FDA GUIDANCE DOCUMENT: Potency Tests for Cellular and Gene Therapy Products

This 2011 final guidance (still in effect) provides recommendations for developing, implementing, and validating potency assays for cellular and gene therapy (CGT) products. "Potency Assurance for Cellular and Gene Therapy Products" introduces a completely new regulatory framework (the Potency Assurance Strategy) and is intended to replace the 2011 guidance. Potency, a measure of a product's biological activity, is a critical quality attribute that must be quantified to ensure product consistency and clinical effectiveness. The guidance emphasizes a phase-appropriate approach, where the potency assay strategy evolves from early-phase characterization to a fully validated, quantitative assay required for product license.

This guidance applies to a broad range of products, including somatic cell therapies, gene therapies, therapeutic vaccines, and combination products.

• Core Principle (Mechanism of Action): The potency assay must measure the product's specific ability to effect its intended result. Therefore, the assay should be based on the product's therapeutic Mechanism of Action (MOA). If the MOA is complex or multifactorial, a combination of assays may be necessary.
• Phase-Appropriate Development: The expectations for a potency assay evolve with clinical development:
  • Early-Phase (IND/Phase 1): Sponsors must establish a biologically relevant assay to measure potency. This assay may not be fully validated, but it must be scientifically sound and provide a quantitative readout. An "assay matrix" approach is often acceptable.
  • Late-Phase (Phase 3/BLA): A single, quantitative, validated potency assay is generally expected generally expected, though for products with complex or multifactorial MOAs, a validated assay matrix may be acceptable at licensure. This assay must be robust, reproducible, and have acceptance criteria justified by manufacturing experience and, ideally, correlated with clinical data.
• The "Assay Matrix" Approach: For complex products with multiple biological activities, a single assay may not be sufficient to measure potency. The guidance allows for an assay matrix, which consists of multiple individual assays that collectively assess the product's quality and activity (e.g., cell viability, transgene expression, cytokine secretion, target cell killing).
• Characteristics of a Suitable Potency Assay: The assay should be:
  • Quantitative, with appropriate standards and controls.
  • Based on a relevant biological function of the product.
  • Able to detect changes in product quality resulting from manufacturing changes.
  • Validated for its intended purpose, demonstrating demonstrating accuracy, precision, specificity, linearity, range, and robustness.
• Reference Standards: The development and use of a qualified reference standard is critical for ensuring the consistency and accuracy of the potency assay over the product's lifecycle. And sponsors must establish procedures for requalification and bridging when new reference standards are introduced