ML20055C703

Requests Commission Approval of Interim Final Rule to Amend 10CFR30 & 35

ML20055C703
Person / Time
Issue date:	05/30/1990
From:	Taylor J NRC OFFICE OF THE EXECUTIVE DIRECTOR FOR OPERATIONS (EDO)
To:
References
TASK-RIA, TASK-SE SECY-90-193, NUDOCS 9006040335
Download: ML20055C703 (51)

Text

{{#Wiki_filter:PDM ,p * * *% 5 p i j \\....+/ RULEMAKING ISSUE M Y 3 199 (Affirmation) SECY-90-193 For: The Commissioners From: James M. Taylor, Executive Director for Operations

Subject:

INTERIM FINAL RULE TO AMEND 10 CFR PARTS 30 AND 35

Purpose:

To obtain Commission approval of an interim final rule amending 10 CFR 30.34--Terms and Conditions of Licenses, 10 CFR 35 Subpart E--Imaging and Localization, and Subpart F-- Radiopharmaceuticals for Therapy.

Background:

Under its 1979 Medical Use Policy Statement, the Commission stated that.it would regulate the medical use of byproduct material in order to protect the health and safety of workers and the public, which includes patients. In general, NRC regulatory requirements in 10 CFR Parts 30 and 35 are oriented to ensuring that a properly prepared radiopharmaceutical is administered to the correct patient as prescribed by an authorized user physician. Specific requirements, such as the use of dose calibrators, are intended to ensure that the correct dose is administered. The proposed medical quality assurance rule (55 FR 1439, January 16,1990) is aimed at preventing errors between what is prescribed and what is administered to patients. License conditions require commercial nuclear pharmacy licensees to follow the manufacturer's instructions, which are approved by the_ Food and Drug Administration (FDA), when preparing radiopharmaceuticals using generators or reagent kits. Regulations in Subpart E at b 35.200(b) require medical use licensees to follow the FDA-ap3 roved manufacturer's instructions when preparing radiopiarmaceuticals using generators or reagent kits. Further, Subpart F at 6 35.300 requires medical use licensees to comply with the FDA-approved package insert instructions regarding indications and method

Contact:

John Telford, RES NOTE: ~TO BE MADE PUBLICLY AVAILABLE 492-3796 WHEN THE FINAL SRM IS MADE Marjorie Rothschild, 0GC AVAILADLE 492-1633 f Qo t l quosovoss ')K? U, -M_

i <a, i' The Commissioners 2 of administration (e.g., to limit the disease states to be treated with each radiopharmaceutical to those listed in its j package insert). Discussion:- Information submitted by the American College of Nuclear petition for rulemaking (y of Nuclear Medicine (ACNP-SNM) i Physicians and the Societ 54 FR 38239, September 15, 1989), provided by the public coments, and obtained during subsequent discussions with licensees, indicates that the requirements of 10 CFR 35 Subparts E and F, in some cases, may prevent authorized user physicians from providing certain nuclear medicine procedures to some patients. For some uncommon disease states or individual patient's medical condition, it may be necessary to depart from the FDA-approved labeling ) (including manufacturer's instructions and package inserts to obtain diagnostic or therapeutic medical results not otnerwise attainable, or to reduce medical risks to particular patients. The ACNP-SNM petition, among other things, requests relief from strict adherence to the manufacturer's instructions for' radiopharmaceutical preparation and the package insert for - therapeutic uses. Although there are provisions in the ,1 regulations for exemptions from these requirements, authorized user physicians often have to make decisions about administra-tion of radiopharmaceuticals on a time scale that is not compatible'with obtaining prior clearance from a Federal agency. Proposal: The statt proposes to adopt an immediately effective interim 4 final rule to allow departures from the'FDA-approved manu-facturer's instructions and package inserts. The amendment is characterized as interim because the rule will be in effect f or a period of 3 years af ter publication in the Federal Register and that a decision will be made at the end of that 3-year period as to whether to extend the interim period for the rule, make the rule permanent, or revise it. This. interim rule would only apply to radiopharmaceuticals for which FDA has approved a New Drug Application (NDA). The rule would continue to provide reasonable assurance of radiological safety as well as a balance between adequate controls and avoidance of undue interference in medical judgments. Because these amendments involve relief from restrictions l-which if left in place could have an adverse impact on public l health and safety and because the NRC has received and .i considered public comments on the petition for rulemaking, good cause exists for omitting the notice of proposed rulemaking and the public procedures thereon as unnecessary and contrary to the public interest. Therefore, these

Do 4 The Comissioners. 3 amendments are being made effective upon publication in the i o tederal Register without the customary 30-day notice. The provisions of the interim rule are as follows: a. Medical use and commercial nuclear pharmacy licensees may depart from the manufacturer's instructions in preparing NDA radiopharmaceuticals it an authorized user physician has made a written directive for a specific departure f or a particular patient, or patients, or a radiopharmaceutical. This written directive would not be required in advance in case of emergent conditions. Specific records are required. These departures i are currently prohibited by license conditions and i 35.200(b). b. A medical use licensee may depart f rom the package insert f or therapeutic uses of radiopharmaceuticals. Specific records are required. These departures are currently prohibited by 5 35.300. Tho statt proviced a draft of the interim final rule to the FDA for its review and received FDA coments on May 18, 1990. FDA recomendations have been incorporated into this rulemaking package. The FDA does not object to NRC issuing an interim final rule (Encicsure 6). For a period of 3 years following publication of this rule, information will be collected and analyzed on the nature of, reasons for, and frequency of the departures. The NRC will provide FDA the opportunity to review this information. -Coordination: The Offices of Acministration, Enforcement, Government and Public Attairs, and Nuclear Material Saf ety and Safeguards concur in this rulemaking. The Office of the General Counsel has no legal objections. A copy of the Federal Register notice has been provided to the Advisory Committee for the Medical Use of Isotopes.(ACMUI). ' The coments from the committee are expected the week of June 4,1990. A sumary of their comments will be provided to the Commission as soon as possible. L Recommendation: That the Commission: 1, After receipt of the ACMUI comments, approve the interim final rule to be immediately effective upon publication in the Federal Register for 3 years (Enclosure 1). 2. Note that: A regulatory analysis (Enclosure 2) will be available in a. the Public Document Room. L 1 l

e e b 4 The Commissioners 4 b. An environmental assessment (Enclosure 3) will be avail- [ able in thc Public Document Room, Congressional committees will be notified of this rule - c. niaking by letter (Enclosure 4). -d. A public announcement (Enclosure 5) will be issued when the interim final rule is filed with the Office of the Federal Register for publication, Copies of the Federal Register notice will be distributed e. to the petitioners, all affected Connission' licensees, all states, and other interested parties. f. Implementation of this rulemaking will increase staff resource requirements by 0.5 FTE. to collect and evaluate the information on the-departures from the package insert. 9 This rulemaking may require OMB ap3roval of the infor-mation collection requirements. T1e staff is working with OMB in parsilel witn Concission review. / ames M. a r xecutive rector for Operations

Enclosures:

l'. . Federal Register Notice-2...Regulotory Analysis ,~ l -3. ' Environmental Assessment 4. Draf t Congressional Letter i

b. 'Uraft Public Announcement L

6. Letter from FDA dated 5/18/90

h '._ '.r. -o 4 5 t Commissio~ners'icomments: or consent should be provided' directly. to the Office of the Secretary by COB Monday, June-18, 1990. 1 Commission Staff' Office comments,: if any,-should be. submitted to the Commissioners-NLT Monday, June 11,-1990, with an'infor-i - mation copy to the Office of_the Secretary. _If the paper 11s of suchu a nature that it requires additional' time for analytical -' review--and: comment, the Commissioners and the Secretariat-should be= apprised of-when~ comments may be expected. This'paperLis tentatively scheduled.for affirmation at an Open Meeting-during the Week of June 18,J1990. Please' refer toLthe t 3 appropriate. Weekly Commission Schedule, when published, for a i( Ppecific date and time. 4 DISTRIBUTION: Commissioners m OGC g OIG 't W LLSS- 'GPA q. REGIONAL OFFICES. EDO ACRS ACNW-ASLDP.- ASLAP SECY: Y + I 1 I J l 9Q I, I j

4 p 4 ' l ] Federal Register Notice l l, i .. ) f .i i k 4 e .v.--

p b t;'. O [7590-01J. c I}' 1 NUCLEAR REGULATORY COMMISSION i i 10 CFR PARTS 30 and 35 f RIN: 3150-AD43 Authorization to Prepare Radiopharmaceutical Reagent Kits and Elute Radiopharmaceutical Generators; Use of Padiopharmaceuticals for Therapy AGENCY: Nuclear Regulatory Commission, f ACTION: Interim final rule with request for comment. I i SUt0ARY: The Nuclear Regulatory Commission (NRC) is issuing an interim j final rule amending its regulations related to the preparation and the' j therapeutic uses of radiopharmaceuticals. This interim rule modifies the' requirement-that licensees who elute generators and prepare reagent kits do so only in accordance with the manufacturer's instructions for eluticn l and preparation in the package insert (a part of.the Food and Drug l Administration (FDA) approved labeling), provided the. licensees meet certain conditions and limitations. The interim rule also permits NRC

licensees using byproduct material in a radiopharmaceutical for a f

therapeutic use to depart from the package insert regarding indications This f and method of administration it certain requirements are met. I amendment is necessary to allow health professionals to provide diagnostic or therapeutic medical results not otherwise attainable or to j reduce medical risks to particular patients because of their medical I l condition while continuing to protect public health and safety adequately. -The interim rule applies only to radiopharmaceuticals for which the FDA has approved a "New Drug Application" (NDA). The interim rule will l i l be effective for 3 years after publication in the Federal Register. l

