By Rose Pagano and Suzanne M. Sensabaugh, MS, MBA

The intention of this guidance was to help sponsors in assessing reproductive toxicity (mostly for the effects on embryo-fetal development (EFD)) for oncology pharmaceuticals and outline recommendations for product labeling on duration of contraception following cessation of therapy to minimize potential risk to a developing embryo or fetus. Evaluation of EFD toxicity for certain types of pharmaceuticals and their intended populations are discussed in the guidance.

Regarding the assessment of embryo-fetal developmental toxicity, the FDA provided some general recommendations. The EFD toxicity testing should follow the International Council for Harmonisation (ICH) guidance for Industry S9 Nonclinical Evaluation for Anticancer Pharmaceuticals (ICH S9). Additionally, a weight of evidence approach that demonstrates potential for reproductive toxicity could eliminate the need for an in depth EFD study. A weight of evidence (WOE) approach can include the following information: reproductive findings in humans, reproductive findings from genetically-modified animals or models during pharmacologic inhibition, information from a surrogate molecule, literature-based assessment of target biology in humans or animals, and alternative assays.

Genotoxic pharmaceuticals are also discussed in the guidance. The Agency suggests that pharmaceuticals that target rapidly dividing cells in general toxicology studies and are genotoxic are presumed to be teratogenic or lethal to the embryo or fetus. For this situation, FDA does not need the EFD studies. Biotechnology-derived pharmaceuticals are also examined in the guidance. For these products, if the WOE is insufficient for EFD hazard identification, an EFD study in one pharmacologically relevant species should be sufficient.

Another category of pharmaceuticals mentioned in this guidance is conjugated pharmaceuticals. When this type of pharmaceutical contains both a biological and a small-molecule moiety, an EFD study design is determined according to several factors. These factors include the binding of the biological moiety to its target, the potential for release of the small molecule, the nature of the small molecule, and information about toxicities.

 Additionally, the guidance covers combination products. A combination product should be used in EFD studies when the pharmaceuticals in the combination are not a part of a monotherapy and the toxicity evaluation is expected to be different in the combination product compared to each pharmaceutical individually. For these products, the EFD of each pharmaceutical alone may provide an incomplete EFD assessment. EFD data or WOE analysis can be provided for each one of the pharmaceuticals in the combination product, demonstrating teratogenicity and embryo-fetal lethality, an additional EFD of the combination product is unnecessary.

The last specific product discussed in this guidance is liposomal products. Liposomal formulations are generated to change the pharmacokinetic parameters of the active pharmaceutical ingredient (API). An EFD study is unnecessary when the liposomal product has a genotoxic pharmaceutical targeting quickly dividing cells or when the WOE indicates teratogenicity or embryo-fetal lethality.

Another major component of the guidance was how to assess fertility. A fertility study is not warranted for pharmaceuticals that are to be used for patients with advanced cancer. Sponsors should use information from toxicology studies on the pharmaceutical’s effect on reproductive organs to deduce if there would be an impairment of fertility. If there is no indication for advanced cancer from research, a stand-alone fertility study may be warranted on a case-by-case basis. Pre- and postnatal development (PPND) studies are also unnecessary for pharmaceuticals intended to treat patients with advanced cancer. However, this type of analysis may be warranted on a case-by-case basis as well.

 Overall, the guidance provides a comprehensive outline of considerations sponsors need to make concerning oncology pharmaceuticals impacting the reproductive systems. 


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Suzanne M. Sensabaugh has advanced the development of over 130 biologics, biosimilars, and combination products since 2009. She can be reached at