Guideline for Industry

Detection of Toxicity to

Reproduction for Medicinal

Products: Addendum on Toxicity

to Male Fertility

April 1996

 ICH S5B
i

Table of Contents

I. INTRODUCTION (1) .................................................. 1

II. AMENDMENTS (2) ................................................... 2

A. Introduction (Last Paragraph) (I.A) .................................. 2

B. Study of Fertility and Early Embryonic Development to Implantation (4.1.1)

............................................................. 2

1. Administration period (IV.A.1.e. (4.1.1)) ........................ 2

2. Observations (IV.A.1.h (4.1.1)) ............................... 2

C. Note 12 (IV.A.1 (4.1.1)) Premating Treatment ......................... 3
This guideline was developed within the Expert Working Group (Safety) of the International Conference on 1

Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) and has been

subject to consultation by the regulatory parties, in accordance with the ICH process. This document has been endorsed

by the ICH Steering Committee at Step 4 of the ICH process, November 29, 1995. At Step 4 of the process, the final

draft is recommended for adoption to the regulatory bodies of the European Union, Japan and the USA. This guideline

was published in the Federal Register on April 5, 1996 (61 FR 15360) and is applicable to drug and biological

products. Although this guideline does not create or confer any rights for or on any person and does not operate to bind

FDA or the industry, it does represent the agency’s current thinking on the detection of toxicity to reproduction for

medicinal products. For additional copies of this guideline, contact the Drug Information Branch, HFD-210, CDER,

FDA, 5600 Fishers Lane, Rockville, MD 20857 (Phone: 301-827-4573) or the Manufacturers Assistance and

Communication Staff (HFM-42), CBER, FDA, 1401 Rockville Pike, Rockville, MD 20852-1448. Send one selfaddressed adhesive label to assist the offices in processing your request. An electronic version of this guidance is also

available via Internet using the World Wide Web (WWW) (connect to the CDER Home Page at

http://www.fda.gov/cder and go to the “Regulatory Guidance” section).

GUIDELINE FOR INDUSTRY 1

DETECTION OF TOXICITY TO REPRODUCTION FOR

MEDICINAL PRODUCTS: ADDENDUM ON TOXICITY TO

MALE FERTILITY

I. INTRODUCTION (1)

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.
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II. AMENDMENTS (2)

A. Introduction (Last Paragraph) (I.A)

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.

B. Study of Fertility and Early Embryonic Development to Implantation (4.1.1)

1. Administration period (IV.A.1.e. (4.1.1))

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).

2. Observations (IV.A.1.h (4.1.1))

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;
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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).

C. Note 12 (IV.A.1 (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 2094 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.