[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





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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