each carbon-14 urea capsule will not exceed one microcurie; (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; (6) The cerbon-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 27

(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§ 32.21a is added to read as follows:

§ 32.21 a Same; Conditions of license. Each license issued under § 32.21 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 28

12) 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."

Dated at Rockville, Maryland this /o {!: day of June, 1997. For the Nuclear Regulatory Commission. mmission. 29

From: To: Date:

Subject:

Emile, Carol Gallagher EI.J 7 /12/97 1 :26pm Comment Letters Could you please send me any comment letters you may have received on the proposed rule on Carbon-14?

Thanks alot, Carol Gallagher}}