Regulatory Trends in the Nonclinical Development of Viral Vector-Based Gene Therapies: A Benchmark Analysis of Approved Products

Abstract

As it is often the case with innovative technologies, regulatory agencies are highly demanding in product safety demonstration from those pioneering breakthrough therapy products. Since the first historically approved gene therapy medicinal product (Gencidine in 2003) by the Chinese National Medicinal Products Administration, gene therapy medicinal products have slowly been emerging in other regions, as illustrated by the first European-approved gene therapy medicinal product (Glybera in 2012) and the first US-approved product (Imlygic in 2015). From then, with the rise of new molecular technologies (e.g., non-viral and viral vector systems), an exponential growth of gene therapies development could be gauged with, for example, the approval of more than thirty gene therapies between 2016-2022.

Using a method based on Preferred Reporting Items for Systematic reviews and Meta-Analyses principle, throughout different literature databases, this review is restricted to the evaluation of viral vector-based gene therapy medicinal products (VV-GTMPs). It also considered relevant guidelines and public assessment reports issued by the EMA and / or the FDA on the products these agencies approved. Then, a benchmark was performed to help stakeholders to identify regulatory trends and to design appropriate nonclinical programs establishing the benefit / risk ratio for patients to be enrolled in clinical trials. The analysis was focused on the nonclinical activities (pharmacology, biodistribution / persistence / shedding, and toxicology) performed by Applicants / Sponsors.

As of 30 March 2023, 18 VV-GTMPs have been authorized by the EMA and 14 by the FDA to treat either orphan diseases or limited number of oncology patients. The majority of these therapies are based on adeno-associated or retroviral viruses (often lentiviruses able to transfect hematopoietic CD34⁺ cells or T-cells). Based on an analysis of the ongoing clinical trials, there is now a trend for developing gene therapies for larger patient populations.

In conclusion, given the VV-GTMPs diversity and targeted indications, a “one-size fits all” nonclinical development plan cannot be considered by default. Instead, individual, risk-based, tailored nonclinical development programs appear more appropriate to assess such products, taking into consideration the lessons learned from the past. In such fast-evolving environment, regulatory agencies need to adapt their evaluation process very rapidly.