ML20198K534

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Informs That Commission Has Considered & Approved Final Amends to 10CFR30 & 32,per .Amends Will Become Effective on 980102
ML20198K534
Person / Time
Issue date: 12/05/1997
From: Trottier C
NRC OFFICE OF NUCLEAR REGULATORY RESEARCH (RES)
To: Fry W
TRI-MED, INC.
Shared Package
ML20198K526 List:
References
FRN-62FR63634, RULE-PR-30, RULE-PR-32 AF70-2-002, AF70-2-2, NUDOCS 9801150031
Download: ML20198K534 (21)
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{{#Wiki_filter:. r i m ase gk UNITED STATE 8 g P) NUCLEAR REGULATORY COMMISSION - kMO k-- g WAsHINGrON O.C. BeteH001 December 5, 1997 i N em, Mr. William A. Fry, President - Tri-Med Specialties, Inc. 1500 Avon Street Ext'd Chad.ottesville,VA 22902

Dear Mr. Fry:

. ' In a letter dated Airjust 23,- 1994, you submitted a retition for rulemakirgroquesting that the

Nucieer Regulatory Commission (NRC) amend its regulations'*to allow for the general licensing d and/or esemption for the commercial distribution by licensed pharmaceutical manufacturers of a.

'9 capsule cordirilrig' one microcurie of carbon-14 urea for in vivo diagnostic testing.' s;;, o., - r As a result of your petition, the Commission has considered and approved the final amendments to 10 CFR Parts 30 and 32. These amendments have been published in the Federal Register (62 FR 63634; December 2,1997) and will become effective on January 2, 1998. A copy of the Federal Register notice is enclosed for your information. Sincerely, 0 NN Cheryl A. Trottier, Chief Radiation Protection and Health Effects Branch Division of Regulatory Applications Office of Nuclear Regulatory Research

Enclosure:

As stated 4.* 4 5 j 4 m n,, e.,- - 4 M 9901150031 980104 PDR PR 30 62FR63634 PDR drr ..,e. r - ui

,a 63034 red:r:1 Regist:r / Vol. 62. No. All / Tuesday, leecember 2,1997 / Rules and Regulttions SUPPLEMENTARY INFORMATION: tha drug for r: diction niety is not mortly form lettus) and 2 letters Wfb 4. BaQround necessary. This amendment makes the opposed the petition. tfents,i su IL Propoacd Rule, Public Comments, The final rule that is the subject of ts to rs a and NRC Responses this correction was intended to provide health care industry This action grants a policy changes to better meet the needs a pntition for rulemaking (PRM-35-12) A proposed rule was published on of the insured, include the current fresh from Tri.Med Specialties,Inc. and lune 16,1997 (62 FR 32552) that would market tomato (dollar plan) completes action on the petition. permit NRC licensees in distribute ' endorsement under the Common Crop capsules containing one microcurie insurance Policy for case of use and EFFECME DATE* Jarmary 2,1998. C-14 urea to any person for "in vivo" consistency of terms, and to restrict the ADDRESS: Copies of the public record, diagnostic use. The public comment effect o' the current tresh market tomato including the final regulatory analysis period closed on July 16,1997. (dollar plan) endorsement to the 1997 and any public comments received on in the preamble of the proposed rule, and prior crop years. the proposed rule, may be examined the NRC stated that, because the and copied for a fee in the capsules prese.it an insignificant Need for Correction Commission's Public Document Roofu radio %n risk to the public and the As published, the final regulation at 2120 L Street, NW, (l.ower Level), en,tronment, the NRC believes the contained a technical error which may Washington, DC. r Aps.*le8 COuld be distributed for "lp el " diagn sti use to persons exempt prove to be misleading and la in need FOR FURTHER INFORMAtlON CONTACT: Dr. of clarification. I* ke" Anthony N. Tse, Jffice of Nuclear T ischa makes the drug more Correctioc. of Publication Regulatory Research., U.S. Nuclear widely available and reduces costs to 8 Accordingly, the publication on 8\\5 patients, insurers, and the health cere 5S 0 phon 3 4 6233 or e-mail at ANT @nrc gov. (e)RC received seven public a 62 14775-14780 i corn > follows: SUPPLEMENTARY INFORMATION: comment lettses on the proposed rule: three from industry, three it. 9 tate PART 457--{ CORRECTED] gdh" "g",I ', fu#b unents. and I agencies, and one from a p

  • man g,

l 457.139 (Corrected) NRC Responses. associated with a university wdical 11L Summary of the Final Amendments. facility. Four commenters supported the On page 14780, in the first column, in IV. Description of the Final Amendments. rule, one opposed the rule, and two S 457.139, the paragraph following V. Agreement State compatibility. provided comments but did not section 14(b)(4)(li)(H)is corrected to VI. Finding of No Significant Environmental explicitly state whether they supported read: Impact: Availability. or opposed the rule. Public comments "(51 Multiplying the result of section VII. Paperwork Reduction Act Statement-and NRC's responses are presented 14(b)(4) by your share." Vill. Regulatory Analysis-below. tX. RegulaWry Meubdity Vedifkation. Comment 1: Under the proposed S6gned in Washington D C. on November X. Small Business Regulatory Enforcement distribution, the NRC should not be Kenneth D. Ackermaa, XI. I c n sis. f thidding research use of this drug by Afanager, Fedeml Crop fnsumnce the same pnysicians who may use it Corpomtion. l.ist of Subjects clinically. Research use also should be IFR Doc. 97-3t545 Filed 12-t-97, a 45 aml I, The Petition for Rulemaking permitted under,this exemption because the radiological risk for using C-14 e cops u w On October 6,1994, the Commission capsules is insigalficant. docketed a petition for rulemakinF Response: The NRC did not change (Docket Na. PRM-35-12) from Tri Med the final rule in response to this NUCLEAR RF.lULATORY Specialties, Inc (Tri# id), in a letter comment, A common rule entitled COMMISSIOP dMed August 23,1994 Tri.Med " Federal Policy for the Protection of 10 CFR Parts, 3 and 32 petiti ned the NRC to amend its iluman Subjects. Notices an i Rules" regulations "to allow for the generel was promulgated : i 16 Federal agencies RIN 3154-AF70 licensing and/or exemption for the on June Ill,1991 (s6 FR 28002) and was c mmercial distribution by licensed intended to ensure the protection of Exempt Distrii ution of a Radioactive pharmaceutical manufacturers of a human research subjects. This rule was Drug Containh g One Microcurie of capsule containing one micro. Curie adopted to implement a Cart >on 14 Ure" (pCi) of C-14.ures for in vivo diagnostic recommendation of the President's AGENCY:Nuclea Regulatory testing." The purpose of this diagnostic Commission for the Study of Ethical j Commist on. test h to detect the presence of the Problems in Medicine and Biomedical + ACTION: Final rule, bacterium HeHcobacMT pylori (IL and Behavioral Research which was [ pylori), a cause of peptic ulcers in established on November 9,1978, by SUMNARY: The Nuclear Regulatory humans-Public Law 95-622. The Federal Policy Commission (NRC)is amending its Following the receipt of the petition, requires that Federal agencies that risulations to permit NRC licensees to the NRC published for public comment conduct, fund, support, or regulate distribute a radioactive drug containing a notice of receipt of petition for research involving human subjects one microcurie of carbon-14 urea to any rulemaking in the Federal Register on ensure adequate protection of the rights person for "in vivo" diagnostic use, The December 2,1994 (59 FR 61831) The of the human subjects. The Federal NRC has determined that the radioactive comment period closed on FeNuary 15, policy' represents a societal component of such a drug in capsule 1995. The NRC received 315 public determination that any research form presents an insignificant radiation commcnt letters, of which 313 (including research involving risk and, therefore, regulatory contml of supported the petition (they were radioactive rnaterial) must provide for