~ t [7590-01J s.1 o t UATE: Effective date: From [ insert date of publication] to [ insert date 3 years from the date of publication]. Cument date: In view of the interim nature of this rulemaking, I comments will be welcome at any time'during the three-year period. ADDRESSES: Submit written comments and suggestions to the Secretary of the Commission, U.S. Nuclear Regulatory Commission, Washington, DC 20555, Attention: Docketing and Service Branch. Hand deliver comments to 11555 Rockville Pike, Rockville, Maryland between 7:45 a.m. and 4:15 p.m. on federa l workdays. Copies of the regulatory analysis, environmental r.ssessment, and the conrnents received on this rule may be examined at thr lommission's PublicDocumentRoomat2120LStreet,NW.(Lowerlevel), Washington,UC, 2055b. Single copies of the Hegulatory Analysis are available from Dr. Anthony Tse, Office of INclear Regulatory Research, U.S. Nuclear Kegulatory Confulbsion, Washington, DC 2055b. FOR FURTHER INFORMATION CONTACT: Dr. Tse, see AUDRESSES heading, telephone-(301)492-3/97. SUPPLEMENTARY INFORMATION: I. Background. A. Nuclear Medicine. Radioactive materials are used in drugs in the field of nuclear l-medicine. Drugs labeled with radioisotopes are known as radiophar-l maceuticals, in diagnostic nnclear medicine, patients receive these materials by injection, inhalation, or oral administration. - Physicians use. radiation detection equipment to visualize the distribution of a l l l 2

-[7590-01] .o radioactive drug within the patient. Using this technology, it is possible to locate tumors, assess organ function, or monitor the ef f ectiveness of a treatment. An estimated 7 million diagnostic nuclear medicine procedures are performed in this country annually. In therapeutic nuclear medicine, radiopharmaceuticals are administered to treat various medical conditions (e.g., hyperactive thyroid). An estimated 30,000 therapeutic procedures are performed each year, Regulatory Program and Policy Regarding Medical Use of Byproduct ti. Materials. in a policy statement, " Regulation of the Medical Uses of Radioisotopes," published on February 9, 1979 (44 FR 6242), the NRC stated: I I (1) The NRC will continue to regulate the medical uses of radioisotopes as necessary to provide f or the radiation safety of workers anc the general public. (2) The NRC will regulate the radiation safety of patients where Justified by the risk to patients and where voluntary standards, or compliance with these standards, are inadequate. (3) The NRC will minimize intrusion into medical judgments affecting patients and into other areas traditionally considered to be a part of the practice of medicine. The NRC has the authurity to regulate medicai use to protect the health and safety of patients, but also recognizes that physicians have NRC the primary responsibility f or the protection of their patients. " Medical use," as defined in 10 CFR 35.2, means the intentional 1 internal or external administration of byproduct material, or the radiation therefrom, to human beings in the practice of medicine in accordance with a license issued by a State or Territory of the United States, the District of Columbia, or the Commonwealth of " Medical use" includes the diagnostic and therapeutic Puerto Rico." use of radiorbarmaceuticals in the practice of nuclear medicine, but does not include in vitro diagnostic tests. 3

p w [7590-01] t ' regulations are predicated on the assumption that properly trained end adequately. informed physic.ans will make decisions in the best interest of their patients. i Under the Feoeral Food, Drug, and Cosmetic Act, as amended, the Food and Drug Administration (FDA) regulates drug research and the manufacture and sale of drugs including radiopnarmaceuticals. FDA has regulated j the saf ety and eff ectiveness of investigational radioactive drugs since 1975, when FDA revoted its 1963 exemption of radioactive drugs f rom the + " Investigational New Drug" (IND) regulations. The NRC withdrew from l 1 regulating radioactive drug safety and efficacy to avoid dual Federal l regulation, but continues to regulate the radiation safet;< of workers, patients, and the public. Each new drug approved for human use by the FDA, including radiopharinaceuticals, has labeling approved by FDA that includes a description of the drug, its pharmacology, indications for use, f contraindications, warnings, adverse reactions, dosage and administration, and other information. The labeling of certain drugs, including some radiopharmaceuticals, includes manufacturer's instructions I that specify the method of preparation. FDA reviews and approves the i information in the labeling to ensure that it accurately reflects the da'a on safety and effectiveness on which the drug approval is based. l NRC has, in the past, relied primarily on FDA's determination of a drug's l safety and effectiveness when it is prepared and used according to the l [ approved labeling, which some NRC regulations refer to as the package insert, as one means of ensuring protection of the public health and f ) safety. HRC regulations in 10 CFR 35.200(b) require medical use licensees to prepare radiopharmaceuticals in accordance with the manufacturer's instructions in the package insert (a part of the FDA-approved f labeling). Similar requirements are placed or, comercial nuclear pharmacies through HRC license conditions. Regulations in 10 CFR 35.300, "Use of Radiopharmaceuticals for Therapy," require, among other things, that the licensees ccmply with the package insert instructions regarding t i ~ indications and method of administration for the therapeutic use of radiopharmaceuticals. 1 l L E 4

[7b90-01] o 11. Petition for Rulemaking tiled By The American College of Nuclear Physicians and the Society of Nuclear Medicine On June 8, the NRC docketed as PRM-35-9 a petition for rulemaking dated June 5, 1989, which was filed By The American College of Nuclear Physicians and the Society of Nuclear Medicine (ACNP-SNM). The ACNP-SNM are composed of over 12,000 individuals who participate in the medical use of byproduct materials. Members include physicians, technologists, and nuclear pharmacists. As characterized by the petitioners, the physi-cians supervise the preparation and administration of radiopharmaceuticals to diagnose and treat patients. Also, technologists administer radio-pharmaceuticals to diagnose and perform clinical procedures under the direction and supervision of an authorized user physician.2 Nuclear pharmacists reconstitute radiopharmaceutical kits, compound radiopharma-ceuticals, ano dispense radiopharmaceuticals for medical purposes. Among other things, the petitioners requested that the NRC amend its-regulations at 10 CFR 35, " Medical Use of Byproduct Material," to recognize their appropriate practice of medicine and to allow (1) departures from the manufacturer's instructions for preparing diagnostic radiopharmaceuticals and (2) the use of radiopharmaceuticais for_ therapeutic indications and methods of administration not included in the~ package insert approved by the FDA. The-petitioners stated that, under current regulations, members of the petitioning organizations believe they cannot appropriately practice their professions. The petitioners also statea that authorized user physicians cannot prescribe certain radiopharmaceuticals or routes of administration for proper pctient care, even though they believe they are permitted to do so by the FDA and by their State medical licenses. According to the petitioners, nuclear pharmacists have been disenfranchised as a professional entity because activities that they believe are permitted by the FDA and by the States are not allowed under 2 Whenever the term " authorized user physician" is used, it means the " authorized user" or the physician working under the supervision of the authorized user. l '

[7590-01) 1 l l NRC regulations. The cetitioners stated that although a nuclear pharmacist is authorized by State license to prepare radiopharmaceuticals upon receipt of a prescription by an authorized user physician, current NRC regulations severely restrict their activity. The petitioners believe that their professional activities are curtailed by the limitations imposed by the NRC on nuclear physicians and pharmacists. A notice of receipt of the petition with a public coment period of 90 days was published in the federal Register on September 15,1989(54 .fR 3B239). The Federal Register Notice set forth the petitioners' proposed arnendments to 10 CFR parts 30, 33, and 35, including the deletion of the restriction regarding the preparation of radiopharmaceuticals in 5 35.200(b) and the deletion of the restriction in i 35.300, with respect to f ollowing the package insert instructions regardingir.diotionsandmethodofadministration(54FR38240). The comment period closed on December 14,1989, and 466 coment letters have been receiveo. Coments were receivea f rom many different sources, such as hospitals, pharmacies, and inedical associations. About 60 percent of the letters were similar to a form letter written for members of ACNp-SNM. These letters-indicated agreement with the petition on all essential points. Fif teen percent of the coment letters were similar to a form letter written for the staff of Syncor international Corporation, also agreeing with the assertions in the petition. Twenty-five percent of the responses were letters f rom other individuals. 1 tost letters (99 percent) supported the petition and stated that the NRC should amend its regulations to relax its current restrictions on the practice of nuclear medicire and nuclear pharmacy. The majority of these letters did not provide specific supporting rationale. Some comenters provided rationale and examples of clinical cases that the comenters believe demonstrate how the relevant NRC regulations prevent physicians from providing proper care for their patients. The comenters stated that, although c licensee may request an exemption from specific requirements in the regulations on a case-by-case basis, this exemption process is timeconsuming and cumbersome. The comenters believe that a delay in order to obtain Hkt approval for a particular departure 6

L7b9001) i from the package insert m6y, in some cases, jeopardize the patient's health. Some examples of clinical cases the commenters provided are described below: i (1) Licensees are not able to use Tc-99m macroaggregated albumin w1th high specific activity and low particle concentration to safely perform lung scans for patients who have pulmonary hypertension because the ranges of specific activity and particle concentration given in the 1 package insert would be exceeded. (2) Licensees are not able to add ascorbic acid as an antioxidant to Tc-99m-DTPA, which would increase stability and enhance image quality, because NRC regulations do not permit departure from the manufacturer's instructions for reconstituting reagent kits. (3) When evaluating potential blood transfusions, licensees are not able to perf orm in vivo crossmatching using potentini donor red cells radiolabeled with Tc-99m because this is not provided for in the package insert. (4) Licensees are not able to use P-32 sodium phosphate to treat primary Thrombocythemia because such use is not specified in the package insert. !!!. Need for a Rule. Information submitted by the ACNP-SNM in the petition f or rulemaking and obtained during subsequent discussions with licensees indicates that the requirements in i 35.200(b) regarding preparation of radiophar-maceuticais and in 6 35.300 regarding indications and method of administration for therapy procedures are preventing authorized user physicians f rom providing certain nuclear medicine clinical procedures. License conditions similar to f, 35.200(b) currently placed on commercial 1 i 1 7

