The role of regulatory flexibility in the review and approval process of rare disease drug development

The role of regulatory flexibility in the review and approval process of rare disease drug and biologics development was recently studied by a Consensus Committee of the National Academy of Sciences, Engineering and Medicine (NASEM 2024). In this article, regulatory flexibility is referred to as the exercise of scientific judgement by the regulatory agencies such as the United States Food and Drug Administration (FDA), in the review and oversight of a wide range of products, diseases and circumstances (see e.g. 21CFR Subpart E). This flexibility is intended to assist the sponsors in obtaining substantial evidence regarding safety and effectiveness of a test treatment under investigation. Applying general scientific principles, regulatory flexibility should be transparent, objective, and applied without undermining the integrity, quality and scientific validity of clinical investigation of the test treatment under study. This article attempts to provide an overview regarding the application of regulatory flexibility in rare disease drug and biologic development, which could also be applied to drug products for normal conditions. In addition, some innovative strategies and approaches which reflect regulatory flexibility and current thinking are proposed. Statistical considerations regarding the implementation of regulatory flexibility and/or current thinking in support of the demonstration of the safety and efficacy in drug development are discussed.