[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
_______________________________________________________________________
Food and Drug Administration
_______________________________________________________________________
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