[759001) o nuclear pharmacies have the same effect. For some uncommon disease J states or patient conditions, in order to provide proper patient care, it may be necessary to depart f rom the FDA-aoproved instructions to obtain diagnostic or therapeutic tuedical results not otherwise attainable or to reouce medical risks to particular patients because of their medical i cc' dition. The NRC believes that continued application of these restrictions i governing the preparation of radiopharmaceuticals and the indications and method of administration for therapeutic use of radiopharmaceuticals would not permit proper patient care to be provided to some patients. l Under its 1979 Medical Use policy Statement (44 FR 8242, february 9, 1979), the liRC stated that it would regulate the medical use of byproduct material in order to protect the health and safety of worLers, patients, and the public, in general, NRC regulatory requirements are oriented to i ensure that the properly prepared radiopharmaceutical is administered to the correct patient as prescribed by an authorized user physician. Aside from the requirements in i 35.200(b) and i 35.300, other requirements in port 35, such as the use of dose calibrators, are intended to ensure that the patient receives the prescribed dose. HRC's regulations need to provide a balance between adequate controls and avoidance of undue interference in medical judgments. The high level of public health and safety protection that accrues froni tollowing the FDA-approved instructions must be balanced with the need to depart from those instructions to obtain diagnostic or therapeutic results not otherwise attainable or to reduce patient risk in some uncommon disease states or patient conoittons in order to provide proper patient care. The diagnostic use 01 radiopharmaceuticals is, in most cases, an area of inherently low radiation risk to patients (policy Statenient, 44 tR 8242, February 9, 19/9). Although there are greater risks inherent in the use of therapeutic levels of radioactive drugs, in light of the information provided with and gathered subsequent to the petition, the NRC does not believe that limiting the therapeutic use of l radiopharmaceuticels in all cases to only the indications and methods of j administration specified in the package insert is justified. Moreover, f as stated in its 1979 policy Statement, the NRC recognizes that physicians Lt.ve the primary resportibility for the protection of their l 8

[759001] patients. The Commission believes that basic decisions concerning the diagnosis and treatment of disease are a part of the physician patient relationship and are traditicnally considered to be part of the practice of medicine. The NRC has made a determination that continued application of the subject requirements, without exceptions, may adversely affect the public health end safety because the delivery of proper patient care may require, in certain instances, that some radiopharmaceuticals be prepared and administered in a manner different from that stated in the FDA-approved instructions. The NRC has reviewed the information on nuclear medicine clinical procedures and believes that adequate protection of the public health anc safety can be maintained while, at the same time, providing proper patient care. Hence, the NRC is issuing an interim final rule that permits, on the direction of an authorirtd user physicien, departures from the manufacturer's instructions in preparing radiopharmaceuticals and departures from package inserts for indications and method of administration for therapeutic use, provided a proper record of the departure is made. These records will be examined by the NRC to determine whether to extend the interim period for the rule, i. make the rule permanent, or revise it based on the nature of, reasons for, and f requency of departures. The NRC will provide FDA the l opportunity to review this information, ticcause these emendments involve relief from restrictions which if left in place could have an adverse impact on public health and safety, and because the NRC has received and considered public comments on the l f petition for rulemaking, good cause exists f or omitting the notice of proposed rulemaking and the public procedures thereon as unnecessary and contrary to the public interest, and for making these amendments effective upon publication in the Federal Register without the customary thirty-day notice. This interim rule will terminate 3 years af ter the date of publication in the Federol Register. l IV. Future Agency Action. This interim rule amending 10 CFR Parts 30 and 35 represents only one phase of NRC's rtsolution of the ACNP-Stiti petition fcr rulemaking. 9 1 i

[759001) o During the 3-year period, the NRC may modity the interim rule or take such other regulatory action as it determines necessary to protect the public health and safety. Based on continued NRC analysis of the i AChP-SNM petition, the consnents on the petition and on this interim rule, experience with the interim rule implementation, and other information, the NRC may propose amendments to this rule or to other provisions of 10 CFR Parts 30 and 35 as part of its resolution of the issues raised in PRil-35-9. V. Discussion. L 35.200 use of Radiopharmaceuticals, Generators, and Reagent Kits for Imaging and Localization Studies. IIRC believes that persons licensed by NRC to elute generators and prepare reagent kits should not always be bound by the requirement specified in 10 CTR 35.200(b) to f ollow the manufacturer's instructions for radiopharmaceuticals for which the FDA has approved an NDA. They shou'Id not be bound if they have a written directive (e.g., prescription) made by an authorized user physician that includes (1) the specific nature of the departure for a particular patient, or patients, or for a radiopharmaceutical, (2) a precise description of the departure, and (3) a briet statenient of the reasons why the departure from the manu-facturer's instructions would obtain medical results, not otherwise attainable or to reduce medical risks to particular patients because of their medica l condition. The NRC recognizes that the physician may f ace severe time constraints during an emergency; therefore, an exception has been provided in 635.200(c). Under the exception, a written directive is not required before preparing the radiopharmaceutical if an authorized user physician determines that a delay in order to make a written directive woulo jeopardize the patient's health. The written directive ano o record of the number of patient administrations under each departure must be retained by the licensee for a period of 3 years and made available for NRC inspection. 10

[7590-01] O 1his interim rule does not address departures f rom " Investigational New Drug" (IND) generator elution instructions or IND protocol directions for reagent Lit preparation, bec6use the departures may compromise the scitntific integrity of the clinical investigation. Therefore, licensees must continue to follow the IND generator elution instructions and IND protocol directions for reagent kit preparation. b 35.300 Use of Radiopharmaceuticals for Therapy. Ior a radiopharmaceutical for which the FDA has approved an NDA, the amendments to 6 35.300 would permit a licensee, under certain circumstances, to use therapeutic radiopharmaceuticals f or indications or a method of adn.inistration not specified in the package insert. Specifically, such use would be permitted if a record is made of the departure which includes the specific nature of the departure and a brief statement of the reasons why the departure would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their iaedical condition. A record of the departures from indications and method of administration and a record of the number of patient administrations under each departure must be retained in an auditable form and be available for inspection f or 3 years, b 30.34 lerms and Conditions of Licenses. Commercial nuclear pharmacies are licensed pursuant to 10 CFR part 30, " Rules of General Applicability te Domestic Licensing of Byproduct These licensees are required by a license condition similar Material." to 5 35.200(b) to elute generators ano prepare reagent kits in accordance with the manufacturer's instructions. NRC believes that authorized users obtaining radiopharmaceuticals from commercial nuclear pharmacy licensees should not be bound by this restriction in the commercial nuclear pharmacy license. Therefore, NRC is amending 10 CFR 30.34 " Terms and Conditions of Licenses," to permit actions within the scope of those permitted by (new) ( 35.200(c). For situations not within the scope of l amended 5 30.34, a commercial nuclear pharmacy licensee may file an 11

[7b90-01] application to have its license amended to permit specific departures the manufacturer's instructions for identified products. Under the interim rule, commercial nuclear pharmacy licensees would no longer be bound by the requirement in their licenses to follow the manufacturer's instructions for a radiopharmaceutical for which the FDA has approved an NDA if there is a written directive made by an authorized user physician directing a specific departure for a particular patient, or patients, or for a radiopharmaceutical, which includes a precise description of the departure and why the departure from the manufacturer's instructions would obtain medical results, not otherwise ottainable or to reduce medical risks to particular patients because of their medical condition. As in 6 3b.200(c), there is an exception to the requirement for 6 written directive before preparing the radio-pharmaceutical in an emergency situation, if an authorized user physician determines that a delay in order to obtain the written directive would jeopardize the patient's health, in this case, the commercial nuclear pharmacy licensee shall cLtain the written directive made by the authorized user physician af ter the emergency has passed. The directive must contain the information regarding the emergency and all of the other required information. Licensees shall Leep those records in an auditable form and availatle f or inspction for 3 years. These amenaments to L 30.34 take precedence over the restrictive cot.d1tions (i.e., on eluting generators and preparing reagent Lits) in the licenses of commercial nuclear pharmacies. Therefore, these license conditions no longer apply during the 3-year period when the interim rule i is in effect. However, NRC reserves the. right to tale sucn regulatory action as it determints necessary to protect the public health and safety. This inter 1m rule does not address departures from IND generator elution instructions or IND protocol directions for reagent Lit preparation, thus licensees shall continue to follow the IND instructions. Continuing Applicability of Regulatory Requirements. NRC notes that this interim rule does not relieve licensees from the requirements to comply with other applicable NRC, FDA ano other Federal, or State replations or NRC orders ur license conditions concerning 10

[7590-01) o poness1on or use of bypreouct material for nedical use or other purposes as specified in 10 CFR parts.10, 32, 33, and 35. Moreover, if a radioactive biologic receives a product license approval (PLA), this interim rule coes not authorize dt.partures from the manufacturer's instructions for preparing the biologic. li, addition, if a kit or generator for a radiopharmaceutical f or therapy receives an approved NDA, this interim rule does not authorize departures from the manufacturer's instructions for eluting the generator or preparing the therapy kit. Neither of these exists at this time and neither is authorized by current regulations. Therefore, there is no need to include a prohibition in this rule. Radiation Safety Responsibilities of Medical Usr. Licenses liRC medical use licenseen ere recuired by 6 35.21 to appoint a Radiation Safety Otticer (R50) responsible f or implementing the licensee's radiation saf ety program. The licensee is required, through the R50, to ensure that radiation safety activitics are being performed in accordance with approved procedures and regulatory requirements in the daily operation of the licensee's byproduct material program. Nothing in this rulemaking relieves the licensee f rom complying with the requirenients of 5 35.21. In accordance with 10 CFR 35.22, NRC medical institution licensees are recuired to establish a Radiation Safety Connittee (RSC) to oversee the use of byproduct material. The duties of the RSC are specified in t 3b.22(b) and include reviews, on the basis uf safety, of numerous aspects of a licensee's use of byproduct material. Nothing in this rulemaking relieves the licensee f rom complying with the requirements of 6 35.22. l l 13