i 63635 Fed:r:1 Register / Vol. 62. No. 231 / Tuesday, December 2,1997 / Rules and Regulations the following minimal protections for ~ of Tc-99m and 1-131, the NRC did not that the NRC take action to expedite the the human subjects: (1) that the research evaluate the dose to the patient because Agreement State regula Response:The NRC has urged the this dose would be justified for medical Agreement States to adopt compatibic j is approved by an Institutional Review reasons. Justification for retaining some changes in their regulations floard (IRil) and (2) that the human bcensing control on the medical use af expeditiously. Ilowever, under NRC's sub)cct gives informed consent to Tc-99m and I-131 while exempting the Adequacy and Compatibility olicy, participate in the research. Further, one microcurie carbon 14 urea capsules Agreement States have up to three year p these protections must be pmvided relies on the rel tive occupational flak cf consequences (including hazards to technicians and physicians to change their regulations for regardless of whether or not there is any radiological consequences). This view is administering the nadiopharmaceuticals. amendments or p Administering an encapsulated that are items of compatibility. Comment 6. The NRC should address l suported by the fact that during the dosage of one microcurie C-14 involves this rule in its ongoing effort to revise pumic comment period 7f the common virtually no occupational dose due to to CFR part 35 in its entirety. The rule, a commenter suggested that all - the low energy beta radiation and minimal possibility for contamination of cornmenter believes that (1) this rule minimal risk research be exempt from represents a piecemeal effort to respond the regulations; however, the final rule personnel or facilities. On the other to a narrow issue and (2) the issue of did not adopt this comment. hand dosages of Tc-99m and 1-131 redi. cod regulation for medical use of C-NRC did not participate in the promulgation of the common rule. entail extracting 10s to 100s of 14 capsules is applicable to the same Subsequently, the NRC adopted 10 CFR millicurie amounts, often in liquid form, extent for virtually the entire range of e 35.6 that requires a licensee who from shielded sources of even higher j conducts research involving human activity. The possibility of direct diagnostic radioisotopes. lle8Ponse:If this rule is combined aubjects using byprouuct material to exposure to gamma radiation and the with the overall to CFR part 35 revision, obtain informed consent from the possibility of contamination requires the C-14 capsules would only be human subjects and obtain prior that radiation protection measures be in available to avthorized user physicians approval by an IR11. Although the NRC place to maintain exposure to staff as during the revision period. Thus, the did not adopt the common rule, the low as is reasonably achievable. NRC decided to proceed with this rule Tc-09m and 1-131, having relatively now tmcause the benefits of making this intentic, in to fnllow the essential short half lives, present minimal requirements of the common rula. environmental hazard. C-14 as urea is capsule available to anyone, inchding primary. care physicians, outweigh the Elecause the common rule does not excreted from the patient as carbon benefits of addressing this issue in the provile an exemption for research dioxide (CO ) which diffuses into the involving minimal risk, the Commission atmosphere. Based on a calculation overall revision of to CFR part 35. 2 has determined that such research use found in the regulatory arialysis for this Comment 7: An appropriate function should not be exempt from to CFR 35,6 rule, the current world inventory of of ti,o reguiatory regime is to assure that naturally occurring C-14 results in an personnel handling and administering Comment 1:Two commenters expressed concerns that the proposed average dose to members of the public ra.ficactive drugs meet certain basic rule language,"not exceeding 07e of about 1.25 mrem /yr. A release of a 6 training and qualification requirements. mictncurie," appeared to indicate that the upper limit of the radioactivity in a curies of C-14 from the 600.000 tests The proposed exemp' ion would impose capsule is exactly one microcurie of expected to be administered annually, no training or qualification C-14. iloth stated that it is not possible would result in an additional average requirements on users. Response:The amount of radiation to make the capsules to exactly one annual dose of 2x10 " miem. microcurie because of statistical Comparing this estimate to the 1.:pA safety training needed for personnel deviations during the manufacturing Clean Air Act reporting level of 1 tr. rem / depends on the level of radiation risk associated with the radioactivo drug. year, this new test is environmentally Because C-14 capsules present process. flesponse:The NRC agrees with the insignificant. commenters. The proposed rule did not comtnent 4: Because of the smah insignificant radiation risk, radiation intend to limit the radioactivity of C-14 quantity of radioactive materialin C-14 safety training for personnel %dling to exactly one microcurie. The final rule capsules, this product may be disposed and administering the cap .s not language has been modified to read of in the general trash. To avoid necessary, and thus, not required. Comment st if the NRC promulgates " capsules containing one microcurie unnecessary concern for health risks in the proposed rule in its present form, C-14 urea (allowing for nominal the disposal of the product, labels the exemption will disest the variation that may occur during the should contain a statement that the manufacturing process)." product may he disposed of in the Agreement States of any authority to regulate this product under a general or Comment 3:One commenter stated general trash. that, when the total amount of energy Response:In the final rule, the label specific license. Ilad the NRC instead released from complete decay of a requirements include a statement that simply proposed a generallicense, radionuclide in considered, one the product may be disposed of in Agreement State agencies would retain the authority to adopt the general microcurie of C-14 Eas the largest ordinary trash. license or continue to require specific Comment 5: The Commenter agrees energy release, hocause of its long half. that the widesprtad use of this product licensing. life, when t.ompared to one microcurie will require uniform regulations and Response:In the draft rulemaking of Tc-99m or 1-131. The commenter concluded that, given the insignificant that Agreement States will need to make plan, the NRC suggested using the radiation risk from the diagnostic use of appropriate regulatory provisions to generallicense approach. The NRC C-14 urea, the radiation risk from the enable persons to receive the drug for received nine comment letters from diagnostic use of Tc-99m or 1-131 also "in vivo" diagnostic use. To avoid Agreement States on the draft confusing licensees and t ers, these rulemaking plar ; three suggested that an would be insignificar.t. flesponse:In comparing the har.ard changes to NRC and Agree nent State exemption app each would be more appropriate t.ecause it would be less significance of the one microcurie C-14 regulations should be ma 2 Urea diagnostic test to the extensive use simultaneously. The com 1 enter urges costly to the Agreement States and their i l i i I

63El6 fcomi Regist:r / Vol. 62. No. 2.$1 ' Tuesday, December 2, linl7 / Rules and Regulations liccusees than tha g:nml license c psutra m:nuf:ctured or prep: red es a the release of 0 6 curies of C-14 from

cpproach, r:dicactivs drug can be distributed to the tot:1 of 600,000 tests casumed to be Based on these comments, the NRC persons exempt from licensing for "in administered annually would result in chose the exemption approach in the vivo" diagnostic use because the an additional average annual dose of final rule plan as more cost. effective capsules present an insignificant 2 x 10" miem. In the event that a recall than a general license approach. The radiological risk to the public and the is necessary, the manufacturer may use final rulemaking plan was revised env;ronment. This exemption only the same process for recalling any other accordingly and wu provided to the applies to the diagnostic use of capsules non radioactive drugs. If C-14 urea Agreement States. No Agreement States containing one microcurie C-14 capsules arr eturned to the expressed opposition to the NRC on the manufactured or prepared as a manufacturers, they will be disposed of exemption approach.

