10594 Federal Register / Vol. 60, No. 38 / Monday, February 27, 1995 / Notices

Drug Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–594–0095.

SUPPLEMENTARY INFORMATION: FDA is

announcing the availability of a draft

guideline entitled ‘‘Draft Guideline on

the Manufacture of Positron Emission

Tomographic (PET) Drug Products.’’

PET is a diagnostic imaging modality

consisting of onsite production of

radionuclides that are 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 where glucose

metabolism is the predominant energy

source (epileptic foci, acute vascular

insufficiency states).

The manufacture of PET

radiopharmaceuticals consists of a

process that takes place within a few

hours. A target material is irradiated by

a cyclotron; chemical synthesis takes

place in a programmed, automated

apparatus; and the final solution is

compounded and filled. 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.

Because of their short half-lives, PET

radiopharmaceuticals are

characteristically manufactured in PET

centers in response to daily demand for

relatively few patients. PET centers are

usually located in medical centers.

PET manufacturing procedures differ

in a number of important ways from

those associated with the manufacture

of conventional drug products, mainly

due to the short half-lives involved:

1. A maximum of only a few lots are

manufactured per day, with one lot

equaling one multiple-dose vial. This is

administered to the patient usually

within a matter of hours. Prolonged

manufacturing time significantly erodes

the useful clinical life of PET

radiopharmaceuticals.

2. The quantities of radioactive active

ingredients contained in each lot of a

PET radiopharmaceutical generally vary

from nanogram to milligram amounts,

depending upon various product

parameters.

3. Because one lot equals one

multiple-dose vial containing a

homogeneous solution of a PET product

(e.g., 2-deoxy-2 [18F]fluoro-D-glucose),

results from end-product testing of

samples drawn from the single vial have

the maximum possible probability of

being representative of all the doses

administered to patients from that vial,

barring sampling or testing error.

4. An entire lot may be administered

to one or several patients, depending

upon the activity remaining in the

container at the time of administration.

Consequently, the administration of the

entire quantity of a lot to a single patient

should be anticipated for every lot

manufactured. This is an important

consideration when establishing the

testing limits for certain attributes such

as endotoxins and impurities.

5. PET radiopharmaceuticals usually

do not enter a general drug distribution

chain. Rather, the entire lot (one vial) is

usually distributed directly from the

PET center either to a single medical

department or physician for

administration to patients or to a

radiopharmacy for dispensing.

Distribution may occur to other centers

when the geographic proximity will

allow for distribution and use within

the drug product’s half-life parameters.

Conventional compliance with CGMP

regulations would be expected where

special characteristics such as those

listed above do not exist; for example,

in large-scale PET operations. Elsewhere

in this issue of the Federal Register,

FDA is publishing (1) A proposed rule

that would authorize the Director,

CDER, or the Director, Office of

Compliance, CDER, to approve

exceptions or alternatives to the

application of the provisions of 21 CFR

part 211 to the manufacture of PET

radiopharmaceuticals, and (2) a notice

of a public workshop and FDA guidance

on the regulation of PET

radiopharmaceuticals.

The guideline entitled ‘‘Draft

Guideline on the Manufacture of

Positron Emission Tomographic (PET)

Drug Products’’ discusses, generally,

quality control units, personnel

qualifications, staffing, buildings and

facilities, equipment, components,

containers, closures, production and

process controls, packaging and labeling

control, holding and distribution,

testing and release for distribution,

stability testing and expiration dating,

reserve samples, yields, second-person

checks, and reports and records.

FDA is making this draft guideline

available for public comment before

issuing a final guideline. If, following

the receipt of comments, the agency

concludes that the draft guideline will

assist persons in determining whether

manufacturing practices used in the

small-scale production of liquid

injectable PET radiopharmaceuticals are

in compliance with FDA’s CGMP

regulations for finished

pharmaceuticals, then the agency will

prepare a final guideline and will

announce its availability in the Federal

Register.

Guidelines are generally issued under

§ 10.90(b) (21 CFR 10.90(b)), which

provides for the use of guidelines to

state procedures or standards of general

applicability that are not legal

requirements but are acceptable to FDA.

The agency is now in the process of

revising § 10.90(b). Therefore, if the

agency makes the guideline final, the

guideline would not be issued under the

authority of current § 10.90(b), and

would not create or confer any rights,

privileges, or benefits for or on any

person, nor would it operate to bind

FDA in any way.

Interested persons may, on or before

May 30, 1995, submit to the Dockets

Management Branch (address above)

written comments on the draft

guideline. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. The draft

guideline and received comments may

be seen in the office above between 9

a.m. and 4 p.m., Monday through

Friday.

Dated: February 17, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95–4689 Filed 2–24–95; 8:45 am]

BILLING CODE 4160–01–F

[Docket No. 93N–0005]

Regulation of Positron Emission

TomographyRadiopharmaceutical

Drug Products; Guidance; Public

Workshop

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

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
Federal Register / Vol. 60, No. 38 / Monday, February 27, 1995 / Notices 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-FFDG). 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

§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
10596 Federal Register / Vol. 60, No. 38 / Monday, February 27, 1995 / Notices

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 §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

§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 §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

§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

DEPARTMENT OF HOUSING AND

URBAN DEVELOPMENT

Office of the Assistant Secretary for

Public and Indian Housing

[Docket No. N–55–3710; FR–3636–-03]

Announcement of Funding Awards

Public Housing Drug Elimination

Technical Assistance Program, FY

1994

AGENCY: Office of the Assistant

Secretary for Public and Indian

Housing, HUD.

ACTION: Announcement of funding

awards.

SUMMARY: In accordance with section

102(a)(4)(C) of the Department of

Housing and Urban Development

Reform Act of 1989, this announcement

notifies the public of funding decisions

made by the Department in a

competition for funding under the

Notice of Funding Availability (NOFA)

for Public Housing Drug EliminationTechnical Assistance Program. This

announcement contains the names and

addresses of the award winners and the

amount of the awards.

FOR FURTHER INFORMATION CONTACT:

Elizabeth Cocke, Drug Free

Neighborhoods Division, Department of

Housing and Urban Development, 451

Seventh Street, SW., Room 4116,

Washington, DC 20410, telephone (202)

708–1197. A telecommunications device

for hearing or speech impaired persons

(TDD) is available at (202) 708–0850.

(These are not toll-free numbers.)

SUPPLEMENTARY INFORMATION: The

Public Housing Drug EliminationTechnical Assistance Program is

authorized by the Departments of

Veterans Affairs and Housing and Urban

Development, and Independent

Agencies Appropriations Act, 1994

(approved October 28, 1993, Pub. L.

103–124).

The NOFA published in the Federal

Register on March 10, 1994 (59 FR

11418) announced the FY 1994

availability of $1,255,175 to fund

qualified applicants selected under the

FY 1993 NOFA and invited additional

applicants for FY 1994. The purpose of