1 [7590-01J c VI. Adannistrative Stetements. Finding of lio Significant Environmental Impact: Availabi lity j The Commission has determined under the National Environmental Policy Act of 1909, as amended, and the Commission's regulations in Subpart A of 10 CFR part 51 that these amendments are not a major n Federal action significantly affecting the quality of the human environment and therefore an environmental impact statement is not required. This interim rule amends 14RC regulations to permit licensees who clute generators and prepare reagent kits to depart from the manufacturer's instructions if those persons have a written directive made by an authorized user physician that requests a specific departure for a particular patient, or patients, or for a radiopharmaceutical. "is directive must provide the specific nature of the departure, a precise description of the departure, and the reasons why the departure f"om the manufacturer's instructions would obtain medical results, diagnostic or therapeutic, not otherwise attainable or to reduce medical risks to particular patients because of their medical condition. The amendment coes not address departures from IND generator elution instructions or IND protocol directions f or reagent kit preparation. The NRC is also niodifying its regulations to permit, if certain requirements are met, the therapeutic use of radiopharmaceuticals without following the package instructions regarding indications and niethod of administration, The interim rule does not affect the exerption in 10 CfR Part 20 for the intentional exposure 01 patients to radiation for the purpose of medical diagnosis and therapy. Although the rule may cause some patients to be exposed to higher or lower levels of radiation than otherwise expected, those exposures would be given to obtain medical results not otherwise attainab,'e or to reduce other risks to the patient. It should be noted that current requirements do not liinit the radiation dose prescribed by the authorized user physician for either diagnosis or therapy. The amendments wculd not relieve licensees from meeting the requirements in l 10 CFR Parts P0 and 35 that restrict radiation exposure to medical care personnel in the restricted area or to the general public in the unrestricted orea, or radioactive efflutrt releases. It is expected that 1 14 1

[759001) there would be no significant change, either increase or decrease, in i radiation exposure to the public or to the environment beyond the exposures currently resulting f rom delivering the dose to the patient, j The Environmental Assessment and Finding of No Significant Impact is available for inspection at the NRC Public Document Room at 2120 L Street,NW,(LowerLevel), Washington,DC,20555. Single copies of the Assessment are available from Dr. Tse (see ADDRESSES heaaing). J Paperwork Reduction Act Statement The information collection requirements contained in this interiin I final rule have been submitted to the Office of Management and Budget for appropriatereviewunderthePaperworkReductionAct(44U.S.C.3501et seq.). Accordingly, the information collection requirements will not become effective until after OMB's approval, Regulatory Analysis The Commission has prepared a regulatory analysis for these \\ amendments. The analysis examines the benefits end impacts considered by tht NRC. The regulatory analysis is available for inspection 6t the NRC Public Document Room at 2120 L St. NW (Lower Level), Washington, DC. SinglecopiesareavailablefromDr.Tse(seeADDRESSESheading). The Commission requests public comments on the regulatory analysis. Comments are specifically requested on or before [TO BE INSERTE0].. Comments on the analysis may be submitted to the NRC as indicated under the ADDRESSES heading. Backfit Anelysis The NRC has determined th6t the backfit rule, 10 CFR 50.109, does not apply to these amendments and thus a backfit analysis is not required f or these amendments because they do not involve any provisions that would impose backfits as defined in 10 CFR 50.109(a)(1). 10 TT-

l [7590-01) i -o e List of Subjects 10 CFR Part 30 l Byproduct material, Criminal Penalty, Government contracts, Intergovernmental relations, Isotopes, Nuclear materials, Radiation protection, Reporting and recordkeeping requirements. 10 CFR Part 35 Byproduct material, Criminal Penalty, Drugs Health facilities, Health professions, incorporation by reference, Medical devices, Nuclear materials, Occupational safety and health, Radiation protection, i Reporting and recordkeeping requirements. For the reasons set out in the preanble and under the authority of the Atomic Energy Act of 1954, cs amended, the Energy Reorganization Act of 1974, as amended, and 5 U.S.C. 552 and 553, the NRC is proposing to adopt the following amendments to 10 CFR Parts 30 and 35. 1 PART 30 - RULES Of GENERAL APPLICABILITY 10 DOMESTIC LICENSillG OF BYPRODUCT MATERIAL i 1. The authority citation for Part 30 is revised to read as tollows: Authority: Secs. 81, 82, 161, 182, 183, 186, 68 Stat. 935, 948, 953, $54, 955 as amended, sec. 234, 83 Stat. 444, as amended (42 U.S.C. 2112, 2201, 2232, 2233, 2236, 2282); secs. 201, as amended, 202, 206, 88 Stat. 1242, as amended, 1244,1246(42U.S.C.5641,5842,5846). Sections 30.7 also issueo under Pub. L. 9b-6U1, sec. 10, 92 Stat. 2951 (42 U.S.C. 5851). Section30.34(b)alsoissuedundersec.184,68 Stat.954,asamended(42U.S.C.2234). Section 30.61 also issued under secs.-187, 68 Stat. 955 (42 U.S.C. 2237). For the purposes of sec. 223, 68 Stat. 958, as amended (42 U.S.C. 22/3);$530.3,30.34(b),(c),(f),(9),and(i),30.41(a),and(c),and 30.53 are issued under nec. 161b, CS Stat. 948, as amended 16 1 t'-

[7590-01] a (42U.S.C.2201(b));andil 30.6,30.9,30.34(g),30.36,30.51,30.52, 30.55,and30.56(b)and(c),areissuedundersec. 1610, 63 Stat. 950, as amended (42 U.S.C. 2201(o)). 2. In i 30.34, paragraph (1) is added to read as follows: 6 30.34 lerms and conditions of licenses. (i)(1) from [ insert date et publication) to [ insert date 3 years from the date of publication], each licensee eluting generators and processing radioactive material with diagnostic reagent kits for which theFoodandDrugAdministration(FDA)hasapproveda"NewDrug Application" (NDA) may depart from the manufacturer's elution and preparation instructions (f or radiopharmaceuticals authorized for use pursuanttoi35.200)providedthat: (i) The licensee has a written directive made by an authorized user physician that airects a specific departure for a particular patient, or patients, or for a radiopharmaceutical, and which includes the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manuf acturer's instructions in preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their redical condition. The licensee shall Leep the written directive ^and a record of the number of prescriptions dispensed under the departure in an auditable form and available for inspection for 3 years; or (ii) An authorized user physician determines, in accordance with i 6 35.200(c), that a delay in preparing the radiopharmaceutical in order to make d written directive would jeopardize the patient's health because of l the emergent nature of the patient's medical condition, in this case, the licensee shall obtain the written directive made by the authorized user physician which contains the notation regarding the emergency and l all the information specified in (i) above within 3 working days af ter the emergency has passed. The licenseee shall keep these records in an auditable form ano available for inspection for 3 years. 17

[7590-01] + a e e (2) Theactionsauthorizedinparagraph(i)(1)arepermitted notwithstanding more restrictive language in license conditions unless i those license conditions specifically reference $ 30.34(i). I (3) Nothing in this section relieves the licensee f rom complying with other applicable NRC, FDA and other Federal, or State regulations governing the elution of generators and preparation of reagent kits. PART 35 - MEDICAL USE Of 8YPRODUCT MATERIAL 3. The authority citation for Part 35 is revised to read as follows: Authority: Secs. 81, 161, 182, 183, 68 Stat. 935, 948, 953, 954, as amended. (42 U.S.C. 2111, 2201, 1132, 2233);_sec. 201, 88 Stat. -1242,~as amended (42 U.S.C. 5841). For the purposes of sec. 223, 68 Stat. 958, as amended (42 U.S.C. 2273); $5 35.11, 35.13, 35.20(a) and (b), 35.22, 35.23, 35.25, 35.2/ (a). (c) and (d), 35.31 (a), 35.49, 35.50 (a)-(d), 35.51 (a)-(c), 35.53 (a)-(b),35.59(a)-(c),(e)(1),(g)and(h),35.60,35.61,35.70(a)-(f), 35.7b,35.60(a)-(e),35.90,35.91(a),35.120,35.200(b)and(c), 35.204,(a)ano(b),35.205,35.220,35.300,35.310(a),35.315,35.320, 35.400,35.404,(a),35.400(a)and(c),35.410(a),35.415,35.420, 35.500,35,620,35.605,35.606,35.610(a)and(b),35.615,35.620, 35.630. (a) and (b), 35.632 (a)-(t), 35.634 (a)-(e) 35.636 (a) and (b), 35.641(a)and(b),35.645(a)and(b),35.900,35.910,35.920,35.930, 35.932, 35.934, 35.940, 35.941, 35.950, 35.960, 35.961, 35.670, and 35.971, are issued under sec. 161b, 68 Stat. 948, as amended (42 U.S.C. 2201(b));andil 35.14,35.21,(b)35.22(b)35.23,(b)35.27,(a)and (c), 35.29 (b), 35.33 (a)-(e), 35.36 (b), 35.50 (e), 35.51 (d), 35.53 (c),35.59(d)and(e)(2),35.59(g)and(i),35.70(g)35.80(f),35.92 (b),35.200(c)35.204,(c),35.300(b),35.310(b),35.315(b),35.404 (b), 35.406 (b) and (d) 3b.410 (b), 35.415 (b), 35.610, (c), 35.615 (d)(4), 35.630(c), 35.632 (g), 35.634 (f), 35.636 (c), 35.641 (c), 35.643 (c),35.645,and35.647(c)areissuedundersec. 1610. 68 Stat. 950, as amended (42 U.S.C. 2201(o)). l 4. In !35.8, paregraph (b) is revised to reed as follows: 18

