[Federal Register Volume 59, Number 40 (Tuesday, March 1, 1994)]
[Unknown Section]
[Page 0]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 94-4568]


[[Page Unknown]]

[Federal Register: March 1, 1994]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 94D-0028]

 

International Conference on Harmonisation; Draft 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 draft 
guideline entitled ``Pharmacokinetics: Guidance for Repeated Dose 
Tissue Distribution Studies.'' The draft guideline was prepared by the 
Safety Expert Working Group of the International Conference on 
Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH). The draft guideline is intended to 
provide guidance on the circumstances when repeated dose tissue 
distribution studies should be considered and on the conduct of those 
studies.

DATES: Written comments by May 16, 1994.

ADDRESSES: Submit written comments on the draft guideline to the 
Dockets Management Branch (HFA-305), Food and Drug Administration, rm. 
1-23, 12420 Parklawn Dr., Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: 
    Regarding the draft guideline: Alan S. Taylor, Center for Drug 
Evaluation and Research (HFD-502), Food and Drug Administration, 5600 
Fishers Lane, Rockville, MD 20857, 301-443-2544.
    Regarding ICH: Janet Showalter, Office of Health Affairs (HFY-50), 
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 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.
    ICH was organized to provide an opportunity for tripartite 
harmonization initiatives to be developed with technical input from 
both regulatory and industry representatives. FDA also seeks input from 
consumer representatives and other interested parties. Through notices 
such as this, FDA invites public comment on ICH initiatives that have 
reached the draft guideline stage. 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, FDA, and the U.S. Pharmaceutical 
Manufacturers Association. The ICH Secretariat, which coordinates the 
preparation of documentation, is provided by the International 
Federation of Pharmaceutical Manufacturers Associations (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.
    At a meeting held from October 27 through 29, 1993, the ICH 
Steering Committee agreed that the draft tripartite guideline entitled 
``Toxicokinetics: Guidance for Repeated Dose Tissue Distribution 
Studies'' should be made available for public comment. The draft 
guideline will be made available for comment by the European Commission 
and Japanese Ministry of Health and Welfare, as well as by FDA, in 
accordance with their respective consultation procedures. After 
analyzing the comments and revising the guideline, if appropriate, FDA 
will determine whether it will adopt and issue the guideline.
    The draft 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 draft guideline 
provides general guidance on the use of radio-labelled compounds, dose 
and species selection, and duration of studies.
    Guidelines are generally issued under Secs. 10.85(d) and 10.90(b) 
(21 CFR 10.85(d) and 10.90(b)), which provide for the use of guidelines 
to establish procedures or standards of general applicability that are 
not legal requirements but that are acceptable to FDA. The agency is 
now in the process of considering whether to revise Secs. 10.85(d) and 
10.90(b). Therefore, if the agency issues this guideline in final form, 
it would not be issued under the authority of Secs. 10.85(d) and 
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 16, 1994, to the Dockets 
Management Branch (address above) submit 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.
    The text of the draft guideline follows:

Pharmacokinetics: Guidance for Repeated Dose Tissue Distribution 
Studies

I. 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 Community, the United States, and Japan, there 
has been a general agreement on the need to conduct single dose 
tissue distribution studies as part of the preclinical package. 
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 repeat dose 
tissue distribution studies should be considered and on the conduct 
of such studies.

II. Circumstances Under Which Repeated Dose Tissue Distribution Studies 
Should Be Considered

    1. When information is available to predict that accumulation of 
a compound will occur in organs and tissues after repeated 
administration, then the extent and the time course of accumulation 
and elimination should be examined by repeated dose tissue 
distribution studies. For example, 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 more than twice the dosing interval in the toxicity studies, 
repeated dose studies may be appropriate.
    2. When repeated dose pharmacokinetic or toxicokinetic data 
suggest an accumulation of the compound and/or metabolites, which 
was not predicted by single dose kinetic studies, repeated dose 
tissue distribution studies should be considered.
    3. When patho-morphological changes are observed that would not 
be predicted from short term toxicity studies and single dose tissue 
distribution 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.

III. Design and Conduct of Repeated Dose Tissue Distribution Studies

    1. The objectives of these studies may be achieved using radio-
labelled compounds or alternative methods of sufficient sensitivity 
and specificity.
    2. Dose level(s) and species should be chosen to address the 
problem that led to the consideration of the repeated dose tissue 
distribution study.
    3. 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 drug and/or 
its metabolites does not reach steady state. It is normally 
considered unnecessary to dose for longer than 3 weeks.
    4. 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.

IV. Conclusions

    Tissue distribution studies are an essential component in the 
preclinical kinetics programme. 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. 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, 1994.
Michael R. Taylor,
Deputy Commissioner for Policy.
[FR Doc. 94-4568 Filed 2-24-94; 1:35 pm]
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