[Federal Register Volume 60, Number 38 (Monday, February 27, 1995)]
[Notices]
[Pages 10594-10596]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4691]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 93N-0005]


Regulation of Positron Emission TomographyRadiopharmaceutical 
Drug Products; Guidance; Public Workshop

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is publishing guidance 
on the regulation of positron emission tomography (PET) 
radiopharmaceutical drug products. FDA has developed this guidance to 
make clear the regulatory approach designed to help ensure the safe and 
effective use of these products. The agency is also announcing a public 
workshop to facilitate an understanding of regulatory requirements 
regarding these products.

DATES: The public workshop will be held on March 21, 1995, 8:30 a.m. to 
4 p.m. Registration will be between 8 a.m. and 8:30 a.m. Due to limited 
space, interested persons must preregister before March 7, 1995, by 
telephoning [[Page 10595]] the contact person listed below. Interested 
persons may submit data, information, or views on this subject to the 
Dockets Management Branch (address below).

ADDRESSES: The public workshop will be held at the Parklawn Bldg., 
conference rooms G and H, 5600 Fishers Lane, Rockville, MD 20857. 
Written data, information, or views regarding the workshop may be 
submitted to the Dockets Management Branch (HFA-305), Food and Drug 
Administration, rm. 1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: John W. Levchuk, Center for Drug 
Evaluation and Research (HFD-322), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-0095.

SUPPLEMENTARY INFORMATION:

I. Background

    PET is a diagnostic imaging modality consisting of onsite 
production of radionuclides that are usually intravenously injected 
into patients for diagnostic purposes. The potential usefulness of a 
PET radiopharmaceutical is based upon the product's interaction with a 
biochemical process in the body. For example, the product may be 
substituted for glucose in anaerobic glycolysis, theoretically 
localizing in ischemic tissues (epileptic foci, acute vascular 
insufficiency states) where glucose metabolism is the predominant 
energy source.
    The manufacture of PET radiopharmaceuticals consists of a process 
that takes place within a few hours. A target material is irradiated in 
a cyclotron; chemical synthesis takes place in a programmed, automated 
apparatus; and the final solution is prepared. The biological 
distribution of a PET radiopharmaceutical in the body is monitored by a 
positron tomograph, or PET scanner, which detects the photons emitted 
as a result of the radioactive decay of the PET radiopharmaceutical.
    Currently, there are two FDA approved PET radiopharmaceuticals: 
Rubidium-82 (rubidium chloride ([<SUP>82Rb]RbCl)) and fludeoxyglucose 
(<SUP>18-F-FDG). At present, most investigational PET radionuclides are 
manufactured by cyclotrons at PET facilities, which generally are 
located at major teaching hospitals or their adjacent universities. 
Because PET radiopharmaceuticals contain positron emitting isotopes 
that have relatively short half-lives (minutes to hours), they are 
manufactured near the site of administration to patients. Products may 
be distributed t o other institutions when the geographic proximity of 
these locations will allow for distribution and use within the 
product's half-life parameters.
    The development of PET radiopharmaceuticals has increased 
considerably over the past several years. As this technology has 
advanced, questions have been raised about the most appropriate 
approach to regulation of PET radiopharmaceuticals. FDA held a public 
hearing on March 5, 1993, to receive information and views on this 
issue from interested groups and individuals. The docket established 
for the receipt of comments (Docket No. 93N-0005) remained open for an 
additional 2 weeks after the hearing.Additionally, FDA has received 
several citizen petitions on PET radiopharmaceuticals to which it will 
be directly responding.
    Having considered the available information, including that 
presented to the agency at the hearing and in written materials, FDA 
has concluded that radiopharmaceuticals should be regulated under the 
drug provisions of the Federal Food, Drug, and Cosmetic Act (the act). 
Under section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B)), drugs 
are considered adulterated unless manufactured in conformity with 
current good manufacturing practice (CGMP). Because of unique features 
of PET radiopharmaceuticals, the applicability of certain requirements 
in the CGMP regulations for finished pharmaceuticals (part 211 (21 CFR 
part 211)) to PET radiopharmaceuticals may differ from the 
applicability of these requirements to drugs produced through 
traditional manufacturing methods. Consequently, elsewhere in this 
issue of the Federal Register, FDA is publishing a proposed rule that 
would authorize the Director of the Center for Drug Evaluation and 
Research (CDER) or the Director of the Office of Compliance, CDER, to 
approve exceptions or alternatives to the application of the provisions 
of part 211 to the manufacture of PET radiopharmaceuticals.
    In order to assist manufacturers in complying withapplicable CGMP 
requirements, FDA has also developed a ``Draft Guideline on the 
Manufacture of Positron Emission Tomographic (PET) Drug Products.'' A 
notice of availability of this draft guideline, on which the agency is 
inviting comments, is also published elsewhere in this issue of the 
Federal Register.
    Under section 505 of the act (21 U.S.C. 355), ``new drugs,'' such 
as radiopharmaceuticals, must be the subjects of approved new drug 
applications (NDA's) or abbreviated new drug applications (ANDA's) 
before marketing. In order to be approved, the products must be shown 
to be safe and effective for their intended uses through adequate and 
well-controlled studies (21 U.S.C. 355(d)). Investigational use of drug 
products is governed, in general, by the requirements in part 312 (21 
CFR part 312). Special provisions concerning radioactive drugs for 
certain research uses are contained in FDA regulations at 21 CFR 361.1. 
Under these special provisions, use of radioactive drug products in 
human subjects during the course of limited kinds of research projects 
may occur if the use is approved by a properly constituted Radioactive 
Drug Research Committee and if other conditions are met.
    Section 502 of the act (21 U.S.C. 352) sets forth misbranding 
provisions applicable to drug products. Among other circumstances, a 
drug is considered misbranded if the product labeling is false or 
misleading or if the drug is dangerous to health when used as suggested 
in the labeling (21 U.S.C. 352(a) and (j)). For prescription drugs, 
section 502(n) of the act describes certain information that must be 
included in all advertisements or other printed materials. FDA's 
regulations also establish labeling and advertising requirements in 
more detail (21 CFR parts 201 and 202).
    Section 510 of the act (21 U.S.C. 360) requires persons who own or 
operate establishments for the manufacture, preparation, propagation, 
compounding, or processing of drugs (with certain exceptions) to 
register the establishments with FDA. Individuals who must register 
their establishments under section 510 of the act must also file a list 
of all the drugs being made or processed at the establishment. Drug 
registration and listing regulations are codified at part 207 (21 CFR 
part 207).