L7690-01) i 35.8 Information Collection Requirements: OMB approval. (b) The approved information collection requirements contained in this part appear in il 35.12, 35.13, 35.14, 35.21, 35.22, 35.23, 35.27, 35.29, 35.31, 35.33, 35.50, 35.51, 35.53, 35.59, 35.60, 35.61, 35.70, 35.80, 35.92, 35.200, 35.204, 35.205, 35.300, 35.310, 35.315, 35.404, 35.406, 35.410, 35.415, 35.006, 35.610, 35.615, 35.630, 35.632, 35.634, 35.636, 35.641, 35.643, 35.645, and 35.647. 5. In 6 35.200, paragraph (c), is added to read as follows: 6 35.200 Use of rediophorinaceuticals, generators, and reagent Lits for imaging and localization studies. (c) (1) from [ insert date of publicationj to Linsert date 3 years from the date of publicationj, a licensee may depart f rom the manufacturer's instructions for eluting generators and preparing reagent kits for which FDA has approved an NDA, provided that the licensee has a written directive made by an authorized user physician that directs a specific departure for a particular patient, or patients, or for a radio-pharmaceutical, and which includes the specific nature of the departure, a precise description of the departure, and a brief statement of the reasons why the departure from the manufacturer's instructions in preparing the radiopharmaceutical would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of tht:ir medical condition. if the authorized user physician determines that a delay in preparing the radiopharmaceutical in order to male a written directive would jeopardize the patient's health because of the emergent nature of the patient's medical condition, the radiopharmaceutical may be prepared without first making a written directive. The authorized user physician shall make notation of this determination in the written directive within 3 working days after the emergency ha passed. 19

[7590-01] o e (2) The licensee shall keep the written directive and a record of the number of paticht administrations under the departure in an auditable torin and avt.ilable for inspection f or a period of 3 years. (3) Nothing in this section relieves the licensee f rom complying with other applicable NRC, FDA and other Federal, or State regulations governing the elution of generators and preparation of reagent kits. 6. Inb35.300,theexistingtextisdesignatedasparagraph(a) and a new paragraph (b) is added to read as follows: 6 35.300 Use of radiopharmaceuticals f or therapy. (b) (1) from Linsert date of publication) to [ insert ante 3 years from the date of publication), a licensee may depart from the package insert instructions regarding inc1 cations or method of administration for a radiophoriaaceutical for which FDA has approved an HDA, provided that the authorized user physician makes a record of the departure which includes the specific nature of the departure and a brief statement of the reasons why the departure would obtain medical results not otherwise attainable or would reduce medical risks to particular patients because of their medical condition. (2) The licensee shall make this record within 3 working days of the administration and keep this record and a record of the nuebtr cf patient administrations under the departure in an auditable toria and available for inspection for 3 years. 20 0

i ? -[759001) l (3) Nothing in this section relieves the licensee from complying with other applicable NRC, TDA (including requirements governing the f submission of an IND) and other Federal, or State regulations governing I the use of radiopharmaceuticals for therapy, l t Dated at Rockville, Maryland, this day of

1990, l

i For the Nuclear Regulatory Commission. 1 ? I Samuel J. Chilk, Secretary of the Commission i T i i -i \\ i i N" i r! I l ~ li h F i-21

i L s e i i i i ? Regulatory Analysis 4 i

Regulatory Analysis 10 CFR Parts 30 and 35 Authorization to Preaare Radiopharmaceutical Reagent Kits and Elute Radicpiarmaceutical Generators; Use of Radiopharmaceuticals f or Therapy 1. Statement of Problem The NRC has received and docleted a petition for rulemaking filed by the American College of Nucleer physicians and the Society of Nuclear medicine ($4 r FR 38239, September 15, 1989). The petitioners stated that, under current NRC-regulations, nuclear physicians and nuclear pharmacists cannot appropriately practice their professions. The petitioners requested that, among other things, the NRC (a) allow inedical use and commercial nuclear pharmacy licensees to depart from package insert instructions for preparing radiopharmaceuticals using generators or reagent Lits and (b) allow medical use licensees to depart from p6ckage insert instructions regarding indicativ or method of administration for therapeutic use of radiopharmacet- 'tals. Current license conditior.s require commerch q clear pharmacy licensees Administration (FDA)jturer's instructions, which e v part of the Food and Drug to follow the manufa approved lbbeling, when preparing radiopharmaceuticals using generctors or reeget.t Lits. Regulations in Subpart E at i 35.200(b) require r.iedical use licensees to follow the FDA-approved instructions when preparing radiopharmaceuticals using generators or reagent Lits.

Further, bubpart f at i 35.300 requires medical use licensees to comply with the FDA-approved package insert instructions regarding indications and method of administration, e.g., to limit the disease states to be treated with each radiopharmaceutical to these listed in its package insert, or to prohibit administration of an oral radicpharmaceutical by intravenous injection.

2. Objectives, In medical use, NRC's objectives are to protect the public health and saf ety, including patients, from radiological hazards and, at the same tirne, to permit the widest possible use of byproduct material in providing medical benefit to patients. I TDA is tht national authority for drug saf ety and efficacy, including raciopharmaceuticals. Before a drug can be legally marketed in the.Unitea Statts, the FDA must cetermine that the drug is safe and effective and approve the instructions contained in the package insert, including the manuf acturer's instructions for preparing radiopharinaceuticals. L r

o s 3. Alternatives lwo alternatives have been considered: (A) Maintain the status quo pending resoluticn of all issues of the petition. (D) Amendparts30and35(onaninterimbasis): (a)toallowmedicaluseand commercial nuclear pharmacy licensees to depart from manufacturer's instructions for preparing radiopharmaceuticals using generators and reagent kits, and (b) to allow medical use licensees to depart f rom package insert instructions regarding indications and method of administration for therapeutic use of radiopharmaceuticals. The interim rule will te effective f or 3 years af ter the date of publication. 4 Consequences (A) The first alternative, maintaining the status quo, would continue to prohibit preparation of radiopharmaceuticals or therapeutic use not described in the FDA-approved instructions. This alternative may prevent medical use licensees f rom providing diagnostic or therapeutic niedical results not otherwise attainable or to reduce the medical risks to particular patients because of their medical condition. (B) The second alternative, promulgating an interim rule, would allow niedical use licensees to exercise profession 61 discretion in the selection and use of the proper diagnostic or therapeutic procedures even if these procedures are not described in the package insert. in most cases, an area of The diagnostic use of radiopharmaceuticals is,though there are greater inhertntly low radiation risk to patients. Al risks inherent in tht use of therapeutic levels of radioactive drugs, in light of the information provided with and gathered subsequent to receipt of the petition, KRC does not believe that limiting the therapeutic use of rad 10 pharmaceuticals in all cases to only the indications and niethods of auministration specified in the package insert is justified. Moreover, as stated in its 1979 policy statement, the NRC recognizes that physicians have the primary responsibility for the protection of their patients. The Connission believes that basic cecisions concerning the diagnosis and treatment of disease are a part 01 the physician-patient relationship and are traditionally considered to be part of the practice of medicine. L No data exist on the nature of, reasons for, and f requency of the oepartures that would be permitted under this interim rule. Phile the interim rule is in effect, this information will be collected and ex6 mined to determine whether to extend the interim period for the rule, make the rule permanent, or revise it. ?

i \\

o

) 5. Decision Rationale The NRC has made a determination that continued rpplication of the subject requirements, without exceptions, may adversely affect the public health and safety because the delivery of proper patient care may require, in certain instances, that'some radiopharmaceuticals be prepared and administered in a The NRC manner ditterent from that stated in the FDA-approved instructions. has reviewed information on nuclear medicine clinical procedures and believes that adequate protection of the public health and safety can be maintained Hence, the NRC is while, at tne same time, providing proper patient care. issuing this interim final rule.

6. -

Jinplementation Because these amendments involve reliet f rom restrictions wnich if lef t in place coulo have an adverse impact on public health ano safety, and because the NRC has received and considered public concents on the petition for good cause exists for omitting the notice of proposed rulemaking rulemaking,lic procedures thereon as unnecessary and contrary to the public and the pub interest, and for making these amendments effective upon publication in the This interim rule federal Register without the customary thirty-day notice. will tie Tii ef f ect f or a period of 3 years af ter publiration in the feceral

Register, s

~ t I

i f.nvironmental Assessment l I t I )

I, ' i ENYlkONMENTAL ASSESSMENT; FINDING OF NO SIGNIFICANT IMPACT FOR THE IMMEDIATELY EFFECTIVE INTERIM FINAL RULE AMENDING 10 CFR PARTS 30 AND 35 ELUTION OF GENERATORE AND PREPARATION OF REAGENT LITS IN ACCORDANCF. W11H THE MANUFACTURER'S INSTRUOTIONS; USE OF RAD!0 PHARMACEUTICALS FOR THERAPY 1. INTRODUCTION Tht: huclear Regulatory Commission (NRC) is amending, on a three year interim b6 sis, its regulatiens at 10 CFR Parts 30 and 30 related to the preporation anc uses of radiopharmaceuticals. 1he interim rule modities the only in accordance with the Food and Drug Administration (FDA) gent Lits requirement that licensees who elute generators and prepare rea approved manufacturer's instructions ingluded in the package insert; licensees would have to comply with certain conditions and limitations. The interim rule would also permit NRC licensees using byproduct material in a radiopharmaceutical for a therapeutic use to depart from the package insert instructions regarding ly to indications and method of administration. The interim rule would only app (HDA). radiopharmaceuticals f or which FDA has approved a *New Drug Application Antormation submitttd by the American College of Nuclear Physicians (ACNP) and the Society of Nuclear Hedicine (SNM) in a petition for rulemaking (54 FR 38239, Septencer 15,1989) and information obtained f rom public comments and during subsequent discussions with licensees, indicates that these requirements may, in some cases, prev-snt authorized user physicians f rom providing certain clinical procedures to some patients. Departures from the manufacturer's instructions may be necessary to obtain improved images and examination results or to diminish the rtst to specific patients with uncommon disease states. I 11, THE NEED FOR THE FINAL ACT10h The NRC has made a determination that continued application of the subject requirements, without exceptions, may adversely affect the public health and safety because the delivery of proper patient care may require, in certain instances, that somt radiopharmaceuticals be prepared and administered in a manner ditterent f rom that stated in the FDA-approved instructions. 111. THE ENVIRONMENTAL IMPACT OF THL FINAL ACTION The regulatory action. The interim final rule does not identify specific types of departures f rom tTie manuf acturer's instructions that can be made. This rule