radioactive drug to make a clear in accordance with the manufacturer's Among the seven public comment distinction between this radioactive possession license. A user, however, can letters mceived on the proposed rule. drug that is intended for ingestion by dispose the C-14 urea capsules as Iwo were from Agreement States and humans and other uses of C-14 urea and ordinary trash. Meuscal users of the G-one from a non Agreement State. All byproduct material distributed under 14 urea test would be unlikely to three supported the proposed rule. $$ 30.14 and 30.18. acquire significant quantities of Comment 9:The enviruumental Comment !2:The ACMUI's (Advisory capsules because they can be ordered traessment fails to consider the fact that Committee on Medical Uses of within a few days. Thus, even under a another equally noninvasive, but Radioisotopes) conclusions that either recall, the impact of disposing of C-14 nonradiological, diagnostic procedure an exemption or general license is urea capsules into landfills by the user (such as G-13 test)is available and appropriate for the C-14 product do not would also be insip,nificant. provides a comparable alternative to the address the fundamental aspects of Con, nent 13:lt is essential that end C-14 test. The apparent assumption nuclear safety. Its judgment was based users be adequately informed of the underlying the environmental partially on the assumptions: (1) the product's radioactive characteristics, so ainessment la that in the absence of tue product may only be dispensed by that some form of storage, use, and C-14 test, the only alternative fos the prescription (2) the product is approved disposal precautions can be followed, detection of 11. pylori is invasive by the Food and Drug Administration. Thus, the labeling must be gutroendoscopy. and (3) the office / facility using the conspicuously and prominently placed. Res nse: Because the C-14 urea product will be subject to Clinical The commenter suggested the following: cepsu es are already available to Laboratory Improvement Amendment (1) the phrase " conspicuously and suthorized user physicians, the ook (CLIA) regulation. rominently"in front of the proposed n ulatory issue in this rulemakini a Response:The transcript from the beling " bears the words Radioactive w ether the G-14 method should b< ACMtn meetlag shows the Committec Material" should be added, and (2) the m:de available to individuals who are did include radiation safety in its NRC should require that the rad'9 active not authorized users, The purpose of the considerations and did not consider it t material legend, " Radioactive Material," environmental assessment is to consider be an issue. Further, as stated in the be included on promotional brochures. and document whether the subject rule supplemental material supporting the Response: Because the radiation risk is expected to have any significant proposed rule, there are no nuclear from C-14 capsules is insignificant, impact to the environment. In this safety issues associated with the use of regulatory control of the use, storage, environment assessment, the NRC his the C-14 capsules for clinical diagnostic and disposal of the drug for purpose of determined that the environmental testing. Therefore, use of either an radiation safety is not necessary. In fact, impact is expected to be insignificant exemption or general license is the label accompanying C -14 capsules because of the extremely low ap ropriate-is t utred to indicate that the capsules rrdiological hazards associated with ths mment 12:The exemption inay se disposed of by users as ordinary urs of capsules contalning one appmach does not provide the NRC trash. Paragraph (a)(6) of 5 32.21 requires microcurie C-14 Laca. The presence of with flexibility to impose a limitation an tdditional non. invasive alternative on the amount of C-14 capsules any that applicants submit co les of procedure does not affect NRC's physician can possess in an office. In prototype labels and broc ures for NRC dItermination of no significant the event there is a recall of the product' appmval. The NRC will ensure that the environmentalim act. or a lar e amount of product becomes labels meet the requirements of $ 32.21a g m th are a roved.S Comment 20 N C's policy in the past unusab o, the NRC will have no control has been not to exempt bypmduct over the disposal of the product. p grap )g p t labe mus d ble d legible miterial that is ingested. Any change in Response:lt is not necessary to this policy would be a significant impose a iossession limit on the P n8P cuously and prominently,is l ,,C departure fmm existing NRC amount o C-14 capsules because the regulations, radiation risk is insignificant. The unnecessary. Promotional brochures are Response: Thk change is a departure earth's atmosphere contains an f r information only: manufacturers are imm existing NRC regulatioes. In the inver. tory cf naturally occurring C-14 of not mquired to indicate on the st:tement of consideration for the about 3.8 million curies which is in Pmmotional brochures that C-14 is a radioactive material proposed rule, under the heading addition to the huge inventory of about " Current NRC Regulations on 240 million curies in the world's III. Summary of the Final Amet. aments Exemptions From Licensing," the NRC oceans. The small amount of C-14 Final Amendment to 10 CFR Part 32 at:ted that, although two broad matenal released into the atmosphere from the exemptions ($ 30.14, " Exempt use of this test would mix with the The regulations in 10 CFR part 32 are concentrations," and 5 3018. " Exempt global inventory and would have no amended to add new SS 32.21 and qu:ntitles") exclude the transfer of impact on public health. The curreat 32.21a, to provide requirements for a byproduct material contained in any world inventory of naturally occurring specific license to manufacture, prepare, product designed for ingestion or C-14 results in an average dose to the process, produce, package, repackage, or inhalation by a human being, the C-14 public of about 1.25 mrem per year, and transfer for commercial distribution,

Federal Register / Vol. 62. No. 231 / Tuesday, December 2,1997 / Rulee and Regulations 63637 capsules containing one microcurie of authorized in S.i0.21 to differentiate it capsules to persons who are exempt C-14 urea, as a radioactive drug, to be from the term " medical use" becausm from licensing. distributed to any person for "in vivo" (1)" Medical use" limits Sev: tion 32.21 Radioacthe Drug: diagnostic use. These requirements are administration to authorized users; use Afonufacture, Prepamtion, or Tmnsfer consistent with the existing of this drug would not be so limited; for Commercial Distribution of Capsules requirements on other items under the and.. Medical use,, includes the Containing one Afictr. curie Carbon 14 heading " Exemptions" in 10 CFR part (2) g ,,g g,o" Diagnostic use

30. The amendment includes a reminder administration of the drug to a human gp g,,,p, y,,,

that licensees distributing the research subject, which would continue gy, i radioactive drug to persons exempt from to require a specific license pursuant to l licensing would not be relieved from Part 35 under this rulemaking. paragraph (a) other applicable Federal le#, FDA) or Effects of the final Amendinents This paragraph establishes the { State requirements governing the The final amandments make the drug *1uirements for approval of a license manufacture and distribution of drugs. available to any person, for "in vivo" application to manufacture, prepare, The amendment requires that the diagnostic use, without need for an NRC Pmcess, roduce, package, re ckage,or transfer or commercial distri ution, manufacture or preparation of capsules or Agreement State license. Because the capsules containin one microcune containing one microcurie of C-14 urea receipt and use of the drug are exempt carbon.14 urea cac for,'in vivo be prepared by persons who meet the - from NRC licensing, Agreement States disguostic use, to persons exempt from [o current ARC regulations to manufacture need to make appropriate provisions in and cormnercially distribute radioactive their regulations to recognize the IIC"RSI"8- "",Pt distribution of the drug, for "in Paragraph (a)(1) 'j n 1I neede r vi hig vivo diagnostic use. Thus after the This paragraph limits issuance of an confidence that the rug contains one d " exempt distribution license" for microcurie of C-14 urea and o es not dn g ie N C and t g n ent Stams distribution of the capsules to persons contain any other radioactive will not regulate the use of the drug as exemP rom licensing to only hose tf contaminants

  • lon8 as its use is for "in vivo" dia8nostic who possess either a NRC or Agreement final Amendment to ;0 CFff Part 30 use. This means that, under NRC and Staw " spec fic license" for possession

"[,"'*[dnt [Od t and use of byproduct material. The NRC has determined that the i,, t drug in cap - de form resents an " authorized users" in order to Paragraph (a)(2) administer the drug, and do not need t To assure ' hat the capsules contain iront antal ti k and th t t is i t refer their patients to nuclear medicine one microcurie of carbon.14 and present necessary to regulate the use of this drug phy sicians. This should result in cost no other radiological risks, this for its radioactive component. saving8 to Patients. Other Ftderal and paragraph requires that the persons Therefore the NRC can not justify Staw organizati ns with responsibilities manufacturing and/or commercially requiring physicians, or any other for regulating drugs will determine and distributing the capsules for "in vivo" person, to meet NRC training and '"8"I"" who can receive and use the diagnostic use must also meet the experience criteria directed at the safe drug for 'in vivo, diagnostic use. NRC requirements of $ 32.72(a)(2), use of radioactive drugs, or to become wm conunue t regulate the use of the Sp(ecifically, these persons must be:1) an " authorized user." llence, the drug for research involving human capsules can be distributed to any subjects under a specific part 35 hcense. FDA as a drug manufacturer; or person. tiowever, other Federal or State (2) Registered with or licensed by a agencies may limit the receipt and use IV. Description of the Final ea a8 d f stf3) fe d s a h "a"cy" *bte of the capsules in accordance with their Amendments own requirements. The final amendments are the same as floard of Pharmacy; or The regulations in to CFR part 20 are the proposed amosidments except for (4) Operating as a nuclear pharmacy amended to add a new S 30.21, to permit two minor changes. Public comments within a Federal medical institution. i any person to rece6e, possess, use, suggested that the phrase " carbon 14 transfer, own, or acquire for "in vivo" urea capsules not exceeding one Paragraph (a)(3) diagnostic use, capsules containing one microcurie" used in the proposed rule This paragraph requires applicants to [ microcurin of C-14 urea without a may be interpreted as an exact limit of pmvide evidence that each carbon.14 ) license. The final regulation includes a one trJcrocurie per capsule (See urea capsule contains one microcurie. reminder that persons receiving the Comment 2 under the heading "Public The NRC's evaluation that the capsules capsules would not be relieved from Comment and NRC Responses). The would result in insignificant radiation other Federal or State law governing final rule has been modified and the risks was based on the capsules drugs. Further, in accordance with the phrase " capsules containing one containing one microcurie of carbon 14 NRC's provisions for research involving microcurie carbon 14 urea (allowing for urea. Therefore, applicants must human subjects (10 CFR 35.6), the nominal variation that may occur during demonstrate that the activity of each exemption permitting receipt and use of the manufar turing process)" is used. carbon-14 capsule contains one the capsules for "in vivo" diagnostic use Another public comment suggested that microcurie, allowing for nominal does not extend to use of the capsules labels should contain a statement that variation that may occur during the I for research involving human subject $- the product may be disposed ofin the manufacturing process. Any person desiring to use the capsules general trash. In the final rule, the label Paragraph (a)(4) for human research would still be requirements include such a statement. This paragraph prohibits carbon.14 required to submit an application for a specific license under part 35. The Afanufacturer und Distnbutors area from being contained in any food, phrase "in vivo diagnostic use" was A new section is added to 10 CFR Part beverage, cosmetic, drug or other selected to describe the activity 32 to permit the distribution of the commodity designed for ingestion or

