FDA proposes using existing science, regulatory knowledge for gene therapy development

The U.S. Food and Drug Administration on Tuesday issued draft guidance meant to accelerate the development of gene therapies for patients with rare and life-threatening diseases by allowing developers to use publicly available information and regulatory knowledge, including chemistry, manufacturing and controls (CMC) data as well as nonclinical study results and clinical information.

By “making greater use” of existing scientific and regulatory knowledge, the agency said its proposal is designed to expedite regulatory submissions and subsequent FDA reviews of human gene therapy (GT) products incorporating ex vivo and in vivo genome editing (GE) of human somatic cells (GE products).

The FDA’s draft guidance states that the “scientific soundness of leveraging CMC knowledge may depend on the similarities in the molecular structure of a component or product and its manufacturing process,” including facility and equipment operating conditions.

“By outlining how sponsors can intelligently build upon existing nonclinical, clinical, and manufacturing knowledge, we can meaningfully streamline development programs and lower the cost barriers that have historically slowed access to these potentially life-changing treatments,” Vijay Kumar, acting director of the Office of Therapeutic Products in the FDA’s Center for Biologics Evaluation and Research (CBER), said in a statement.

Kumar added that “leveraging prior knowledge” gained from developing and manufacturing similar products and processes “does not mean lowering the bar” but in fact raises “our collective efficiency while maintaining the highest standards of safety and efficacy.”

The Alliance for Regenerative Medicine (ARM) in a statement said it welcomed the FDA’s “detailed” draft guidance, having previously convened a scientific exchange with the agency on gene editing platform technologies.

“We believe that leveraging prior knowledge and platforms is an important element in streamlining development to get therapies to patients more quickly,” ARM said.

While the draft guidance focuses on GE products, the FDA said some of its recommendations — when finalized — may also be applicable to other cell and GT products such as adeno-associated viral vectors, nanoparticle-based GT products, and ex vivo-modified cell-based GTs that do not incorporate GE. However, the agency noted that additional considerations may apply to these types of products — based on the specific product and manufacturing process that are beyond those recommended in the draft guidance.

Flexible approach to CMC

The FDA is pursuing a flexible approach to overseeing CMC requirements for cell and gene therapies intended to expedite product development and help guide the agency’s evaluation of developer strategies in preparation for Biologics License Application (BLA) submissions.

The agency contends that CBER has historically had similar CMC expectations across products including small-batch products such as cell and gene therapies, which are complex biologic products — often individualized for patients — and need sophisticated manufacturing under time constraints.

Tuesday’s draft guidance “supports the development of a wide range of cell and gene therapy products, including those that use genome editing, and is part of a broader set of complementary FDA actions in this area,” according to the announcement.

FDA’s Plausible Mechanism Framework

The agency said the latest draft guidance on Tuesday complements its Plausible Mechanism Framework released in February, which covers the development and approval of individualized therapies that target specific genetic conditions with known biological causes, with the goal of accelerating gene and gene editing therapies for diseases affecting exceedingly small patient populations where a randomized trial would not be feasible.

The FDA’s Plausible Mechanism Framework outlines a set of recommendations to help developers of individualized therapies generate sufficient clinical safety and efficacy data to demonstrate that a drug or biological product is safe and effective for the intended use — and that it can be manufactured to regulatory quality standards.

Given the shortened clinical investigation phase expected for individualized therapies, the FDA said in the framework CMC development should evolve concurrently with clinical development.

“Due to the limited number of subjects being treated in clinical trials to support approval, it is expected that CMC development will occur rapidly,” according to the FDA’s draft guidance. “The sequence, structures (e.g., various modifications, conjugations), stereochemistry, and other physicochemical characteristics critical to the performance of the product should be well-defined, confirmed, and controlled to ensure consistency, where applicable.”

As a result, the FDA said multiple aspects of the commercial manufacturing process should be considered when developing the manufacturing process to support the initial Investigational New Drug (IND), such as scale, validation, and commercial feasibility. Not surprisingly, the Plausible Mechanism Framework has significant CMC hurdles. 

In a March 31 article published in the American Journal of Human Genetics, authors from the Children’s Hospital of Philadelphia and Penn Medicine reported initial proof-of-concept studies supporting a customizable in vivo prime editing platform.

While the article showed that the FDA’s Plausible Mechanism Framework can help streamline nonclinical and clinical requirements for personalized gene therapies, its authors noted that CMC requirements in the framework remained challenging to meet and suggested further potential to streamline them to benefit patients with ultra-rare diseases.