O does not authorize departures f rom the manuf acturer's instructions for " Investigation 61 New Drug" (IND) products. 1he NFC anticipatts that changes in the Ef fects of the regulatory action. ~ preparation of diagnostic radiopharmaceuticals and changes in the indications and method of administration for therapeutic radiopharmaceuticals may result in increased or decreased specific activity, differences in biodistribution, and dif f erences in solubility when compared to radiopharmaceuticals prepared following administration of a accorcing to the FDA-approved instructions, diagnostic or therapeutic radiopharmaceutical to the patient, other ef fects, such as altered t6rget to non-target ratio, biological half-life of the radiopharmaceutical, data acquisition time, or sensitivity and specificity of. The changes may result in a minur the diagnostic examination may be seen. increase or decrease in radiation exposure to the patient, physicians and technologistr., medical care personnel, and the general public. Departures from the FDA-approved instructions may also cause a minor increase or decrease in radiation levels in restricted and unrestricted areas. Impact on the patient. Although the interim rule may cause some patients' orgons and tissue to'be exposto to higher or lower levels of radiation than those upected 11 the manufacturer's instructions wtre followed, these expo-sures would be for the purpose of obtaining diagnostic results not otherwise obtainable or would reduce other medical risks to particular patients because Routine exposures for diagnostic nuclear medicine of their medical conditions. examinations are usually less that 500 millirem to the whole body and are The interim rule does not aff ect regarded as being of low risk to the patient.the (xemption in 10 CFR radiation for the purpose of medical diconosis and thcrapy. that current requirements do not limit the radiation dose prescribed by the authorized user physicien f or either diagnosis or therapy. Licensees performing rddiopharmaceutical therapy will no longer be compelled to iollow the package insert instructions regarding indications and Under the interim methods of administration as required under 10 Cff,35.300. rule, authorized user physicians will be free to exercise their professional juogment regarding the appropriate use of radiopharmaceuticals f or therapy. Under the interim rule, the application of therapeutic radio-pharmacevoicals may increase or decrease radiation exposure to selected patients and their organs and tissues. rule will diminish the licensee's obligatio 10 CFR 35.75 regarding the release of patients containing radiopharmaceuticals. Under the interim rule, the specific departure requested by the authorized user physiciar, must state the naturf. of the departure, a specific description of the departure, and the reasons why the departure would obtain medical results not otherwise attainable or would reduce medical risks to particularin so patients because of their medical condition,provice improved diagno advantages for thcie patients with uncorron medical conditions. l 2

Impact on medical care personnel. Medical care personnel may be exposed to increased or decreased radiation during the preparation and administration of the radiopharmaceutical and through contact with the patient, contaminated patient care materials, patient seliva, perspiration, urine, or excrement. The impact on personnel exposure is limited by the iniplementation of radiation safety procedures, radiation protection surveys, persunnel radiation exposure monitoring, and the routine use of personal protective nieasures such as anti-contamination gloves and lab coats. The rule does not relieve the licensee trom meeting the radiation safety requirenients in 10 CFR Part 20, " Standards for Protection Against Radiation," and the administrative and technical requirements in 10 CFR Part 35, "Medicel Use of Byproduct Material." These regulations provide limits for radiation cose rates and air concentrations of radioactive materials in restricted areas and impose requirements to evaluate radiation horards, provide personnel monitoring, conduct contamination surveys, and implenient weste disposel procedures. These requirements ensure that radiation doses to medical care workers who are potenti611y exposed to radiation are as low cs reasonably achievable and are well under the maximum personal exposure levels described in 10 CFR part 20. Impact on menters of the public. The general public might be exposed to slightly increased or decreased radiation or radioactive materials resulting from contect with the patient. The majority of nuclear medicine procedures use technetium 99m, which has e half-lif e of six hours. For technetium-99m proce-cures, the dose rate to the general public reduces dramatically within 24 hours; thus, patients undergoing diagnostic nuchar medicine examinations are generally not restricted to controlkd areas after radiopharmaceuticals are administered. NRC has regulations that protect the general public f rom the patient who has been administered byprocuct material in quantities that may unnecessarily l expose niembers of the general public. For e> ample,10 CFR 35.75 prohibits the release from continement for medical care et a patient who has been administered a radiopharmaceutical until either the measured dose rate f rom the patient is less than 5 millirems per hour at a distance of one meter or the activity in the patient is less than 30 millicuries. j NRC's requirements on waste disposal by decay in storage,10 CFR 36.92, only allow disposal to unrestricted areas af ter the waste has been decayed in i storage for 10 hall-lives and measured to ensure that there is no detectable radiation prior to releast. The NRC specifically exempts contaminated excreta f rom individuals undergoing medical diagnoris or therapy from regulatory restrictions when it is released to sanitary sewerage systenis (see 10 CFR 20.303(d)). The hkC believes that the interim rule will have little effect on the amount of radioactivity released to the sanitary sewerage systems. 3

O j c impact on the ecosystem. Under the interim rule, radiation exposure to the ecosystem will not be significantly dif ferent from the exposures under current regulations, which is small. Thus, it is likely that the interim rule will not have a significant impact on the ecosystem. IV. ALTERNAT!WS TO THE flNAL ACTION The NRC has identified one alternative to issuing the interim finel rule, it is described in the following paragraphs. No action. The NRC could take no action and continue to require its medical ~use licensees to follow the inanutar.turer's instructions f or the preparation of HDA products. This would not result in any change in radiation exposures to n oical care personnel, patients, or the general public. However, it would likely result in certain patients being denied diagnostic and therapeutic clinical procedures niodified to take into account their unique disease states or conditions. If no action is talen, NRC would continue to require NRC licensees to follow the FDA-opprosed instructions, anc hRC wou M be required to review and possibly approve individual licensees' amendment requests for approval of specific departures from the manufacturer's instructions for preparing each Although the NRC could evaluate each license amendment radiopharmaceutical. request on the basis of radiation safety, the NRC would not be able to make determinations about the medical safety and effectiveness of each departure without assistance. License amenduent requests would have to be forwarded to the FDA tor review and opproval of medical safety and effectiveness. If approved, license anendments permitting the specific departure from a manufac-turer's instruction f or preparing cach radiopiarmaceutical requested by the licensee woulo need to be issued. Although the review and approvbl process described above would inform NRC of the types of specific departures licenstes want to make, the delays encountered during the license amendment process would serve to deny timely li there were many requests for departures, this medica l care to patients, process could increase the NRC's licensing burden by increasing the number of Individual license amendments processed esery year, in sumniary, if no action were taken there would be little change in radiatton exposures currently received by medical care personnel, patients, and the general public. However, there would be administrative and financial burdens to licensees and to the NRC. There also might be unacceptable delays in medica l care. V. ALTERNATIVE USE Of RESOURCES The NRC will use about 0.5 staf t years to collect and evaluate the inf orn:6 tion cn the drpartures f rom the package insert in the preparation of radiopharmaceuticals and additional radiopharr:aceutical therapy proc (dures. 4

(- O VI. AGENCIES AND PERSONS CONSULTED The NRC staff has discussed this interim rule with the statt from the FDA's Center for Drug Evaluation and Research and Center for Biologics Evaluation and Research. The staff also provided a draft of the interim final rule to the FDA for review and has received and incorporated its recorcendations. The FDA does not object to NRC issuing an interim final rule. Vll. flND]NG 0F NO SIGNlrlCANT IMPACT: AVAILABILITY The commission has determined under the National invironmental Policy Act of 1969, as amended, and the Commission's regulations in Subpart A of 10 CFR Part 51, that these amendments are not a major federal action significantly of fecting the quality of the human environn.ent, and therefore, an environmental impact statement is not required. This interim rule amends NRC regulations to permit licensees who elute generators and prepare reagent kits to depart from the manufacturer's instructions if those persons have a written directive made by.an authorized user physician which requests a specific departure for a particular patient, or patients, or for a radiopharmaceutical. This directive must provide the specific nature of the departure, a precise description of the departure, 6nd the reasons why the departure from the manufacturer's instructions would obtain diagnostic or therapeutic medical results not otherwise attainable or to reduce medical risks to particular patients because of their medical condition. The amendment does not address departures from IND generator elution instructions or IND protocol directions for reagent kit preparation. The NRC is also modifying its regulations to permit, if certain requirements are met, the therapeutic use of radiopharniaceuticals without following the FDA-epproved package insert regarding indications and method of administration. The interim rule does not of fect the exemption in 10 CfP Part 20 f or the intentional exposure of patients to radiation for the purpose of medical diagnosis and therapy. Although the rule ruay cause some patients to be exposed to higher or lower levels of radiation than otherwise expected, those exposures would be given to obtain taedical results not otherwise attainable or to reduce other risks to the patient. It shobid be noted that current requirements do not limit the redtation dose prescribed by the authorized user physician for either diagnosis or thcrapy. The amendments would not relieve licensees from rnecting the requirements in 10 CFR Parts 20 and 35 that restrict radiation exposure to medicel care persor.nel in the restricted area, or to the general public in the unrestricted area, or radioactive effluent releases. It is i expected that there would be no significant change, either increase or decrease, in radiation exposure to the public or to the environment beyond the exposures currently resulting from delivering the cose to the patient. 5

