Society Responds to FDA’s Potency Assurance for Cellular and Gene Therapy Products

ASGCT submitted comments to the Food and Drug Administration (FDA) regarding Potency Assurance for Cellular and Gene Therapy Products; Draft Guidance for Industry. The mission of ASGCT is to advance knowledge, awareness, and education leading to the discovery and clinical application of genetic and cellular therapies to alleviate human disease. Many of our members have spent their careers in this field performing the underlying research that has led to today’s robust pipeline of transformative therapies. 

Without a doubt, advances in manufacturing processes have improved production, control, and characterization of CGT products. However, the link between product characteristics and clinical performance often remains product-specific, particularly early in development. Potency assays play a key role in informing this link. However, there are technical and scientific challenges associated with potency test design, execution, and analysis. Challenges associated with potency assays can lead to development delays, including clinical holds. These effects can result in stopping further development of products to address unmet medical needs of patients suffering from serious and life-threatening diseases. 

The Society appreciates FDA’s efforts in developing a cohesive strategy to address the complexities associated with evaluating and assuring potency. The draft guidance, however, did not provide needed clarity and direction to sponsors in the CGT field. ASGCT commented on three overarching themes that should be addressed in the final guidance.  

1. Phase Appropriateness – Although the Agency acknowledges the degree of potency assurance should be phase appropriate, ASGCT recommended that the guidance acknowledge this throughout the document and clarify that potency assays, critical in late-stage development/pivotal trials, may not be possible early in clinical development due to assay complexity/variability, small sample sizes (difficult to reach statistical significance), and/or lack of mechanistic understanding. Examples of places within the draft where phase appropriate language is essential are Section IV.C (Gaining Product and Process Understanding), IV.D (Risk Assessment), and IV. F (Control Strategy). 

2. Number/Type of Assays – ASGCT recommended a risk-based approach which includes the development of one robust in vitro potency assay addressing the main mechanism of action of the final drug product for product release. The Society suggested that additional measures of potency throughout development and manufacturing should be implemented as characterization assays providing qualitative information, rather than requiring release testing with "acceptance criteria". ASGCT also recommended providing expectations for the type or types of potency tests for classes of therapeutic products such as CAR-Ts (individual product CMC data including potency tests are proprietary, but when large numbers of products in a class exist, generalized information about acceptable potency assays could be shared by the Agency). Additionally, there are potential unintended consequences for patients as additional testing ultimately leads to less product for patient dosing.  

3. Integration with Existing Standards – ASGCT recommended that the potency assurance strategy not add additional complexity and requirements to already existing quality risk management system ICH Q9 (R1), manufacturing change plans, and product control strategies. The additional documentation and analysis specific to potency assurance creates a significant burden on sponsors, which is largely redundant to existing quality expectations.  

Potency assays are a key part of product development. ASGCT believes that addressing the overarching concerns with FDA’s outlined potency assurance strategy through these comments will enhance the value of the final guidance document to assist CGT product developers as they address product potency. For more information on ASGCT’s specific comments, read the letter here. 

Margarita is ASGCT's Director of Policy and Advocacy.

Related Articles