[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]
BILLING CODE 4160-01-F