II. Guidance: Regulation of PET Radiopharmaceuticals

    FDA regulates PET radiopharmaceutical drug products used in purely 
physiologic research, where the results of such research are not used 
to guide patient management or treatment decisions, as well as in 
investigational clinical trials and clinical practice. All facilities 
that manufacture PET radiopharmaceuticals must be registered with FDA 
in accordance with FDA regulations on the registration and listing of 
producers of drugs (part 207). Facilities that manufacture PET 
radiopharmaceuticals are not exempt from registration under 
Sec. 1A207.10 because their activities do not fall within the scope of 
the regular course of the practice of the profession of pharmacy. This 
policy statement [[Page 10596]] supersedes the ``Nuclear Pharmacy 
Guideline; Criteria for Determining When to Register as a Drug 
Establishment'' issued by FDA in May 1984.

A. Physiological Research

    Facilities using PET radiopharmaceuticals for purely physiological 
research, where the results of such research are not used to guide 
patient management or treatment decisions, should establish a PET 
Regulatory Committee (PRC) in accordance with Sec. 1A361.1 Radioactive 
drugs for certain research uses (21 CFR 361.1). The PRC will monitor 
all physiological research of the PET facility. Facilities using PET 
radiopharmaceuticals for purely physiological research are not required 
to submit an investigational new drug application (IND) or NDA as long 
as this research is intended to obtain basic information regarding 
metabolism or physiology and is not intended to guide or be part of 
therapeutic, diagnostic, or clinical management plans.
    FDA will approve and monitor the PRC, which should consist of at 
least five individuals. In accordance with Sec. 1A361.1(c), each PRC 
should include: (1) A physician recognized as a specialist in nuclear 
medicine; (2) a person qualified by training and experience to 
manufacture PET radiopharmaceuticals; and (3) a person with special 
competence in radiation safety and radiation dosimetry. The remaining 
PRC members should include individuals qualified in various disciplines 
pertaining to the field of nuclear medicine, and should be sufficiently 
diverse to permit expert review of the technical and scientific aspects 
of proposals submitted to the committee. In addition to the 
requirements in Sec. 1A361.1(c) and with the exception of the member 
qualified by training and experience to manufacture PET 
radiopharmaceuticals, PRC membership should include a representative of 
a consumer group, and the members should not have scientific, clinical, 
financial, or administrative conflicts of interest.
    The PRC should have three main responsibilities: (1) To approve 
research protocols; (2) to prepare annual reports; and (3) to determine 
when purely physiological research has ended.
    In approving protocols, the PRC should: (1) Determine if the 
investigator meets the qualifications specified in the protocol; (2) 
review the research protocol design; (3) review and monitor the 
selection of research subjects; (4) ensure that the research subjects 
have signed informed consent documents; (5) review and monitor the 
quality of the PET radiopharmaceuticals administered; (6) evaluate all 
reports of adverse events; and (7) confirm concurrence of Institutional 
Review Board approval.
    The annual report should follow the format and contents prescribed 
in Sec. 1A361.1(c)(3), summarizing the conditions of use, doses, route 
of administration, protocols, adverse events reported in the safety 
information, and the chemistry, manufacturing, and control data. The 
PRC should submit the completed annual report to FDA.
    The PRC is also responsible for determining when purely 
physiological research becomes investigational clinical use. This 
determination should be based on whether the data obtained will be used 
in the diagnostic, therapeutic, or clinical management of patients. 
Once trials are proposed for investigational clinical use, the facility 
must submit an IND before starting to conduct the trials.

B. Investigational Use

    Manufacturers of PET radiopharmaceuticals intended to be used in 
investigational clinical trials must submit an IND to FDA in accordance 
with the regulations in part 312. Institutions or investigators working 
together with the same PET radiopharmaceutical may submit one IND for 
that drug product, covering studies conducted at more than one site or 
institution.

C. NDA Approval

    Submission of an NDA, in accordance with FDA regulations in part 
314 (21 CFR part 314), is required for PET radiopharmaceuticals used in 
clinical practice. Institutions or investigators working together with 
the same PET radiopharmaceutical may submit one NDA for that drug 
product. All sites that produce the same drug product would be covered 
by the submitted NDA. Once an NDA is approved, other PET facilities 
with a radiopharmaceutical that is an equivalent finished product, but 
which did not participate in the NDA or did not submit manufacturing 
data, could submit an abbreviated new drug application (ANDA) 
demonstrating that their drug is bioequivalent to the innovator drug, 
in accordance with FDA regulations in part 314. Alternatively, the NDA 
holder could submit a supplement to add these other facilities as new 
manufacturing sites.
    PET radiopharmaceuticals are also subject to the adulteration and 
misbranding provisions of the act. Facilities where PET 
radiopharmaceuticals are manufactured are subject to inspection by FDA 
for compliance with CGMP requirements and other drug-related 
requirements.

    Dated: February 17, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4691 Filed 2-24-95; 8:45 am]
BILLING CODE 4160-01-F