[Federal Register Volume 60, Number 40 (Wednesday, March 1, 1995)]
[Notices]
[Pages 11274-11275]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-4959]




[[Page 11273]]

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Part XI





Department of Health and Human Services





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Food and Drug Administration



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International Conference on Harmonisation; Guideline on Repeated Dose 
Tissue Distribution Studies; Notice

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

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.

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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 
Sec. 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 Sec. 10.90(b). Therefore, this 
guideline is not being issued under the authority of Sec. 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. [[Page 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-by-case basis.

    Dated: February 23, 1995.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 95-4959 Filed 2-28-95; 8:45 am]
BILLING CODE 4160-01-F