Trial by "Firsts": Clinical Trial Design and Regulatory Considerations in the Development and Approval of the First AAV Gene Therapy Product in the United States

Abstract

Given the therapeutic potential of supplying a normal copy of a mutant gene to the correct target tissue, gene therapy holds extraordinary promise for the treatment of genetic disease. Like other novel classes of therapeutics however, gene therapies must overcome a range of clinical, regulatory, and manufacturing hurdles to reach regulatory approval. This paper reviews key aspects of clinical trial design, development, and evaluation of a novel primary end point, and regulatory interactions that resulted in the first approval by the U.S. Food and Drug Administration (FDA) of an adeno-associated virus (AAV) gene therapy product.

Figure 1.

Phase 3 and long-term follow-up study design. (ITT) Intent-to-treat population. (Figure reprinted from Maguire et al. 2021 under the terms of a Creative Commons license CC BY-NC-ND 4.0.)

Figure 2.

Role of RPE65 in the visual cycle. (Reprinted from Cellular, Tissue and Gene Therapies Advisory Committee October 12, 2017. Meeting Briefing Document, Spark Therapeutics, Luxturna. Full document freely available for download at www.fda.gov/media/108385/download, U.S. FDA 2017a.)

Figure 3.

Multi-luminance mobility test (MLMT) and light levels. (Reprinted from Cellular, Tissue and Gene Therapies Advisory Committee October 12, 2017. Meeting Briefing Document, Spark Therapeutics, Luxturna. Full document freely available for download at www.fda.gov/media/108385/download, U.S. FDA 2017a.)