. ~~._ - -63636' Federd Register / Vol. 62. No. 231 / Tuesday, December 2,1997 / Rules and Regulations ~ inhalation by, or topical a plication to, (1') Identifies the radioisotope, the include " transfer for commercial a human being except for the capsules physical and chemical form of the distribution," which is covered in as described in this section, because radioisotope, the go.ntity of paragraph (cl of this section. sximpt distribution of this drug has radioactivity contamed in each -. Paragraph (b) only been evaluated for "in vivo" container at a specific date; and ~ diagnostic use in the form of a capsule (2) Bears the words " Radios ive This paragraph establishes that persons who desire to ese the drug for containing one microcurie of carbon 14 Material." research involving human subjects must urea. There is no prohibition against the The date requirement is consistent cepsula being combined with food or ~ with labeling requirements for other apply for and receive a specific part 35 beverage at the time of administration so radioactive drugs with a half life of license. Such a license would ensure the that the capsule can be ingested by the greater than 100 days. protection of the rights of the human subjects by requiring that the research patient. Paragraph (b) be approved by an IRB and that the Pcragraph (a)($) This paragraph establishes that, human subjects give their :nformed Because the exempt distribution of consistent with the intended use of the consent to participate in the rea,earch. this drug has only been evaluated for capsules, the label affixed to the Paragraph (c) "in vivo" diagnostic use in the form of immediate container, or an a capsule containing one microcurie of accompanying brochure, must: This paragraph specifies that a ccrbon 14 urea, this paragraph prohibits (1) State that the contents are exempt 8Pocifir: license is needed to incorporation of the capsules into any from NRC or Agreement State licensing manufacture, prepare, process, produce, package, repackage or transfer such manufactured or assembled commodity, requirements; product, or device intended for (2) Bear the words "Redioactive capsules for commercial distribution. commercial distribution. Further, Material. For "In Vivo" Diagnostic Use Paragraph (d) cithough the drug is being distribwed to Only. This Materialis Not To De Used This paragraph declares that the parsons exempt from licensing, this for Research involving fluman Subjects. regulations do not relieve end users raph requires the carbon 14 uros to and Must Not Be introduced into Foods, from complying with applicable FDA, btrafontitled as radioactive because the Beverages, Cosmetica, or Other Drugs or other Federal, or State requirements i drug is being used for its radioactive Medicinals, or into Products content; therefore, the end user must be Manufactured for Ca nmercial g verning the receipt, administration, and use of drugs, provided with information that the drug Distribution. This Product May He contains a radioactive material, Disposed of in Ordinary Trash." V. Agreement State Compatibility e n mquimment ad ut Under the Atomic Energy Act,certain Peregraph (a)(6) in Paragraph (b)(2) is to make clear that regulatory functions are reserved to the As with any product approved for the capsule must remain in the form of NRC. Among these are tie distribution distribution to persons exempt from a capsule and is not to be combined it f;i[d[g,",*di with one of the listed items such as food c g ssed to FR tt licensing, this paragraph requires persons who apply for a license to or beverages which would result in a 150. llence, amendments related to the minufacture or commercially distribute radioactive product other than in the manufacture and commercial these capsules to submit copies of foan of a capsule for commercial distribution of the capsules (10 CFR part prototype labels or brochures for NRC distribution. There is no prohibition 32)is a Division 4 item of compatibility approval. This will allow the NRC to against the capsule being n,mhined (Category NRC under the new ad uacy confirm that the labels or brochures with food or beverage at the time of meet the requirements of $ 32.21a (a) administration so that the capsule can ,"[' C g]'f,bjil [P 1c ev r and (b) be ingested by the patient, This label use (10 CFR part 30) are a Division 1 Paragraph (b) ayfe di p se I ofin o hem of compatibility (Category B under n y tras the new adequacy and compatibility This paragraph declares that the "In Vivo" Diagnostic use by Persons policy) because of the need for regulations do not relieve licensees or Exernpt from Licensing nationwide consistency in the use of Products which are widely distributed. A new secti,is added to 10 CFR Part Therefore, the Agreement States will 1 , at er edera and State requirements governing the manufacture 30 to exempt any person from NRC or need to make appropriate provisions in the Agreement State regulations to thmr regulations to allow any person to and distribution of drugs' receive tha drug for "in vivo" diagnostic receive capsules containing one Section 32,21a Some: Conditions of use for humans. microcurie of carbon 14 urea for "in License Section 30.21 Hadiooctive Drug: vivo" diagnostic use in humans without This section establishes the Capsules Contoining one Microcurie of need for a license. conditions required for a licensee to Cartwmd4 Uno for "in Vivo" Diognostic VI. Finding of No SigniGcant commercially distribute the capsules to use far Humans EnvironmentalImpact: Availability persons exempt from licensing. P g ph (a) The Commission has determined Pcragraph (al - This paragraph provides an under the National Environmental To inform the end user of the identity exemption to any person rom the Policy Act of 1969, as amended, and the 8 of the radiol.otope, the physical and requirements for a license to receive. Commission's regulations in Subpart A chemical form, and the dosage of possess, use, cansfer, own, or acquire of 10 CFR part 51, that the final rule is radioactivity, this paragraph establishes capsules containing one microcurie of not a major Federal action significantly th:t the immediate container of each carbon 44 urea for "in vivo" diagnostic affecting the quality of the human ctpsule or capsules must bear a durable, purposes. It should be noted that the environment; therefore, an legible label that: " transfer"in this paragraph does not environmental impact statement is not

nanm m aam a federal Register / Vol. 62 No. 231 / Tuesday, December 2,1997 / Rules and Regulations 63G39 required. The final rule establishes Regulatory Affairs.NEOB-10202, backfit analpls is not required because rmjulrements for the manufacture and (3150-0001,3150-0017, and 3150-these amendments do not involve any j cornmercial distribution of carbon 14 0120) Office of Management and provisions that would impose backfits urea capsules to persons exempt from iludget. Washington. DC 20503 as defined in 10 CFR 50.109(a)(1). PuMe Prom n Notificati n XII. List of Subjects ern t yl t t i e f rapsmes without an NRC license. The The NRC may not conduct or sponsor, 10 CFR Part 30 Commission believes that the and a person is not requirmi a respond radioactive component of this drug to, a collection rq information unless it Byproduct materiah Criminal presents an insignificant radiation risk displays a currently valid OMH control penaltic6, Government contracts, j and, therefore, regulatory control of the

number, intorgoverrmental relations, Isotopes.

l Nuc! car materials, Radiation protection, "in vivo" diagnostic use of the capsules VIII. Regulatory Analysis Repoiting and rccord keeping for radiation safety is not necessary. It The NRC has prepared a regulatory requirements. is expected that this final rule will not analysis for the final rule. The analysis cause any significant increase in examines the benefits and impacts 10 CFH Part 32 radiation exposure to the public or considered by the NRC. No public B roduct material Criminal. radiatloc release to the environment comments on the draft regulatory Penya ties Laging. Nuclear matenals, beyond tne exposures or releases analysis have been roccived during the Radiatinn protection, Reporting and resulting frem the use of the carbon-14 analysis is availabieriod. The regulatoryle for inspection at the public comment recordkeeping requirements. capsules under the current regulations, Also,it is expected that there will be no NRC Pubilc Document Room,2120 L For the reasons set out in the I non.adiological impacts. One pubile comment on the draft environmental Street NW. (Lower f.evel), Washington, preamble and under the authority of the assessment has been received (See DC. Single copies of the regulatory Atomic Energy Act of 1954, as amended, Comment 9 under the heading analysis are available from Dr. Anthony the Energy Reorganization Act of 1974, " Proposed Pule, Public Comments, and N. Tse Office of Nuclear Regulatory as amended, and 5 U.S.C. 552 and 553. NRC Responses") Research, U.S. Nuclear Regulatory ~ the NRC is adopting the followmg amendments to 10 CFR Parts 30 arid 32. The environmental assessment and Conumssion, Washington, DC 20555-finding of no signlIicant impact on 0001, telephone (301) 415-0233 or e-PART 30-v uLES OF GENERAL which this determination is based is mail at ANT @nrc. gov. APPLICABILITY TO DOMESTIC avadable for inspection at the NRC Regulatwy Flexibility Certiilcation LICENSING OF BYPHODUCT Public Document Room,21201. Street NW. (Lower I.evell, Washington, IK'. As required by the Regulatory MATERIAL Single copies of the environmental Flexibility Act of 19co,5 U.S C. 605(b), assessment and the finding of no the Commission certifies that this rule

