Graphical Analyses in the Regulatory Evaluation of Gene Therapy Applications
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REVIEW
Graphical Analyses in the Regulatory Evaluation of Gene Therapy Applications Xue Lin, PhD1 · Shiowjen Lee, PhD1 · John Scott, PhD1 · Min Lin, PhD1 Received: 27 July 2020 / Accepted: 5 September 2020 © The Drug Information Association, Inc 2020
Abstract 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. Keywords Gene therapy · Biologics · Summary statistics · Data visualization · Swimmer plot · Spaghetti plot · Box plot
Background The Orphan Drug Act of 1983 defines a rare disease or condition as one affecting fewer than 200,000 subjects in the US. Most rare diseases, however, affect far fewer subjects [1]. The National Institutes of Health (NIH) reports that there are approximately 7000 rare diseases affecting more than 25 million Americans. Approximately 80% of them are caused by a single-gene defect, and about half affect children [2]. Only a fraction of identified rare diseases have approved therapies available. Because many of these diseases are serious or/and life-threatening and most of them do not have approved therapies, there remains a significant Disclaimer This article reflects views of the authors and should not be construed to represent the views or policies of US FDA. * Shiowjen Lee [email protected] 1
Division of Biostatistics, Office of Biostatistics and Epidemiology, Center for Biologics Evaluation and Research, U.S. Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20993, USA
unmet medical need for effective treatments. It is widely understood that product development for rare diseases poses numerous challenges including: (1) The patient populations can be heterogeneous and widely dispersed
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