Future perspective of evaluation for developmental and reproductive toxicity of human pharmaceuticals

<p>The need of the regulatory guidelines for nonclinical safety assessment was defined by the thalidomide tragedy. Effects on embryo-fetal development (EFD) should be evaluated using two species (rats and rabbits) because thalidomide was found to cause severe malformations only in a few species including rabbits. Afterward, the internationally harmonized (ICH S5(R2)) guideline was provided for the assessment of nonclinical developmental and reproductive toxicity (DART) testing by the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH). Expert Working Group (EWG) was formed to revise the current ICH S5(R2) guideline in 2015. After the discussion by EWG members, the stage of the ICH S5(R3) guideline has been reached to Step4 in 2020. </p><p>The major parts of the revised ICH S5(R3) guideline are not different from the current ICH S5(R2) guideline. The set of studies conducted should encompass observations through one complete life cycle (i.e., from conception in one generation through conception in the following generation). However, there are some key differences between the current and revised versions. One of the differences is that the purpose of the revised guideline is to describe potential strategies and study designs to supplement available data to identify, and assess risk. For example, assessment strategies for pharmaceuticals being developed can be planned in consideration of the target population or therapeutic indication. Another is that alternative approach is acceptable to assess EFD risk under limited circumstances. According to the revised ICH S5(R3) guideline, alternative assays are encouraged and have the potential to defer or replace conventional in vivo studies and reduce animal use.</p><p>I will show the general considerations and expectations for detecting DART of human pharmaceuticals, in addition to the lessons learned through the activities of revising the ICH S5 guideline. This presentation will give a hint on future approaches for the assessment of DART risk.</p>