Graphical Analyses in the Regulatory Evaluation of Gene Therapy Applications.

The Center for Biologics Evaluation and Research (CBER) at the US Food and Drug Administration (FDA) regulates gene therapies, among other products. The approval of four gene therapy products since 2017 represents a significant milestone for a new class of treatments with the potential to treat or cure diseases, particularly rare diseases, that were previously considered incurable. Several factors have contributed to the recent rapid development of gene therapies including advances in genetics to facilitate target-detection, advances in vectors, and regulatory incentives such as breakthrough therapy designation, priority review and market exclusivity. The patient population affected by a rare disease is typically small, heterogeneous and geographically dispersed. As a result, clinical trials on a rare disease have unique features in terms of study design, subject enrollment, data analyses and interpretation of study results. Given that the patient population affected is small for rare diseases, providing substantial evidence of effectiveness and evidence of safety in trials for rare disease presents challenges. In this paper, we share our experiences in the statistical review of three gene therapy products that have been approved by FDA CBER. Our motivation in writing this paper is to encourage the use of appropriate analysis strategies for other similar small trials, with a focus on data visualization strategies.