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((s*3 a' coq'o,, NUCLE AR REGUL ATORY COMMISSION + UNITF 9 ST ATEs 3 W ' is,j r W ASHINGT ON; D, C. 20$b5 3 t c %,...../ The Honorable Morris K. Udall, Chairman subcommi'; tee on Energy and the Environment Committee on Interior and Insular Affairs United States House of Representatives Washington, DC 20515

Dear Mr. Chairman:

In a f ew days the Nuclear Regulatory Commission will publish in the Federal Hegister the enclosed interim final rule to the NRC's regulations in 10 LFR Parts 30 and 35 concerning the medical use of byproduct material. This interim rule is promulgated in response to a petition for rulemaking submitted by the American College of Nuclear Physicians and the Society of Nuclear Medicire. lhe amendnent will allow (a) medical use and commercial nuclear pharmacy Drug Administration) for preparing radiopharmaceuticals and (b) y th licensees to depart from manufacturer's instructions (approved bmedical use licensees to depart from the FDA a) proved package insert regarding indications and method of administration for tierapeutic use of radiopharmaceuticals, provided certain conditions are met. Current regulations do not permit these departures. This amendment is necessary to allow health professionals to provide diagnostic or therapeutic medical results not otherwise attainable or to reduce medical risks to particular pitients because of their medical condition. 1his interim rule will be in effect for three years af ter publication in the Federal Register. During the three-year period, the NRC will collect informa-tion on the nature of, reasons for, and frequency of departures. This intermation will be examined by the NRC to determine whether to extend the interim period for the rule, make the rule permanent, or revise it. Sincerely, Eric S. BeckJord, Director Office of Nuclear Regulatory Research 'nclosure: Federal Register notice cc: Representative James V. Hansen

k3 C800 1'o,, UNM ED STATES 4 .[. {g NUCLEAR REGULATORY COMMISSION g' s W ASHINotoN, D. C. 20656 0., [ %,... * / The Honorable Bob Graham, Chairman. Subcommittee on Nuclear Regulation Committee on Environment and Public Works United States Senate Washington, DC 20510

Dear Mr. Chairman:

In 6 few days the Nuclear Regulatory Commission will publish in the Federal Register the enclosed interim final rule to the NRC's regulations in~ 10 ctR Parts 30 and 35 concerning the medical use of byproduct material. This interim rule is promulgated in response to a petition for rulemaking submitted by the American College of Nuclear Physicians and the Society of Nuclear Medicine. The amendment will allow (a) medical use and commercial nuclear pharmacy Drug Administration) for preparing radiopharmaceuticals and (b) y the Food and licer. sees to depart from manufacturer's instruc+.uins (approved binedical use licensees to depart f rom the FDA-a) proved package insert regarding indications and method of administration for tierapeutic use of radiopharmaceuticals, provided certain conditions are met. Current regulations do not permit these departures. This amendment is necessary to allow health professionals to provide diagnostic or therapeutic medical result ca. ~harwise attainable or to reduce iredical risks to particular patients b. v.. cheir tredical condition. This interim rule will be in effect for three, vers after r lication in the Federal Register. During the three-year period. n NRC 2 diect informa-This tion on the nature of, reasons for, and frequet., J'- v.t.. information will be examined by the NRC to det* - m% ) extend the m er P ' 4 it. interim period for the rule, make the rule pet-Sincerels Eric S. BeckJoru, Director Of fice of Nuclear Regulatory Research

Enclosure:

Federal Register notice cc: Senator Alan K. Simpson i

+#ps on. o-UNITED STATES g l l' NUCLEAR RECULATORY COMMISSION g 5 W ASHINGTON, D. C. 20656 '4,,..... s o The-Honorable Philip R. Sharp, Chairman Subcomittee on Energy and Power Committee on Energy anc comerce United States House of Representatives Washington, DC 20515 e

Dear Mr. Chairman:

In a few days the Nuclear Regulatory Commission will publish in the Federal Register the enclosed interim final rule to the NRC's regulations in 10 CFRTarts 30 and 35 concerning the medical use of byproduct material. This interim rule is promulgated in response to a petition for rulemaking submitted. I by the American College of Nuclear Physicians and the Society of Nuclear Medicine. The amenet,ent will allow (a) medical use and commercial nuclear pharmacy licensees to depart from manufacturer's instructions (approved by the Food and 1 ' Drug Administration) for preparing radiopharmaceuticals and (b) medical use ticensees to depart from the FDA-a aproved package insert regarding indications and method of administration for tierapeutic use of radiopharmaceuticals, provided certain conditions are met. Current regulations do not permit these l departures, this amendment is necessary to allow health professionals to l provide diagnostic or therapeutic medical results-not otherwise attainable or to reduce medical risks to particular patients because of their medical-i condition. This interim rule will be in effect tor three years after publication in the ' Federal Register. During the three-year period, the NRC will collect inf orma-L tion on the nature of, reasons for, and frequency of departures. This L information will be examined by the NRC to determine whether to extend the L interim period for the rule,.make the rule permanent, or revise it. Sincerely, 1 Eric S. Beckjord, Director i. Office of Nuclear Regulatory Research

Enclosure:

Federal Register notice cc: Representative Carlos J. Moorhead m. m

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E L.,1: DRAF1 NUCLEAR REGULATORY COMMISSION ISSUES INTERIM FINAL RULL ON MEDICAL USE OF HUClEAR MATERIAL 'The Nuclear Regulatory Commission is amending, on a three-year interim basis, its regulations for medical uses of nuclear material to give greater discretion to nuclear physicians and pharmacies in how they prepare, use, and administer prescription drugs containing radioactive materials. l The amendments are in response to a petition filed with the NRC by the American College of fluclear Physicians and the Society of Nuclear Medicine (ACNP-SNM). l The interim rule, which is effective imrnediately, permits, at the direction of an authorized user physician, departures from the manufacturer's instructions in the preparation of radiopharmaceuticals to be used for ~ diagnostic procedures, provided a proper record of the departure is made. 1he manufacturer's instructions are contained in package inserts that are part of the Food and Drug Administration (FDA) approved labeling. The rule also permits departures from package insert instructions for indications and method j of administration for their therapeutic use, provided a proper record of the departure is made. l^

n A o I Current NRC regulations do not permit these departures. The interim rule represents only one phase of the NRC's response to the i ACNP-SNM petition for.rulemaking. Based on continued NRC analysis of the l l petition, comments on the interim final rule, experience with the interim rule implementation, and other information, the NRC will make a decision whether to extend the interim period for the rule, nette the rule permanent, or revise it, i i i i l -j i l i i

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DEPARTMENT OF HEALTH A HtJMAN SERVICES A-Memorandum MAY I 8130 o.s. Carl C. Peck, M.D., Director, Center for Drug Evaluation and Research, Food and Nom Drug Administration (HFD 1) l l Paul D. Parkman, M.D., Director, Center for Biologics Evaluation and Research, Food and Drug Administration (HFB 1) subje:t i Comments on Nuclear Regulatory Commission's March 9,1990 draft interim To final rule to revise NRC's radiopharmaceutical licensing requirements L L Bill M. Morris, Director, Division of Nuclear Applications, Office of Nuclear Regulatory Research, Nuclear Regulatory Commission I' L This memorandum conveys the views of the Center for Drug Evaluation and Research (CDER) and the Center for Biologies Evaluation and Research (CBER).with respect to the Nuclear Regulatory Commission's (NRC's) March 9,1990, draft interim firal rule j to revise NRC's radiopharmaceuticallicensing requirements. 'niis follows a March 23, 1990, letter to you from Gerald F, Meyer, Assistant Director, CDER, which was intended as a provisional response to your March 9 letter, pending careful evaluation of your draft. Presently, NRC regulations restrict deviations by licensges from the product's approved i labeling. NRC inspects nuclear pharmacies to assure compliance with its rules. FDA regulations require that all drugs, including radiopharmaceuticals, have approved hT)As ( in order to be marksted. Pharmacies and physicians are not required to register with l FDA; however, pharmacists and physicians are not relieved of the statutory requirements regarding formulating, labeling, and marketing drug products. As you know, a petition for rulemaking dated Atne 5,1989, which was filed with the l NRC by the American College of Nuclear Physicians and the Society of Nuclear Medicine, requests NRC, Imer 1% to (1) modify its regulations to permit licensees who elute generators and prepare reagent kits to deviate from the manufacturer's instructions for preparation in the approved labeling, and (2) modify its regulations to permit the use .of approved radiopharmaceuticals for therapy for unapproved uses and unapproved l routes of administration. NRC staff provided copies of that petition to CDER and CBER staff, and staff members of CDER, CBER, and NRC have met a number of times and have had a series of telephone conversations in the past several months to discuss the issues raised in the petition and NRC's projected response. L The March 9,1990, draft interim final rule, developed by NRC as a partial response to the issues raised in the' petition, addresses the two issues desenbed abcwe. We appreciate the opportunity you have given us to examine the draft interim final rule, in the cover letter which accompanied your March 9 draft, you asked for comments on safety issues of concern to FDA. Since that letter was issued, NRC has provided o additionalinformation to CDER and CBER and asked the two Centers to examine the L

