[Federal Register Volume 61, Number 67 (Friday, April 5, 1996)]
[Notices]
[Pages 15360-15361]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-8473]
[[Page 15359]]
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Part V
Department of Health and Human Services
_______________________________________________________________________
Food and Drug Administration
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International Conference on Harmonisation; Guideline on Detection of
Toxicity to Reproduction for Medicinal Products; Addendum on Toxicity
to Male Fertility; Availability; Notice
Federal Register / Vol. 61, No. 67 / Friday, April 5, 1996 /
Notices
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[[Page 15360]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 93D-0140]
International Conference on Harmonisation; Guideline on Detection
of Toxicity to Reproduction for Medicinal Products: 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 is publishing a guideline
entitled ``Detection of Toxicity to Reproduction for Medicinal
Products: Addendum on Toxicity to Male Fertility.'' The 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
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: Effective April 5, 1996. 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 the Division of Communications Management (HFD-210),
Center for Drug Evaluation and Research, Food and Drug Administration,
7500 Standish Pl., Rockville, MD 20855, 301-594-1012. An electronic
version of this guideline is also available via Internet by connecting
to the CDER file transfer protocol (FTP) server (CDVS2.CDER.FDA.GOV).
FOR FURTHER INFORMATION CONTACT:
Regarding the guideline: Joy A. Cavagnaro, Center for Biologics
Evaluation and Research (HFM-500), Food and Drug Administration, 1401
Rockville Pike, Rockville, MD 20852, 301-827-0379.
Regarding ICH: Janet Showalter, Office of Health Affairs (HFY-1),
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 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.
In the Federal Register of August 21, 1995 (60 FR 43500), FDA
published a draft tripartite guideline entitled ``Detection of Toxicity
to Reproduction: Addendum on Toxicity to Male Fertility.'' The notice
gave interested persons an opportunity to submit comments by October 5,
1995.
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 on November 29, 1995.
The guideline is an addendum to an ICH guideline published in the
Federal Register of September 22, 1994 (59 FR 48746), entitled
``Guideline on Detection of Toxicity to Reproduction for Medicinal
Products.'' The 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 that are acceptable to FDA. The
agency is now in the process of revising Sec. 10.90(b). Although this
guideline does not create or confer any rights for or on any person and
does not operate to bind FDA, it does represent the agency's current
thinking on the detection of toxicity to reproduction for medicinal
products.
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:
Detection of Toxicity to Reproduction for Medicinal Products: Addendum
on Toxicity to Male Fertility
1. Introduction
This text is an addendum to the ICH Tripartite Guideline on
Detection of Toxicity to Reproduction for Medicinal Products and
provides amendments to the published text.
At the time of adoption, it was accepted that the male fertility
investigation, as included in the currently harmonized guideline,
would need scientific and regulatory improvement and optimization of
test designs.
The amendments are intended to provide a better description of
the testing concept and recommendations, especially those
addressing:
Flexibility
Premating treatment duration
Observations
The general principles and background were contained in two
papers published in the Journal of American College of Toxicology.
These papers contain the necessary experimental data (prospective
and retrospective) for reaching consensus and have been commented
on. The individual data from the Japanese collaborative study were
also published in the Journal of Toxicological Science.
[[Page 15361]]
2. Amendments
Introduction (Last Paragraph)
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.
4.1.1. Study of Fertility and Early Embryonic Development to
Implantation
Administration period
The design assumes that, especially for effects on
spermatogenesis, use will be made of available data from toxicity
studies (e.g., histopathology, weight of reproductive organs, in
some cases hormone assays and genotoxicity data). Provided no
effects have been found in repeated dose toxicity studies of at
least 4 weeks duration that preclude this, a premating treatment
interval of 2 weeks for females and 4 weeks for males can be used
(Note 12). Selection of the length of the premating administration
period should be stated and justified. 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 histopathologic
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 histology of reproductive organs in males or
females, or if the quality of examinations is dubious, or if there
are no data from other studies, the need for a more comprehensive
study should be considered (Note 12).
Observations
At terminal examination, the following should be done:
Perform necropsy (macroscopic examination) of all
adults;
Preserve organs with macroscopic findings for possible
histopathological evaluation; keep corresponding organs of
sufficient controls for comparison;
Preserve testes, epididymides, ovaries, and uteri from
all animals for possible histopathological examination and
evaluation on a case by case basis;
Count corpora lutea, implantation sites (Note 16);
Count live and dead conceptuses; and
Sperm analysis can be used as an optional procedure for
confirmation or better characterization of the effects observed
(Note 12).
Note 12 (4.1.1) Premating Treatment
The design of the fertility study, especially the reduction in
the premating period for males, is based on evidence accumulated and
on re-appraisal 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 states and weight of testis; 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 of
spermatogenesis. Good pathological and histopathological examination
(e.g., by employing Bouin's fixation, paraffin embedding, transverse
section of 2-4 microns for testes, longitudinal section for
epididymides, PAS and hematoxylin staining) of the male reproductive
organs provides a direct means of detection. Sperm analysis (sperm
counts, sperm motility, sperm morphology) can be used as an optional
method to confirm findings by other methods and to further
characterize effects. Sperm analysis data are considered more
relevant for fertility assessment when samples from vas deferens or
from cauda epididymis are used. Information on potential effects on
spermatogenesis (and female reproductive organs) can be derived from
repeated dose toxicity studies or reproductive toxicity studies.
For detection of effects not detectable by histopathology of
male reproductive organs and sperm analysis, mating with females
after a premating treatment of 4 weeks has been shown to be at least
as efficient as mating after a longer duration of treatment (2 weeks
may be acceptable in some cases). However, when 2 weeks treatment
period is selected, more convincing justification should be
provided. 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.
Dated: March 29, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-8473 Filed 4-4-96; 8:45 am]
BILLING CODE 4160-01-F