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

significant impact are available from Dr. does not have a sh nificant economic Anthony N. Tse. Office of Nuclear impact upon a r .antial number of Authartry: Secs. 81,87, int.1a2,183. t en, Hegulatory Researt h, U S. Nuclear small entities. T or lnal rule permits f,8 Stat. 935. 94H. 953. 954. 955.as amended, Regulatory Commission, Washington, physicians and other health care sec. 234. a3 stat. 444. as amended (42 U.S C. DC 20555-0001, telephone (301) 415-providers to use an additional 2111. 2 t 12, 2201, 2232. 2233. 2236. 22a2). 6233 or e-mail at ANTdnrc. gov. diagnostic test without having to obtain wct 201, as amended. 202,2ns, as stat. an NRC license, thus, would provide 1242,as amended. 1244.1246 (42 U.S C. 5841,5842,Sa46L VII, Paperwork Reduction Act cost savings to patmnts. insurers, and g,,,g Secti n 30.7 also issued under Pub. L This final rule amends information t pos a a in i i collection requirements that are subject obligatioes on entit'ics that may fall arna m h 102486, a 2g2. to the Peperwork Reduction Act of 1995 within the definition of"smalientities" 1M at 3123. H2 M C,5851L Smmn (44 U.S C. 3501 et seg J. Thes" as set forth in Section 601(3) of the 3 3 also s un asu,la 68 requirements were approved by the Regulatory Flexibility Act; or withtu the tat , as amem d H2 USE 22M Office of Management and Hudgct. definition of "small busine.s" as found approval numbers 315(b0001,3150-in Section 3 of tim Small Business Act-187,68 Mat 055 H2 UE 2234 0017 and 3150-0120. 15 U.S C. ti32; or within the sire standards adopted by the NPC on April 2, in S 30.t!, paragraph (b) is revised to co t n fint n tio is sti t ito 1,19% H30 l R 18344). read as follows: average 16 hours per response, including the time for reviewing X. Small Business Regulatory $ 30 8 information conection instructions, searching existing data Enfortement Fairness Act r:.,quirements: OMB approvat. sources, gathering and maintaining th" In accordance with the Small a data needed, and completing and Business Regulatory Enforcement "EE reviewing the co!bdion of information. Fairness Act of 199ti, the NRC has collecuan requirements contained in i Send comments on any aspect of this d t nnin d that dus action is qot o a this part appear in 55 30.9,30.11,30.15, ~ and has mified thu 30.18.30.19,30.20,30.21,30.32.30.34 collection of information, including rnaim ru@un suggestions for reducing the burden, to Ith the Office of 30.35,30.36,30.37,30.38,30.41,30.50. the Information and Records Management Hranch (T4 F33). U.S. f[th, h"a 30.51,30.55. appimdices A and C to this t part. Nuclear Regulatory Commission. a Washington, DC 20555-0001 or by XI. Backfit Analysis Inturnet electronic mail at ~ The NRC has determined that the

3. A new $ 30.21 is added under the UlSl@NRC GOV; and to the Desk backfit rule.10 CFR 50109, does not undesignated center heading Offic.er Office of Informat.on and apply to this rule, and thatefare. a

" Exemptions" to read as follows:

~ a- .e. 63840 Federal Regist:r / Voi, 02, No. 231- / Tuesday, December 2.1997 / Ruies and Regulations ' $ 30.21 Rameset6ve drug: Capsules $ 32.21 Rad 6oactive drug: Manufacture, quantity of radioactivity of each capsule oontaining cartsor>14 proa for "In vivo" preparat60n, or transfer for commercial at a specific date; and magnoot6c vos for humans. metritiution of capsules containing cart >on-(2) Bears the words " Radioactive 14 urea each for 'in vivo" diagnostic use Material." (a) Except as provided in paragraphs for humans to persons esempt from (b) and (c) of this section, any person is Hoensing: Requin>ments for a Heense. (b)In addition to the labeling axempt from the requirements for a (a) An application for a specific information required by paragraph (a) of license set forth in Section 81 of the Act license to manufacture, prepare, this section, the label affixed to the end from the regulations in this part and process, produce, package, repackage, or immediate container, or an part 35 of this chapter provided that transfer for commercial distribution accompanying brochure also must: such person receives, possesses, uses, capsules containing 37 LBq (1p Cl) (1) State that tb tents are exempt transfers, owns, or acquires capsules carbon.14 urea (allowing for nominal from NRC or Agr-a St State licensing containing 37 kBq (tp Cl) carixm.14 variation that may occur during the recyirements; and urea (allowing for nominal variation manufacturing process) each for "in . (2) Bear the words " Radioactive that may occur during the vivo" diagnostic use, to persons exempt Material. For "In Vivo" Diagnostic Use manuf acturing process) each, for "in from licensing under $ 30.21 of this Only. This Material Is Not To Be Used vivo" diagnostic use for humans. chapter or the equivalent regulations of for Research involving fluman Subjects an Agreement State will be approved if: and Must Not Be Introduced into Foods, (b) Any person who desires to use the (1) The applicant satisfies the general Beverages Cosmetics, or Other Drugs or sules for research involving human ce[jects shagI apply for and receive arequirements ecified in 5 30.33 of this Medicinals' or into Products chapter, provi d that the requirements Manufacturod for Commercial su specific license pursuant to part 35 of of 5 30.33(a)(J) at d (3) of this chapter d Distribution. This Material May Be this chapter, not apply to an application for a license Disposed of in Ordinary Trash." (c) Any person who desires to to transfer b roduct rnaterial Dated at Rockville* Maryland, this 24th day manufacture, prepare, process, produce, manufacture pre ared, processed,- g g, y, pedage, re >ackage, or transfer for produced, package, or repackaged For the Nuclear Regulatory Commission. commercia distribution such capsules Pursuant to a license issued by an shall apply for and receive a specific Agreement State; l'ha C II"7 ^ 3 license pursuant to $ 32.21 of ti"s (2) The applicant meets the scen sary of Ae comimssen. l c;tapter. requirements under $32.72(a)(2)of this (FR Doc. 97-315 4 Fded 12-1-97;il 45 aml swo eme mo*e Pa (d) Nothing in this section relieves persons from complying with applicable that each capsule contains 37 kBq (1p 4 FDA, other Federal, and State Cl) carbon.14 urea (allowing for NUCLEAR REOULATORY requirements governing receipt, nominal variation that may occur during COMMISSION administration, and use of drugs. the manufacturing process); 10 CFR Part 73 (4) The carbon.14 uroa is not PART 32-SPECIFIC DOMESTIC contained in any food, beverage. LICEv4SES TO MANUFACTURE OR cosmetic, drug (except as described in RIN 3150-AF5J TRANSFER CERTAIN ITEMS this section) or other commodity CONTAINING BYPRODUCT HATERIAL designed for ingestion or inhalation by, Changes to Nuclear Power Plant l or topical ap lication to, a human being: Security Requirements

4. The authority citation for Part 32 (5) The car n.14 urea is in the form AGENCY: Nuclear Regulatory continues to read as follt,ws:

of a capsule, identified as radioactive, Commission. Authority Secs. 81, Mt.182,183,68 Stat. and to be used for its radioactive 935,94a, esa,954, as amended '42 U.L;, p operties, but is not incorporated into ACTION: Final rule. 211t,220s,2232,2233); sec. 20s, as stat. any manufactured or assembled 1242,as amended (42 U.S.C sa4tl. commodity, product, or device intended sunseAARY: The Nuclear Regulatory for commercial distribution: and Commission (NRC)is revising its

5. In 5 32.e paragraph (b) is revised to (6) The applicant submits ce pies of regulations to delete certain security read as follows:

prototype labels and brochures and the requirements assoc!ated with an NRC approves these labels and internal threat. This action follows the $ 32.s informat6on conecuon. brochures. NRC's reconsideration of nuclear power '*9"*"*"#8 '"# (b) Nothing in this section relieves the plant physical security requirements to licensen from complying with identify those requirements that are (b) The approved information applicable FDA, other Federal, and State marginal to safety, redundant, or no colketion requirements contained in requirements governing dmgs. longer effective. This action will reduce this part appear in $$ 32.11,32.12,

7. A new $ 32.21a is added to road as the regulatory burden on licensees 32.14,32.15,32.16,32.17,32.18,32.19, follows:

without compromising physical Protection against radiological sabotage

32. 20, 32.21, 32.21 a, 32.22, 32.23, 32.25 - S 32.21s Same: Conditions of heense.

required for public health and safety. 32.26, 32.27, 32.29, 32.51, 32.51 a, 32.52, EFFECTWE DATE: January 16,1998. 32.53,32.54,32.55,32.56,32.57,32.58, th part is su ect to the o11o g 3 2.61, 32.62, 32.71, 3 2.72, 3 2.74, and conditions: FOR FURTHER INFORnfATION CONTACT: Dr. 32.21a (a) The immediate container of the Sandra Frattall, Office of Nuclear capsule (s) must bear a durable, legible Regulatory Research, U.S. Nuclear

6. A riew $ 32.21 ir added to read as label which:

Regulatory Commission, Washington, follows: (1) Identifies the radioisotope. the DC 20555-0001, telephone (301) 415-physical and chemical form, the 6261, e-mail sdf@ntc. gov. -? ~ ~.

u. - o' 3 Associateiwith z 62 FR 63634 (December 2,~1997) j REGUl.ATORY ANALYSIS g . FOR FINAL RULEMAKING - i " EXEMPT DISTRIBUTION AND USE OF A RADIOACTIVE DRUG L CONTAINING ONE MICROCURIE OF CARBON 14 UREA" 10 CFR PARTS 30 AND 32 - 1.

