The regulator’s guidance document contains recommendations for evaluating what the potential is for API exposure in males to adversely affect offspring development.

In its guidance Assessment of Male-Mediated Developmental Risk for Pharmaceuticals, the FDA is making recommendations for assessing risks to embryo/fetal development that could result from investigational API administration to males via an effect on male germ cell or seminal transfer of an API.

While there’s guidance related to the need to assess pharmaceuticals’ potential for genetoxic and embryo/fetal developmental toxicity before their administration to pregnant women, there’s a lack of consistency in the design of clinical trial protocol when it comes to pregnancy risks for a sexual partner of a man being administered an API.

When a clinical trial with an investigational drug is being designed, nonclinical studies are likely the only source of information about potential risks to male reproduction or the development of offspring. The guidance states when a trial involves exposure to a potential reproductive or developmental toxicant, investigators should consider issues of risk characterization, informed consent and contraceptive options. In designing a clinical study that involves male subjects, investigators must consider the potential for adverse effects on the conceptus of a sexual partner who is or may become pregnant, the FDA wrote. Due to a lack of clinical information, nonclinical data will be used to assess risk and to inform decisions about the need for appropriate precautions during clinical trials.

Specifically, the FDA is advising sponsors on how to examine what the potential is for API exposure in males to adversely affect offspring development based on three considerations, including the evaluation of studies on mechanisms of action, genetoxicity, reproductive toxicity and developmental toxicity; known effects of API or pharmaceutical in animals or humans; and assessment of possibly embryo-fetal exposure through the transfer and vaginal uptake of reproductive toxicants that secrete into seminal fluid.

The document also goes over factors that investigators should take into account when they test new APIs in males and risk mitigation recommendations.

The FDA lists the reproductive and developmental toxicity of the pharmaceutical; the cytotoxic or genotoxic properties of the drug; pharmacologic properties suggesting risk; and the absorption, distribution, metabolism and excretion properties of the drug as factors to consider when evaluating the potential for developmental toxicity.

The regulator wrote that it intends to consider the totality of provided evidence to support recommendations on the need for male contraception during trial design or to support labeling requirements during drug approval. Contraceptive use recommendations apply to reproductively competent men and vasectomized men, unless existing data shows that only germ cells are affected.

The regulator recommends male subjects in clinical trials take precautions to prevent pregnancy and exposure of a conceptus throughout and following pharmaceutical exposure if an API’s genetoxicity and reproductive and developmental risk potential is unknown or if it was identified as having genotoxic, reproductive and/or developmental effects in nonclinical studies.

The guidance document also lists nonclinical studies applicable to the assessment of drug-induced male-mediated developmental effects in animals, including in vitro studies such as pharmaceutical effects on sperm, in vivo studies such as general toxicity with semen analysis in adult males, and ADME information.