. c, e,,, 3 E 6 c, e a i a E g g ,corc~-or ~ comp /couu . to to >; 3 q 2 draft interim final rule in light of the additionalinformation provided. The two Centers have done so. Bued on this information and on a number of discussions with members of your staff, we believe that the major concerns expressed in CDER's March 23 letter have been met. Accordingly, CDER and CBER do not object to NRC's iuuance of an interim final rule based on the March 9 draft. While we do not now object to issuance of the interim final rule, we do have some suggestions that you may wish to consider in developing your document. We believe that inclusion of our suggestions in the text would make the document more consistent with. the policies, goals, and missions of both FDA and NRC. This doeurnent bypasses the notice and comment rulemaking process because it is being published as an interim final rule. The document will allow certain actions which have been archibited and it will set forth new requ!rements applying to nuclear pharmacies . and pysicians. Accordingly, CDER and CBER suggest that NRC might wish to add a - specific provision to the document providing for a comprehensive re evaluation of the interim final rule and its impact on nuclear pharmacists and practitioners of nuclear medicine, prior to its being converted into a final rule. One mechanism that compels such a re examination is a sunset provision, which, after a specified period. requires such a re evaluation, necessitating a positive action to extend the rule, make it permanent, or i l revise it. Other mechanisms requiring re examination of rules are also available. We l would suggest that the review of this interim final rule - whether through a sunset provision or some other prodsion - take place after 3 years, because that period would-se consistent with your inspection cycle. 1 ne draft interim final rule requires licensees to record deviations, and we agree that suitable recordkeeping requirements should be part of this rulemaking. Appropriate recordkeeping requirements should enable NRC to gather comprehensive data for review and analysis of the experiences of nuclear pharmacies and practitioners of nuclear l medicine under the revised regulation. If a sunset clause or other mechanism requiring a re examination of the interim final rule after a specific period is added, the review and analysis could take place at the time of the activation of the provision (and, if the mechanism is a sunset provision, prior to the expiration of the interim final rule). Such a database would provide NRC with sufficient information and support to convert the rule into a final rule, modify it, or terminate it. In our opinion, the codified recordkeeping requirements should be consistent with the language of the preamble and should yield information that will provide a reasonable basis for further consideration of the form and content of the final rulemaking document. The preamble indicates that the record of deviations is intended to provide information on "the ty7es of, reuens for, and frequency and patterns of deviation from the package inserts." idowever, the codified section states that the directive should (1) direct a speelfic deviation for a particular patient, patients, or radiopharmaceutical, and (2) state the reasons why the deviation from the manufacturer's instructions would be in the patient's best interest. Of course, each directive need not include every data

g,,, ..) 3 l .I element; however, we believe that the directives should include dueriptions of the nature of deviations in the directives that are sufficiently detailed to allow extraction and j analysis of the data elements ductibed in the praamble, j We suggest that directives for deviations include the following data elements: (1)a specific direction for a patient, patients, or radiopharmaceutical for a particular deviation from the manufacturer's instructions for preparation in the approved labeling for a radiopharmaceutical for diagnostic purposes, or the indications or method of administration in the approved labeling for a radiopharmaceutical for therapy, (2) a precise description of the modification, and (3) a statement describing why'the deviation is in the best interests of the patient (e.g., deviation from the manufacturer s instructions in the approved labeling will obtain results not otherwise attainable or reduce other risks to the patient). Ideally, we would find it helpful if NRC could devise a methodology by which directives and the prescriptions prepared pursuant to the directiva could be g i L related to one another, so that data coulc show more clearly the number of patients who i are administered drugs prepared or administered under deviations. We understand that this may not be feasible in every cue. While we believe that, optimally, you might wish to require periodic reporting of deviations, we understand that the constraints under which you operate may make such reporting impracticable, Another part of the draft commits NRC *to work closely with FDA to share the l information obtained on licensees' deviations from the manufacturers instructions" after the interim final rule becomes effective. While CDER and CBER are interested in reviewing information that NRC derives from the recordkeeping requirements in the interim final rule, we do not believe that the details for the sharing and use of such information are appropriate for this rulemaking. This agency's staff would be pleased to meet with NRC to develop a process that would assure that information derived from the recordkeeping required by hRC under the rulemaking is shared with FDA, and that FDA provides NRC with the results of any review it undertakes as the result of information provided to it by NRC. A memorandum of understanding (MOU) would be one way of memorializing the process developed through these meetings. As previously discussed with your staff, the medicalliterature reveals that a kit for a radiopharmaceutical for therapy is currently being investigated. CDER and CBER are concerned about the potential adverse clinical impact that might ensue if a kit for a radiopharmaceutical for therapy were approved and there were deviations from the manufacturer's instructions for preparation in the approved labeling for eluting L generators and preparing reagent kits for radiopharmaceuticals for therapy, whether or not deviations are at the direction of a physician. Specifically, we are concerned that the therapy dose of radiation in such a kit, if approved, could go to a site in the body other than that imended in the event of such deviation. Substantial morbidity or, perhaps, mortality could be an outcome. We understand that the interim final rule will not authorize any deviation from manufacturer's instructions for preparation of radiopharmaceutical therapy kits and that the preamble to the rule and the regulatory text will reflect our concerns about such deviations. L

r, .9 9. 2 9. ev N ~ 1 o N. ^ s 4 7 L While the responsibility for replatiry radiopharmaceuticals lies primarily with CDER, we expect CBER to have an increu og role in regulation of these products. CBER's area of responsibility involves radiolabeled monoclonal antibody products, which are L subject to icensure under the Public Health Service Act,42 U.S.C. 262. When CBER evaluates the purity and potency of a biological product for approval, the determination of the product's biological effect is based solely on labeling instructions. If the product is ? art of a kit, approval is bued on the use of the kit's components. Because no ratiolabeled monoclonal antibody products have been licensed by CBER, we have no n p first hand experience upon which to predict the other ways that these products may be l used.by nuclear physicians: nor can we predict future safety concerns thP.t will result from unapproved uses, particularly where a modl5 cation would involve using products' t ll that are not part of an approved kit. The products subject to CBER's responsibility have a much shorter track record than the ones which have prompted the petition, and t radiopharmacists will also have less experience modifying these products. These comments on products regulated by CBER are intended for your information only, and, at present, we anticipate no action on your part with rupect to these products. However, the issues related to the uses of radiolabeled monoclonal antibody products L and any other novel products may require separate consideration as NRC evaluates the petitioner's other requests, and as we become familiar with the way monoclonal antibody products will be used. Evaluating the records of the deviations will be not only appropriate, but important in assessing safety concerns related to monoclonal antibody l products. L To assure that the interim final rule,if ado ted, accurately reDeets the policies of FDA as well as those of the NRC, we are offeri or your consideration some suggestions for specific changes in the language of the arch 9 draft. We have appended these suggestions to this letter. I hope this information is helpful. If you have any questions, please contact Richard L. Ark n in CDER's Drug Regulations Branch (HFD 362),5600 Fishers 1.ane, Rockville, MD 20857, (301) 295 8046, or P. Michael Dubinsky in CBER's Division of Regulations and Bioresearch Monitoring (HFD 130), 8800 Rockville Pike, Rockville, MD 20892, (301) 295-8110. /lpPeck (X O, M.D. yk ,1, Paul D. Parkman, M.D. Enclosure Specific comments on NRC's March 9 draft

go~e!.; q :ee au4xw vm-a ens , [.f n. ) . w.. O o 1 SPECIFIC COMMENTS In eeneral: The terms " package insert" and " labeling

• are used interchangeably in the preamble.

e NRC use of these terms is not consistent with FDA conventions. We suggest that you consider using one term, for example, " approved labeling." If you are constrained by the use of other terms in other regulations or in other parts of this regulation, you may wish to explain the meaning of your terms in the taxt. Similarly, the terms ' directions" and " manufacturer's instructions" are used e interchangeably in the draft interim final rule. We would suggest that you g L consider using a single term, for example " manufacturer's instructions for i preparation in the a? proved labeling." If you are constrained by the use of other l-terms in other tei;u ations or in other parts of this regulation, you may wish to explain the meanng of your terms in tse text. f.agL3: We do not believe FDA policy is accurately described by the statement that roads; s ' Ordinarily,- FDA does not attempt to limit the manner in which a physician l administers an FDA approved drug," or by the similar statement on page 4 that. reads:"However, FDA does not ordinarily limit how the physician may use the drug." Because there is no need to characterize FDA's position on this issue in order to implement the interim final rule, we recommend that both statements be deleted. Pane 4: 1 We are not satis 5ed with the characterization of FDA's role in drug approval in l e the first full paragraph on the page. We would suggest substituting the lollowing language: L Each new drug approved for human use by the FDA, including radiopharmaceuticals, has labeling approved by FDA that includes a description of the drug, its pharmacology, indications for use, contraindications, warnings, adverse reactions, dosage and administration, and other information,. Certain drugs, including some radiopharmaceuticals, include manufacturer's instructions that specify the method of preparation. FDA reviews and approves the L information in the labeling to ensure that it accurately reflects the data on safety and effectiveness on which the drug approval is based. NRC has, in the past, relied primarily on FDA's determination of a drug's safety and effectiveness when it is prepared and used according to the labeling, which some NRC regulations P

,04.

• 10. _, 0 0 028 23 PM' "a' C F C CF ' COMP >CCCR

~~ 'P OD ' ~ P ., ya o l 2 refer to as the package insert, as one means of assuring p2otection of the public health and safety. hink e It is our understanding that the term " medical uses" does not include in vitro diagnostics. If this is not something that the radlegharmaceutical industry would assume, we suggest adding a statement to that effect in the preamble. Page 19. 21: t it Jis our understanding that you have included the emergency provision at e 630.34(f)(2 (fi) on your own initiative, and are not responding to a request in the petition. T)ou may wish to include in your preamble an explanation for the of this paragraph. s We believe that clarification of the paragraph requiring the determination that no IND is needed would be desirable. %e are concerned that licensees may interpret this paragraph as requiring that the determination be made by FDA. We suggest L that you mace clear that this determination is to be made by the licensee. l .}}