[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 ([82Rb]RbCl)) and fludeoxyglucose
(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]
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