Marks calls for new gene therapy development paradigm

Regulatory NewsRegulatory News | 05 April 2022 |  By 

CBER director Peter Marks

The head of the US Food and Drug Administration’s (FDA) biologics center says the current drug development process is not well-suited for gene therapy products. He says there needs to be a total rethinking from clinical trial designs, statistical tools, manufacturing practices to global regulatory harmonization to get new gene therapies to patients more effectively.
Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), says there needs to be a paradigm shift to help get new gene therapies to market in an article published in Expert Opinion on Biological Therapy on 3 April. While noting there have been some successes in the gene therapy space, he questions why more patients haven’t been able to reap the benefits of gene therapies.
“Although there is obviously no single correct answer to this question, one can start by considering whether the current framework for the clinical development of small molecule drugs frequently being followed for the development of gene therapies is the wholly appropriate paradigm to be following,” Marks wrote. “Certainly, there are aspects of the paradigm that are quite applicable, such as understanding the non-clinical aspects of the product in development, the use of good manufacturing practices for production, and the demonstration of safety and effectiveness for the intended use. However, there are other aspects of gene therapies that may lend themselves to the application of other paradigms.”
Specifically, Marks says current gene therapies use a vector backbone, usually an adeno-associated virus (AAV) or a lentivirus, to deliver the transgene. He says new gene therapies could reuse information related to the vector backbone to speed their development.
Part of proving to regulators a product is effective is showing that its endpoints are statistically significant which can be extremely difficult especially when they are meant to treat rare diseases in small patient populations.
Marks suggests one area to look at to overcome that challenge in gene therapies is to use biomarkers in non-clinical models where there is a correlation with therapeutic response. He also suggests use of Bayesian clinical trial designs, which allow researchers to calibrate the trial based on ongoing data gathering, can be another useful means of dealing with extrapolating data from small patient populations.
In addition to clinical trial issues, Marks notes there are certain manufacturing hurdles which make it hard to mass-produce gene therapies after the initial therapies are developed in academic and smaller lab settings for clinical trial purposes. He notes transferring production can be time consuming and costly.
“This might be addressed by a combination of process standardization and leveraging of the inherent properties of gene therapy vectors,” said Marks. “Were academic institutions and smaller entities to standardize their protocols for early production of clinical grade material, the transfer to a variety of contract manufacturers could be facilitated.”
“Additionally, reuse of well-characterized gene therapy vectors being used for commercial product production could streamline the ability to move from one gene therapy to another addressing different disease entities,” he added. “Obviously, there would need to be specified parameters, such as insert size and type of protein to be expressed. However, this approach could be transformational in expanding the reach of gene therapy.”
On the topic of regulation, Marks says that gene therapy developers should engage with FDA early to work out what the agency needs to see to be able to determine the product is safe and effective. However, beyond the US, he also notes that differences in regulatory regimes across the globe can be a significant hurdle and disincentive for developers.
“The need in some cases to conduct different additional non-clinical studies prior to initiating clinical investigation to satisfy requirements for either the purpose of supporting initial clinical studies in humans or to assess environmental impact, along with potentially varying requirements for manufacturing, become a disincentive for developers to make their products available internationally,” he said.
“Convergence of regulatory requirements could facilitate both the clinical investigation and commercialization of gene therapy products globally,” Marks said, noting ongoing efforts by the World Health Organization. (RELATED: WHO charts path to convergence on cell and gene therapies, Regulatory Focus 14 January 2022)


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