Background

L 1.1 Statement of the Problem On October 6,1994, the Commission docketed a petiten for rulemaking (Docket No. PRM 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 (pci) of "C-urea for in vivo diagnostic testing." The purpose of this diagnostic test is to detect the presence of the bacterium H61icobacter pylori (H. pylori), a cause of peptic ulcers. I " Peptic ulcer disease is a chronic inflammatory condition of the stomach and duodenum that affects as many as ten 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 economic costs." -(Source: Article included as an appendix to the peution, from JAMA, July 6, - 1994 Vol 272, No.1, "H. pylori in Peptic Ulcer Disease-NIH Consensus Conference"). l; in the petition dated August 23,1994, the petitioner stated the following: Rocent medical research has found that peptic ulcers are commonly caused by a bacterium cal'ad H. pylori. This bacterium lives in the stomach of most ulcer sufferers. By treating ulcer patients with antidotics, doctors can now cure most ulcer problems. j: It is therefore necessary to detect the presence of H. pylori bacteria in ulcer patients so that the new treatment can be given appropriately, in the past, this was done by a gastroenterologist who took biopsy samples of the stomach lining t at endoscopy,- a procedure which was uncomfortable and expensive ($1000). I With the new test, H. pylori can be detected noninvasively using a "C-urea tracer. "C-urea is broken down by H. pylori to form labeled CO, which is expired. in the breath. To do tha test, a doctor asks the patient to swallow the capsule c with 30 mis of water. After 15 minutes the patient blows 2 liters of breath into a L collection bag (a mylar balloon) which is mailed to a testing laboratory. if "C-CO more than twice background is present in the breath sample, then the ' 1 2 - patient must be infected with H. pylori. c ( i + a re'-r w-9 tu wh w-Tre w dr w^-ed ma1dTe 't W s efP Si*

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,5 1.2 Current NRC Regulations in 10 CFR Part 32, " Specific Domestic Licenses To Manufacture or Transfer Certain items Containing Byproduct Materials," 9 32.72, " Manufacture, prepre on, or transfer for commercial distribution of radioactive drugs containing byproduct material E medical use under Part 35," provides for commercial distribution of radioactive drugs containing byproduct material for use by persons authorized pursuant to Part 35. Thus, the regulations currently would permit Part 32 licensees to commercially distribute capsules containing 1 pCi of "C-urea to persons authorized pursuant to Part 35. In 10 CFR Part 35,

  • Medical Use of Byproduct Material," sets forth radiation safety requirements, including requirements for the training and experience of authorized user physicians to assure the safe possession and use of radioactive drugs containing byproduct material.

Existing exemptions for use of byproduct material in 9 30.14 " Exemption concentrations" and 9 32.18, " Manufacture, distribution and transfer of exempt quantities of byproduct material: Requirements for license," do not permit the exempt 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. Therefore, undar current regulations, the "C-urea capsules must be used under a Part 35 license. 1.3 Eart:ar NRC Actions Following the receipt of the petition, a " Notice of receipt of petition for rulemaking" was published for public e,omment in the Federal Reaister on December 2,1994 (59 FR 61831). A total of 315 public comment letters were received. Of these,313 supported the petition (they were mostly form letters) and two letters opposed the petition. The two letters opposing the petition stated that (1) the product should not receive an exempt status because the uncontrolled distribution and application of this product could lead to significant risk to the public and (2) medical uses should be restricted to short lived isotopes because of disposal problems presented by long lived isotopes. This petition was discussed with NRC's Advisory Committee on the Medical Uses of Isotopes (ACMUI) at the October 1995 meeting. The ACMUI indicated that it endorsed the wide availabllity of this diagnostic test and that the radioactive drug could be used under a general license or an exemption, whichever the NRC may determine to be procedurally easier. A rulemaking plan was prepared. After receiving comments from Agreement State:> on the draft rulemaking plan, the Commission approved a final rulemaking plan to develor) a proposed rule to amend 10 CFR Parts 30 and 32 allowing the distribution of the Carbon-14 capsules as an exempt material to any person. 2

~_.- 3;. i .z 1 l i t 1.4 _ Procosed Rule and Pubhc Comments The proposed rule was published in the Federal Register (62 FR 32552, June' 16,1997) for a - 30<$ay public comment period.' The NRC received seven public comment letters. Four-commenters supported the rule,'one opposed the rule,'and two provided comments without j - explicitly stating whether they support or oppose the rule. A summary of public comments and - g NRC's responses are presented in the preamble of the Federal Register notice. Except a minor change in wording, the final amendmena are the same as the isc--:::i amendments. No ' [ comments related to the draft Regulatory Guide has been received. F . 2.- Objective h The objective of the rulemaking is to amend 10 CFR Part 32 to permit the manufacture and - h t commercial distribution of "C-urea capsules to any person (including physicians who are not l' - " authorized users" under Part 35) and to amend 10 CFR Part 30 to permit any person, without an NRC hoense, to receive and use the capsules for in vivo diagnostic use for humans. 3. Alternatives [ Three al ematives have been considered in the regulatory analysis: deny the petition, i.e., t maintain the status quo, permit _the distribution'of the capsules to persons exempt from licensing, and permit the distribution of the capsules to generallicensees. Under the first altemative, only physicians who are authorized users under Part 35 would be i ' allowed to possess and administer the "C ures test. Any physician could apply to become an authorized user. However, the NRC expects few physicians would apply for a Part 35 license for the sole purpose of using the capsules because of the requirement for training and experience and the associated costs of obtaining and maintaining a Part 35 license. 4 - Altematively, physicians who are not authorized users can continue to refer their patients to physicians who are authorized users to undergo the diagnostic test. However this would not relieve the current expense, inconvenience, and oelay encountered in an otherwise straight-2 - forward procedure. - Under the second attemative,'10 CFR Paits 32 and 30 would be amended.10 CFR Part 32 l . would be amended to permit the manufacture and commercial distribution of "C-urea capsules - - to any person (including physicians who are not " authorized users" under Part 35): 10 CFR - Part 30 would be amended to permit the manufacture and commercial distribution of the capsules to any person, for in vivo diagnostic use for humans. - The NRC has determined that the radioactive component of this drug presents an insignificant radiation risk and, therefore, regulatory control of the capsules is not necessary. 1-Under the third altemative,10 CFR Part 35 would be amended to permit any physician to e receive' and use the capsules under a general license. The health and safety concems for this attemative are tha same as the Attemative 2. However, if this attemative were adopted, there

uld be a burden to those Agreement States that normally require registration of general 3

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m license holders.. An additional burden could also be imposed on general licensees located ini th's Agreement State if the State charges a license or registration foe; i 4. Value-imond Analysis -_a O1 '4.1 The Petitioner's Asammament i 1 in the letters dated August 23,1994 and November 30,1994, the petitioner stated, respectively: y y If exempted, the C-14 breath test could be done by most doctors for less than $100 cost

to the patient. This is a considerable savings over endoscopy and biopsy ($1000).

i Mhe test is 95 percent accurate and quite inexpensive because of its simplicity. - The : test would permit doctors to determine easily whether or not ulcer patients have been cured of their infection. 3y providing the public with an inexpensive, easily mocessible

  1. 5+n": tort, more individuals would be accurately diagnosed and treated for their:

