11274 Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

[Docket No. 94D–0028]

International Conference on

Harmonisation; Guideline on Repeated

Dose Tissue Distribution Studies;

Availability

AGENCY: Food and Drug Administration,

HHS.

ACTION: Notice.

SUMMARY: The Food and Drug

Administration (FDA) is publishing a

final guideline entitled

‘‘Pharmacokinetics: Guidance for

Repeated Dose Tissue Distribution

Studies.’’ This guideline was prepared

under the auspices of the International

Conference on Harmonisation of

Technical Requirements for Registration

of Pharmaceuticals for Human Use

(ICH). The guideline is intended to

provide guidance on the circumstances

when nonclinical repeated dose tissue

distribution studies to support drug

registration should be considered and

on the conduct of those studies.

DATES: Effective on March 1, 1995.

Submit written comments at any time.

ADDRESSES: Submit written comments

on the guideline to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857. Copies of the guideline are

available from CDER Executive

Secretariat Staff (HFD–8), Center for

Drug Evaluation and Research, Food

and Drug Administration, 7500 Standish

Pl., Rockville, MD 20855.

FOR FURTHER INFORMATION CONTACT:

Regarding the guideline: Roger L.

Williams, Center for Drug

Evaluation and Research (HFD–4),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–594–6740.

Regarding ICH: Janet J. Showalter,

Office of Health Affairs (HFY–20),

Food and Drug Administration,

5600 Fishers Lane, Rockville, MD

20857, 301–443–1382.

SUPPLEMENTARY INFORMATION: In recent

years, many important initiatives have

been undertaken by regulatory

authorities and industry associations to

promote international harmonization of

regulatory requirements. FDA has

participated in many meetings designed

to enhance harmonization and is

committed to seeking scientifically

based harmonized technical procedures

for pharmaceutical development. One of

the goals of harmonization is to identify

and then reduce differences in technical

requirements for drug development

among regulatory agencies.

ICH was organized to provide an

opportunity for tripartite harmonization

initiatives to be developed with input

from both regulatory and industry

representatives. FDA also seeks input

from consumer representatives and

others. ICH is concerned with

harmonization of technical

requirements for the registration of

pharmaceutical products among three

regions: The European Union, Japan,

and the United States. The six ICH

sponsors are the European Commission;

the European Federation of

Pharmaceutical Industry Associations;

the Japanese Ministry of Health and

Welfare; the Japanese Pharmaceutical

Manufacturers Association; the Centers

for Drug Evaluation and Research and

Biologics Evaluation and Research,

FDA; and the Pharmaceutical Research

and Manufacturers of America. The ICH

Secretariat, which coordinates the

preparation of documentation, is

provided by the International

Federation of Pharmaceutical

Manufacturers Association (IFPMA).

The ICH Steering Committee includes

representatives from each of the ICH

sponsors and IFPMA, as well as

observers from the World Health

Organization, the Canadian Health

Protection Branch, and the European

Free Trade Area.

Harmonization of repeated dose tissue

distribution studies was selected as a

priority topic during the early stages of

the ICH initiative. In the Federal

Register of March 1, 1994 (59 FR 9748),

FDA published a draft tripartite

guideline entitled, ‘‘Pharmacokinetics:

Guidance for Repeated Dose Tissue

Distribution Studies.’’ The notice gave

interested persons an opportunity to

submit comments by May 16, 1994.

After consideration of the comments

received and revisions to the guideline,

a final draft of the guideline was

submitted to the ICH Steering

Committee and endorsed by the three

participating regulatory agencies at the

ICH meeting held in October 1994.

The guideline recommends that

repeated dose tissue distribution studies

should not be required uniformly for all

compounds and should only be

conducted when appropriate data

cannot be derived from other sources.

Repeated dose studies may be

appropriate for compounds which have:

(1) An apparently long half-life; (2)

incomplete elimination; or (3)

unanticipated organ toxicity. The

guideline provides general guidance on

the use of radio labelled compounds,

dose and species selection, and duration

of studies.

In the past, guidelines have generally

been 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, this guideline is not being

issued under the authority of § 10.90(b),

and it does not create or confer any

rights, privileges, or benefits for or on

any person, nor does it operate to bind

FDA in any way.

