Reproductive Toxicology

Reproductive toxicology is the study of adverse effects on male fertility and female fertility and the growth and development of the next generation. The International Conference on Harmonisation (ICH), Safety (S) guideline 5, revision 3 (R3) Detection of Reproductive and Developmental Toxicity for Human Pharmaceuticals, provides guidance to assess the hazard of a pharmaceutical to reproduction including the next generation. As most pharmaceuticals, whether small or large molecules, and medical devices are not developed to be used during pregnancy, the purpose of establishing the hazard to reproduction is to provide information for the drug label. The patient and doctor can then make a risk to benefit decision on whether to use a drug to treat a specific disease. Human data generated in clinical trials provides the most relevant information for the safe use of any new drug. However, since the fetus can never give consent to participate in a clinical trial, the hazard of a new drug in terms of functional fertility and pregnancy has for many years come from nonclinical animal studies. This chapter (1) reviews the various animal study designs for evaluating fertility and development of the offspring, (2) provides information on the unique aspects of testing biopharmaceuticals, (3) reviews when, during the drug development process, the various studies should be conducted to support clinical trials, and (4) provides information on the end points evaluated, the outcomes expected, and the use of the data in the risk/benefit process. Information on the requirements to validate an alternative (nonmammalian) assay for reproductive and developmental toxicity is also discussed as these assays will become more and more relevant to the hazard assessment process for reproductive toxicity.