- H. pylori infection. This would save the United States an estimated $500 million per ' annum over conventional therapy. The petitioner estimates annual benefits to be on the order of $500 million/ year. This assumes approximately 600,000 "C-urea breath tests / year, at an average cost of $100, in lieu of performing endoscopy at an average cost of $1000/ test. It assumes that the lower oost and greater availability of an unregulated breath test would result in a complete substitution for i endoscopy. Tri-Mets benefit analysis provides a measure of the total benefits associated with - the test and docs not focus on the incremental benefits of administering the test pursuant to - 10 CFR 35.100 regulation (status quo) nrsus releasing the test to all physicians (NRC licensed and non licensed alike). Implicit in Tri-Mess estimated annual benefits is the presumption that L none of these t*C tects and corresponding savings would accrue if the petition were denied. in reality, under the status quo, the test would be available and administered by physicians or . clinics holding a license under NRC's Part 35 or an equivalent Agreement State regulations. N Further, Tri-Med's estimate did not allow for the substitution of other non invasive tests (e.g., pf serological test for igg antibodies to H. pylori antigens) for both endoscopy and "C-urec tests. 4.2 The NRC's Assessment (a) Cost Savinas A=ar-W with Amendinsnts to 10 CFR Part QQ De value impact analysis focuses _on the incremental benefits of granting reliV consistent with L* _ Attemative 2 or 3, as specified in Section 3 above. The analysis looks solely at changes relative to the base case or status quo. - In this analysis, tim comparison is between regulated [ and unregulated!*C-urea breath tests, not unregulated "C-urea breath tests and endoscopies ' or other noninvasive tests. For the purposes of this regulatory analysis, the NRC assumes that - , the same number of breath tests (i.e.,600,000 tests) will be administered regardless of the . level of NRC regulatory control. This view is predicated on the belief that each physician's-p primary motivation is to provide the best possible care to his or her. patients; if the breath test is 1]udged preferable to endoscopy, or other procedure, any physician not authorized to use the t test will refer his or her patient to authorized users who could perform the test under existing i p L 4 e'

--~ ~.--.- - f 2 I h + - NRC regulations.'. This appears fully consistent with standard medical' practice,- whereby l n patients are referred routinsly to laboratories and specialists for a wide array of tests and. procedures. ~' W - The benefus of adopting the petition accrue'as a result of reduced patient cost and reducod health-care cost resulting from the elimination of the need for referrels from a physician who is hot an authorized user (e.g, gastrointestinal specialist). There would also be some regulatory : savings because the NRC would not have to expend resources reviewing new applications for - specific medical use licenses.. However, these sayings would be small because the NRC - expects that few phys,1cians who are not authorized users would apply for a specific NRC ' license for use of this one product. ) The benefit calcu'#on is based on the assumption that as a result c' this rulemaking action, a : significant portion of the 600,000 patients would receive the "C bresa test from physicians who are not authorized users (e.g., pastrointestinal specialists). The actual savings would be dependent on t% number of tests ultimately administered by physicians who are not authorized i beers, thereby eliminating the need for a referral to physicians who are authorized users (e.g.,. ' nuclear medicine specialists), The annual savings could be as high as approximately $20 million if there were complete shift of the administration of the tests from physicians who are authorized users (i.e., base case) ta physicians who are not authorized users. The basis for this estimate!s as follows. Assuming adoption of the petition eliminates the need for up to 600,000 referrals, patient savings in averted travel expenses (transportation and personal time incurred with medical referral) would be: Assuming round trip of 20 miles @ $0.25/ mile, and personal time of 0.5/ hours / trip valued at $25.00/ hour 600,000 trips / year x (20 miles / trip x $0.25/ mile + 0.5 hours / trip x $25.00/ hour) = $10.5 million/ year Health Care Savings in averted administrative expenses (administrative costs incurred with i medical referral) would be: 600,000 patients / year x $19,00/ patient = $11 A million/ year Assuming $19.00 (administrative cost / patient) as the differential between the cost of an office visit to a general family practice physician by an established patient ($45.90), and - the cost to a new patient ($64.90 per visit) for completion of new patient paperwork,' reviewing health history, maintaining medical records, etc. The patient who is referred to an authorized user (e.g., nuclear medicine specialist) for the "C-urea breath test would most likely be a new patient for the authorized user. 5 d y y, ,-,n-<v.- m e + ,e -sr.

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_, m_ ., j... : Is o q Tot'ai SOlngsi $10.5 million/ year + $11.4 million/ year = $ 21.g million/ year j Altomatik, if only 200,000 or 400,000 of the 600,000 tests were performed by a physician - who is not an authorized user, the annual cost savings would be approximately $7 million per -

year and $15 million per year, respectively.
if Altemative 3 were adopted, it would permit any physician to receive and use capsules

q containing 1 pCl "C-urea for human use under a general license. The health and safety conoems for this altamative are the same as Altemative 2. However, the adoption of Altemative 3 could add unnecessary burden to those Agreement States and Agreement State licensees in States that assess licensing or registration teos for general license holders. - Altemative 2 also imposes incremental cost burden for manufacturers or commercial aistributors of the' capsules h= they would need to obtain an exempt distribution license. Each application is estimated to take up to 16 hours to prepare. Assuming 3 applicants por t year, the total reporting burden would be 48 hours. For recordkeeping burden, assuming each. . of the 3 applicants in a year would need 2 hours to reprogram its computer to print additional - words on.the label or brochure, the one-time total recordkeeping burden would be 6 hours. ) Assuming a labor rate of $125 por hour, the totcl burden would tw about $6,750 per year. There would be costs for the Federal and State govemments if Altemative 2 or 3 is adopted. ' Under both Altematives 2 or 3, the NRC and some Agreement States would need to amend their regulations to permit the use of the capsules by persons other than physician who are authorized usersc e I .(b)_ Health and Safety Effects Ftr the purposes of this regulatory analysis, the NRC assumes that the same number of breath teso (i.e.,600,000 tests) will be administered regardless of the level of NRC regulatory control. . This dew is predicated on the belief that each physician's primary motivation is to provide the best pos:ible care to his or her patients, In addition, the routine and accidental exposures per carbon 14 uros breath test is not expected to be affected by the level of NRC legulatory control. Thus, radiation exposures to the workers and members of the public would be the same [ regardless of which attemative is adopted.- The NRC has concluded that the human use of these capsules results in insignificant exposures as depicted below: 4 4 1l ~ 6- .a.j-o-. -f y.y -:N -9m

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Scenario Maximum Exposed Routine Exposure Individual Worker administering "C-Full-time worker, 8,000 Less than 0.7 mremlyr urea breath tests patients /yr Routine exposure of patients Patient tests negative 0.38 mrem / capsule from "C-urea breath tests Patient tests positive 0.18 mrem / capsule Release of 150 pCi of "CO, Member of public in the Less than 0.0002 mrem into administration administration area facility from fire Rupture of a capsule Skin (100 cm') exposed for 5.8 mrad skin dose, causing skin contamin-one hour prior to washing: 0.029 mrem (CEDE) ation of worker or patient 0.075 pCi skin absorption Furthermore, the NRC concluded that the impacts associated with any releases of "C to the surrounding cavironment are expected to be very small and the expected risks are minimal. The earth's atmosphere contains an inventory of naturally occurring "C of about 3.8 million curies (equivalent to the activity in 3.8 trillion breath tests), which is in additiot, ;o the huge inventory of about 240 million curies in the world's oceans. The "C released into the atmosphere from the use of this test wouk' mix with the globalinventory ar'd expose the public and other.Wtic components of the environment to "C intakes from Inhalation, drinking water, and all possible food palhways in the same manner as naturally occurring "C. The current world inventory of natural!y occurring "C results in an average dose to the public of about 1.25 mrem / year, and the release of 0.6 curies of "C from the total of 600,000 tests assumed to be administered annually would result in an additional average annual dose of 2 X 104 mrem to the public. This is far below the EPA reporting level of 1 mrem / year required under the Clean Air Act for routine exposures to a member of the public, and the 4 mrom/ year EFA limit for public drinking water. In a total population of about 260 million people in the U.S., the collective annual dose to the public from the breath tests would be about 0.051 person-rem. l'1 addition, the doses from normal use of breath tests, or from any accidental release of "C to the environment also are expected to be very small because the concentration of CO, released is very low and it would mix immediately with the atmosphere. Exposure to patients was not considered when calculating the individual or collective doses resulting from the diagnostic tests. The small dosos from naturally occurring "C are of little significance to human health and the environment. Potentiallong-term impacts from widespread releases of the long-lived "C (5,730 year radiological half life) from breath tests were concluded to be insignificant. Assuming that the testing in the U.S. would increase over a period of time to an average of a million tes's per year for 50 years, the collective dose to the U.S. population would be a total of about 5 person-rem cver the 50 year period. This dose is very small when compared to the annual collective dose to the U.S. population from naturally occurring "C of over 300,000 person-rem, and about 78,000,000 perrn-rem from all naturally occurring radiation. Clearly, an increase of a few person-rem will o gnificantly change these exposures, and thus there is no expected impact from the widespresd use of the breath test on the entire U.S. population. 7

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.{ S =; 4 t As a result of this analysis, the NRC concludes that Altematives 2 and 3 are clearly preferable;

to the no action altemotive,; This is because either of the two altematives will result in -