As with all of FDA’s guidelines, the

public is encouraged to submit written

comments with new data or other new

information pertinent to this guideline.

The comments in the docket will be

periodically reviewed and, where

appropriate, the guideline will be

amended. The public will be notified of

any such amendments through a notice

in the Federal Register.

Interested persons may, at any time,

submit written comments on the

guideline to the Dockets Management

Branch (address above). 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 guideline and received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

The text of the guideline follows:

Pharmacokinetics: Guidance For Repeated

Dose Tissue Distribution Studies

Introduction

A comprehensive knowledge of the

absorption, distribution, metabolism, and

elimination of a compound is important for

the interpretation of pharmacology and

toxicology studies. Tissue distribution

studies are essential in providing information

on distribution and accumulation of the

compound and/or metabolites especially in

relation to potential sites of action; this

information may be useful for designing

toxicology and pharmacology studies and for

interpreting the results of these experiments.

In the European Union, United States, and

Japan, there has been a general agreement on

the need to conduct single dose tissue

distribution studies as part of the nonclinical

program. These studies often provide

sufficient information about tissue

distribution.

There has been no consistent requirement

for repeated dose tissue distribution studies.

However, there may be circumstances when

assessments after repeated dosing may yield

important information.

This paper provides guidance on

circumstances when repeated dose tissue

distribution studies should be considered

and on the conduct of such studies.
Federal Register / Vol. 60, No. 40 / Wednesday, March 1, 1995 / Notices 11275

Circumstances Under Which Repeated Dose

Tissue Distribution Studies Should Be

Considered

1. When single dose tissue distribution

studies suggest that the apparent half-life of

the test compound (and/or metabolites) in

organs or tissues significantly exceeds the

apparent half-life of the elimination phase in

plasma and is also more than twice the

dosing interval in the toxicity studies,

repeated dose tissue distribution studies may

be appropriate.

2. When steady-state levels of a compound/

metabolite in the circulation, determined in

repeated dose pharmacokinetic or

toxicokinetic studies, are markedly higher

than those predicted from single dose kinetic

studies, then repeated dose tissue

distribution studies should be considered.

3. When histopathological changes, critical

for the safety evaluation of the test

substances, are observed that would not be

predicted from short-term toxicity studies,

single dose tissue distribution studies and

pharmacological studies, repeated dose tissue

distribution studies may aid in the

interpretation of these findings. Those organs

or tissues which were the site of the lesions

should be the focus of such studies.

4. When the pharmaceutical is being

developed for site-specific targeted delivery,

repeated dose tissue distribution studies may

be appropriate.

Design and Conduct of Repeated Dose Tissue

Distribution Studies

The objectives of these studies may be

achieved using radiolabelled compounds or

alternative methods of sufficient sensitivity

and specificity.

Dose level(s) and species should be chosen

to address the problem that led to the

consideration of the repeated dose tissue

distribution study.

Information from previous

pharmacokinetic and toxicokinetic studies

should be used in selecting the duration of

dosing in repeated dose tissue distribution

studies. One week of dosing is normally

considered to be a minimum period. A longer

duration should be selected when the blood/

plasma concentration of the compound and/

or its metabolites does not reach steady state.

It is normally considered unnecessary to dose

for longer than 3 weeks.

Consideration should be given to

measuring unchanged compound and/or

metabolites in organs and tissues in which

extensive accumulation occurs or if it is

believed that such data may clarify

mechanisms of organ toxicity.

Summary

Tissue distribution studies are an

important component in the nonclinical

kinetics program. For most compounds, it is

expected that single dose tissue distribution

studies with sufficient sensitivity and

specificity will provide an adequate

assessment of tissue distribution and the

potential for accumulation. Thus, repeated

dose tissue distribution studies should not be

required uniformly for all compounds and

should only be conducted when appropriate

data cannot be derived from other sources.

Repeated dose studies may be appropriate

under certain circumstances based on the

data from single dose tissue distribution

studies, toxicity and toxicokinetic studies.

The studies may be most appropriate for

compounds which have an apparently long

half-life, incomplete elimination or

unanticipated organ toxicity. The design and

timing of repeated dose tissue distribution

studies should be determined on a case-bycase basis.

Dated: February 23, 1995.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 95–4959 Filed 2–28–95; 8:45 am]

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