[Federal Register Volume 60, Number 161 (Monday, August 21, 1995)]
[Notices]
[Pages 43500-43501]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-20609]
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[Docket No. 93D-0140]
International Conference on Harmonisation; Draft Guideline on
Detection of Toxicity to Reproduction: Addendum on Toxicity to Male
Fertility; Availability
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice.
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SUMMARY: The Food and Drug Administration (FDA) is publishing portions
of a revised draft guideline entitled ``Detection of Toxicity to
Reproduction: Addendum on Toxicity to Male Fertility.'' This draft
guideline was prepared under the auspices of the International
Conference on Harmonisation of Technical Requirements for Registration
of Pharmaceuticals for Human Use (ICH). The draft guideline is intended
to reflect sound scientific principles for reproductive toxicity
testing concerning male fertility, and is an addendum to an earlier ICH
guideline on the detection of toxicity to reproduction for medicinal
products.
DATES: Written comments by October 5, 1995.
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. Copies of the draft
guideline are available from the 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: Joy A. Cavagnaro, Center for Biologics
Evaluation and Research (HFM-2), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852, 301-827-0379.
Regarding the ICH: Janet J. Showalter, Office of Health Affairs
(HFY-20), Food and Drug Administration, 5600 Fishers Lane, Rockville,
MD 20857, 301-827-0864.
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 Industries
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 Associations (IFPMA).
The ICH Steering Committee includes representatives from each of
the ICH sponsors and the 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 on March 29, 1995, the ICH Steering Committee
agreed that a draft guideline entitled ``Detection of Toxicity to
Reproduction: Addendum on Toxicity to Male Fertility'' should be made
available for public comment. The draft guideline is the product of the
Safety Expert Working Group of the ICH. Comments about this draft will
be considered by FDA and the Expert Working Group. Ultimately, FDA
intends to adopt the ICH Steering Committee's final guideline.
This draft guideline is an addendum to an ICH final guideline
published in the Federal Register of September 22, 1994 (59 FR 48746)
entitled ``Guideline on Detection of Toxicity to Reproduction for
Medicinal Products.'' This draft guideline is intended to reflect sound
scientific principles for reproductive toxicity testing concerning male
fertility.
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),
[[Page 43501]]
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.
Interested persons may, on or before October 5, 1995, submit to the
Dockets Management Branch (address above) 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:
Detection of Toxicity to Reproduction: Addendum on Toxicity to Male
Fertility
1. Introduction
1.1 Objective
Addendum to ICH--S5A Tripartite Guideline
1.2 Male fertility investigation, as included in the currently
harmonized guideline, was accepted to recommend scientific and
regulatory improvement and optimization of test designs.
1.3 Better description is needed of the testing concept and
recommendations with regard to male fertility assessment, especially
those addressing:
Flexibility
Premating treatment duration
Observation
1.4 The general principles and background are contained in two
papers accepted for publication to the Journal of American College
of Toxicology.
These papers contain necessary experimental data (prospective
and retrospective) for reaching consensus, and have been discussed
among the expert working group. The ``raw data'' from the Japanese
study will also be published.
1.5 The projected timeframe proposed:
--Step 2 in Washington, March 1995
--Step 3 in Brussels, July 1995
--Step 4 in Yokohama, November 1995
2. The guideline draft texts are attached.
3. For glossary see the harmonized S5--A guideline
Introduction
(Last paragraph revised)
To employ this concept successfully, flexibility is needed (Note
1). No guideline can provide sufficient information to cover all
possible cases. All persons involved should be willing to discuss
and consider variations in test strategy according to the state-of-
the-art and ethical standards in human and animal experimentation.
(Delete next sentence)
Note 12 (4.1.l) Premating Treatment
(Revised)
The design of the fertility study, especially the reduction in
the premating period for males, is based on evidence accumulated and
reappraisal of the basic research on the process of spermatogenesis.
Compounds inducing selective effects on male reproduction are rare;
compounds affecting spermatogenesis almost invariably affect
postmeiotic stages; mating with females is an insensitive means of
detecting effects on spermatogenesis. Histopathology of the testis
has been shown to be the most sensitive method for the detection of
effects on spermatogenesis. Good pathological and histopathological
examination (e.g., by employing Bouin's fixation, paraffin
embedding, transverse section of 2 to 4 microns for testes,
longitudinal section for epididymides, PAS, and haematoxylin
staining) of the male reproductive organs provides a quick direct
means of detection. Sperm analysis (sperm counts and optionally
sperm motility, sperm morphology) can be used as a method to confirm
findings by other methods and to characterize effects further. Sperm
are derived from the more mature stages. Samples from ejaculates,
from vas deferens, or from cauda epididymis should be used.
Information on potential effects on spermatogenesis (and female
reproductive organs) can be derived from repeated dose toxicity
studies.
For detection of effects unrelated to spermatogenesis (sperm
abnormalities, mating behavior), mating with females after a
premating treatment of 2 and 4 weeks has been shown to be at least
as efficient as mating after a longer duration of treatment. When
the available evidence suggests that the scope of investigations in
the fertility study should be increased, appropriate studies should
be designed to characterize the effects further.
Administration Period
(Revised)
The design assumes that, especially for effects on
spermatogenesis, use will be made of data (e.g., histopathology and
weight of reproductive organs, hormone assays, and genotoxicity
data) from repeated dose toxicity studies. Provided no effects have
been found that preclude this, a premating treatment interval of 2
weeks for females and 4 weeks for males (2 weeks may be acceptable
in some cases) can be used (Note 12). Selection of the length of the
premating administration period should be stated and justified (see
also chapter 1.1, pointing out the need for research). Treatment
should continue throughout mating to termination for males and at
least through implantation for females. This will permit evaluation
of functional effects on male fertility that cannot be detected by
histologic examination in repeated dose toxicity studies and effects
on mating behavior in both sexes. If data from other studies show
there are effects on weight or histologic appearance of reproductive
organs in males or females, or if the quality of examinations is
dubious, or if there are no data from other studies, then a more
comprehensive study should be designed (Note 12).
4.1.1 Study of Fertility and Early Embryonic Development to
Implantation
Observations
(Revised)
At terminal examination, the following observations should be
made:
Necropsy (macroscopic examination) of all adults;
Preserve organs with macroscopic findings for possible
histological evaluation; keep corresponding organs of sufficient
controls for comparison;
Preserve testes, epididymides, ovaries, and uteri from all
animals for possible histological examination and evaluation on a
case-by-case basis;
Count corpora lutea, implantation sites (Note 16);
Live and dead conceptuses; and
Sperm analysis as an optional procedure for confirmation or
better characterization of an effect observed (Note 12).
Dated: August 14, 1995.
William K. Hubbard,
Acting Deputy Commissioner for Policy.
[FR Doc. 95-20609 Filed 8-18-95; 8:45 am]
BILLING CODE 4160-01-F