';significant cost savings with no measurable adverse effect on health and safety - Furthermore ; . the NRC's recommended option is Altemative 2 because it would avoid the unnecessary cost. l ~ i burden to some Agreement States and their general licensees.' Therefore, by promulgating the final rule, the cost savings would be maxirbed without anyJ measurable adverse effect on public_ health and safety. 5. Decision Rationala r ' Based on the above analysis, the NRC is amending its regulations to permit the manufacture and commercial distribution of Cartx,n-14 urea capsules to any person (including physicians 1 who are not "authortzed users" uador Part 35) and parmit any person, without an NRC Ir.,enne, f h b h dl i l 1_ j to receive and use the capsules forin vivo diagnostic use or umans ecause t e ra io og ca - } risk from such distribution would be insignificant and the savings to patients could be significant. f 1 4 a 4 'h {. \\ d J T s ' 4 a: 1 e Q f

j m.(e ~ y >w AP70r2_ h) Associated with 62 FR_63634-(December 2,1997) l Environmental Assessment-For Final Amendments to 10 CFR Parts 30 and 32 "" Distribution of a Radioactive Drug Containing One Microcurie of - Carbon-14 Uros as Exempt Material for "In Vivo" Diagnostic Testing" ( Sts.tament of the FinW Adion The Nuclear Regulatory Commission (NRC) is amending its egulations to eBow NRC : licensees to distribute a r=eawelve drug containing one microcurie of carbon-14 uros to any . erson for "in vivo" diagnostic use. The NRC has determined that the radioactive component of ~ ~ p I such capsules presents an insigni6 cant radiation risk and, therefore, regulatory control of the I drug for radiation safety is not necessary. This amendment makes the drug more widely available, thus reducing costs to patients, insurers, and the health care industry. This action is l being taken in response to a petition for rulemukhig (PRM 3612) submitted by Tri-Med Specialties, Inc. Need for the Amendments The amendments have been developed to grant the petition for rulemaking. The final . rule permits manufacturers or commercial distributors to distribute arbon-14 urea cepsules as . exempt material to any person Th9 Commission is promulgating this rulemaking because it I believes that the radiological risk from such distribution would be insignificant and the savings to _. patients could be significant.- In addition, the Commission recognizes that other Federal and - State ages cies (e.g., Food and Drug Administration and the State Boards of Pharmacy) are - responsible for the receipt and use of drugs that do not contain byproduct materials, and would provide necessary oversight for the safe use of these carbon-14 urea capsules as drugs. ~ ~'y ~

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i ke Allematives Considered I Three altematives have been considered regarding the petition: deny the notition, i.e., l maintain the status quo, permit the distribution of the capsules as e'xempt maten y, and permit the distribution of the capsules to generallioensees, j Under the first altomative, the current situadon would continue: only physicians who are j authorized users under Part 35 would be allowed to possess and adrainister the C-14 uros test. LAny physician could apply to become an authorized user. However, the NRC expects few ^ physicians would apply for a Part 35 license for t:m sole purpose of using such capsules because of the requirement for training and experience and the associated costs of obtaining f - and maintaining a Part 35 license. Altomatively, physicians who are not authorized users een l continue to refer their patients to physicians who are authorized users to undergo the diagnostic - test. However this would not relieve the current expense, inconvenience, and delay encountered in an otherwise straight-forward procedurs. Under the second altemative,10 CFR Parts 32 and 30 would be amended. Part 32 . would be amended to establish requirements for the manufacture and distribution of C-14 uros - capsules to persons exempt from licensing, i.e., any perwn (including physicians who are not " authorized users" under Part 35); Part 30 would be amended to termit any person to receive, possess, use, transfer, own, or acquire the capsules for in vivo diagnostic use for humans - without a license. The NRC has determined that the radioactive component of thi., drug i: presents an insignificant radiation risk and, therefore, regulato y control of the capsules is not necessary. Under the third attemative,10 CFR Part 35 would be amended to permit any phyrian to receive rnd use the capsules under a general license. The health and safety concems for this - 4 l altemative are the same as the Altemative 2. However, if this attemative were adopted, there. could be a burden to those Agreement States that normally require registration of general: licerme holders. -An additional burden could also be imposed on general licensees located in I - the Agreement State if the State charges a license or regktration fee. Based on the Draft Regulatory Analysis prepared for this proposed rule, the Commission concludes that Attematives 2 and 3 are clearly preferable to the no action attemative. This is because either of the two attematives will result in significant cost savings with no measurable ]- adverse effect on health and safety. Furthermore, the NRC's recommended option is 2 g d .Y e. h-n-a----.v,'.--,,,~~,--r r'-w a n,v -,--c-- w -. e y -m e,

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Attornative 2 because it avoids the unnecessary cost twrden to some Agreement States and.

t their licensees.- n n Imamed on the Phand the Environment ' The amendments are expected to have an insignificant impact on the pubic and the environment. The NRC assumes that the same number of breath tests will be edministered 3 regardless of the level of NRC regulatory control. :This view is predicated on the bs, lief that oach physician's primary motivation is to provide the best possible care to his or her patients. - if - the breath test is judged p,ine to endoscopy, or other procedure, any physician not authortred to use the test will refer h!a or her patient to authorized users who could perform the

test under existing NRC regulationc. ' under this assumption, this rulemaking action is expected to result in no change in radiation exposures to the workers and patients when compared with b

the status quo. Similarly, it is expected that there will be no change in impact to the environment because the Commission assumes that the same number of tests will be ! administered rogardless of which alternative is adopted.- The earth's atmosphere contains an inventory of naturally occurring C-14 of about 3.8 million-curies which is in addition to the huge inventory of about 240 million curies in the world's oceans. The small amnunt of C-14 released into the atmosphere from the use of this test a would mix with the globalinventory and wuuld have no impact on public health. The current L world inventory of naturally occurring C 14 results in an average dose to the public of about 1.25 mmm per year, and the release of 0.6 c.uties of C-14 fro.m the total of 600,000 tests assumed to be administered annually would result in an additional average annual dose of 2 X 101 mrom. This is far below the EPA reporting level of 1 mrem / year required under the Clean Air Act for routine exposures to a member of the public, and the 4 mrom/ year EPA limit for public drinking water. 7 + List of Aaencies and Persons' Consulted and Identification of Sources Used Following the receipt of the petition for rulemaking, a " Notice of receipt of petition for I: rulemaking" was published for public comment in the Federal Register on December 2,1994, ~ (59 FR 61831). A total of 315 public comment letters, 313 supporting (mostly form letters) and E2 opposing letters, were received. This petition was discussed with NRC's Aavisory Committee 3 ...m-,. r .,.J,,

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on the Medical Uses of isotopes ACMul) at the' October 1995 meeting, Furthermore, the draft

> rulemaking pl6n was forwarded to 29 Agreement States for comments. lA proposed rule was published in the Federal Register (62 FR 32552, June 16,1997) for - 1 a 30 day-public comment period. The NFIC received seven'public comment letters. Four. commenters supported the rule,'one opposed the rule, and two provided comments without Lexplicitly stating suppon of or opposition to the rule. A summary of public comments and NRC's respor:ses are presented in the preamble of the Federal Registar not!ce. Except a minor change irmording; the final amendments are the same as the proposed amendments. - One commenter addressed the draft environmental Assessment. The commenter stated + that the environmental Assessment fails to consider the fact that another equally non-invasive, but non<adiological, diagnostic procedure (such as C-13 test) is available and provides s' ooraparable altamative to the C-14 test. The commenter apparently conc'uded that the assumption unde 1ying the environmental assessment is that in the absence of the C-14 test, I the onQ altemative for the detection of H. pylorl is invasive gastroendoscopy. The purpose of the environmental assessment is to address and document the expected impact to the environment of subject rule. As presented in the regulatory analysis prepared for - this rule, the NRC has determined that the environmental impact is expected to be insignificant I because of the extremely low radiological hazards associated with the use of capsules - containing one microcurie C-14 urea. If the environmentalimpact had been significant, then the existence of a non-radioactive altemative would have been a factor in assessing the cost - benefit of this rulemaking. However, the impact is not significant. Hence, the regulatory issue in this rulemaking is whether the C-14 method should be made available to physicians who are not authorized users, and not whetner there exists a non-radioactive attemative. 1 ' Fir,dinc of No Sionificant Imnacts 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 amendments will not be a major Federal action significantly affecting the quality of the human environment, and therefore an er,vironmental impact statement is not required. The final rule amends 10 CFR Part 32 to permit the manufacture and commercial distribution of C-14 urea - capsules to any person (including physicians who are not " authorized users" under Part 35) and 4 w c -..- r ~. m

~ 9. to amend 10 CFR Part 30 to permit any person, without an NRC license, to receive and use the capsules for in vivo diagnostic use for humans. The Commission believes that the radioactive component of this drug presents an insignificant radiation risk and, therefore, regulatory control - of the capsules for "in vivo" diagnostic use is not necessaryi it la 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.- i a G 4 5 1 = 9 5 <-s r-w r}}

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