FDA Grapples with the Promise and Perils of Gene Therapy

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High price tags threaten to block patient access to potentially life-saving cures and treatments.

The challenges in developing gene and cellular therapies have made headlines over the past year, as biotech companies have launched a wave of development programs despite ongoing concerns about treatment safety and efficacy plus unknown long-term effects. High price tags on these breakthrough treatments, moreover, threaten to block patient access to potentially life-saving cures and treatments. FDA scientists and reviewers are working to advance the field, with new guidances and advice for manufacturers on appropriate testing of treatments to minimize risks to patients and fill gaps in data.

New gene therapies for debilitating rare conditions stand to advance from an FDA collaboration with the National Institutes of Health (NIH) and a cadre of pharma companies, small biotechs, and patient groups, formally announced Oct. 27, 2021. The Bespoke Gene Therapy Consortium (BGTC) will be managed by NIH’s Accelerating Medicines Partnership program and the Foundation for the NIH and will provide public and private resources to support the development of gene therapies to treat rare diseases.

To start, the BGTC plans to initiate preclinical and clinical trials for four to six monogenetic rare diseases that currently lack any treatment. Such advances will facilitate a better understanding of the biology and production of adeno-associated virus (AAV) vectors utilized to deliver gene therapies to individual patients. The consortium will provide $76 million over five years from NIH and private partners to fund a range of research, such as establishing standardized analytical test methods to improve AAV production and use and to advance toxicology testing for preclinical development. The term “bespoke” reflects the need for efficient methods for developing highly individualized therapies to fit the genetic specifics of one or two patients.

The BGTC initiative has been under development for several months, as seen in remarks at the September 2021 PDA/FDA conference by Peter Marks, director of the Center for Biologics Evaluation and Research (CBER), on how the program could standardize methods for developing and manufacturing bespoke therapeutics. Marks outlined efforts to leverage methods and data from one application to another to reduce prohibitive R&D costs that threaten product development and patient access. In advancing the development of gene therapies for very rare disorders, he noted the importance of collecting baseline natural history data on target diseases and of public-private partnerships to enable streamlined production through a “cookbook” for developing bespoke therapeutics.

Safety scares


This public-private collaboration is particularly timely in the wake of recent patient deaths and safety issues linked to experimental gene therapies involving AAV delivery. FDA’s Cellular, Tissue, and Gene Therapies Advisory Committee met in early September to discuss these concerns, noting the limitations of preclinical animal models in predicting potential risks from viral vectors. Panel members cited the need for clearer standards related to gene therapy development, for more comprehensive patient screening, and for longer assessment of patients following treatment to better track side effects that may emerge later.

Even though the experts stopped short of recommending specifics curbs on developing these advanced treatments, FDA put a clinical hold on an early study for gene therapy from BioMarin. In addition, Pfizer halted studies on two experimental gene therapies following reports of adverse events in early studies.

Meanwhile, CBER seeks to expand the resources and expertise for its Office of Tissues & Advanced Therapies (OTAT) to better oversee and provide advice on developing genetic and other advanced products. Despite a slowdown in biopharmaceutical research due to the pandemic, CBER officials continue to see a strong flow of applications to test experimental cell and gene therapies, many requesting meetings with OTAT staff to discuss research plans. OTAT director Wilson Bryan noted the importance of transparency on safety issues related to gene therapy in a Nov. 12, 2021, presentation at a meeting sponsored by Prevision Policy. One critical issue to explore is whether the effectiveness of gene therapy treatment wears off over time, warranting re-administration. To address these unknown and continuing safety concerns, Bryan emphasized the importance of long-term follow-up of all gene therapy patients—maybe following gene therapy patients “forever,” he commented.

Sources: NIH, FDA, BioMarin, Pfizer