USFDA Guidance: Potency Assessment of Active Immunotherapy Products & FAQ's on Developing Potential Cellular and Gene Therapy Products

Sharan Murugan
58 minutes ago
4 min read

Active immunotherapy products (ACTIMPs) are designed to treat existing diseases or conditions by inducing, stimulating, or modulating immune responses. Because their therapeutic effect depends on the interaction between the product and the immune system, demonstrating and maintaining product potency is an important part of development.

The FDA has issued draft guidance on Potency Assessment of Active Immunotherapy Products, providing recommendations for developing and evaluating potency assays as part of an overall potency assurance strategy. The guidance covers peptide- and protein-based products, vectored products, personalized products, and cell-based products. The FDA's guidance on Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products also provides broader development considerations for cellular and gene therapy products, including product quality, analytical methods, potency, and regulatory interactions.

Why Potency Assessment Is Important

Active immunotherapies are intended to produce an antigen-specific therapeutic effect by activating or modifying the immune system. ACTIMPs may contain peptide or protein antigens, vectors that express antigens, or cells that present or express antigens.

Because the biological activity of an ACTIMP can depend on the patient's immune response, potency assessment can be challenging. This can be particularly complex for personalized products where patient-specific antigens may require product-specific approaches.

The FDA therefore recommends a science- and risk-based approach to developing suitable potency assays.

Regulatory Expectations for Potency

Potency assessment is important for demonstrating that a biological product can perform as intended and that its quality remains consistent.

Potency assays may be used for lot release testing, stability testing, and comparability assessments. For licensed ACTIMPs, the application should contain information demonstrating potency and continued assurance of potency.

For investigational ACTIMPs, the amount of information needed to assure product quality can depend on factors such as the phase of development, duration of the investigation, dosage form, and available product information.

Identifying Potency-Related CQAs

Understanding the mechanism of action (MOA) of an ACTIMP is important for identifying potency-related critical quality attributes (CQAs).

Sponsors should consider information from preclinical or proof-of-concept studies, previous clinical experience, and in vitro cellular or biochemical characterization studies.

Potency-related CQAs should be identified by considering the product's MOA, product characterization data, the relationship between CQAs and biological activity, and data from studies of candidate CQAs.

Approaches for Measuring Potency

The FDA describes different approaches for measuring ACTIMP potency.

Bioassays provide a direct assessment of biological activity by measuring the product's effect on living cells, tissues, or animals. In vitro assays may measure immune responses such as cellular proliferation, cytokine production, or cytotoxicity. In vivo approaches may also be used where appropriate.

Physicochemical assays can be used when established product characteristics are sufficient to assess potency. When a single assay cannot adequately evaluate all relevant potency-related CQAs, multiple complementary assays may be used.

The FDA encourages approaches that replace or reduce animal use whenever possible.

Peptide- and Protein-Based ACTIMPs

For non-personalized products containing defined peptides or proteins, potency assays and the necessary reagents should be developed during product development.

When physicochemical characteristics can adequately demonstrate the ability of the product to produce the intended immune response, these characteristics may be used for potency evaluation.

When physicochemical testing cannot adequately measure biological activity, a bioassay may be needed. This can be particularly relevant for products containing multiple proteins or products where changes in structure may affect antigen processing or presentation.

For products containing different subsets of peptides or proteins in separate vials, potency assessment should consider each vialled subset.

Vectored and Personalized ACTIMPs

Vectored ACTIMPs use systems such as viruses, microbes, DNA, or RNA to deliver sequences that express target antigens.

For these products, potency assessment may include quantitative bioassays that measure protein expression or the immune response associated with the expressed antigen, depending on the product and its mechanism of action.

Personalized ACTIMPs can involve patient-specific epitopes. Developing a separate product-specific bioassay for every patient lot may not always be practical.

In such situations, physicochemical methods may be used to assess relevant potency-related CQAs when supported by appropriate manufacturing controls and scientific justification.

Cell-Based Active Immunotherapy Products

Cell-based ACTIMPs can include living cells, irradiated cells, or cell-derived products used to induce antigen-specific immune responses or modulate immune responses.

For live cell-based ACTIMPs, potency assays should measure an activity of the cellular product that reflects its intended function.

For products expressing known antigens or immunomodulatory molecules, potency-related CQAs can include the expressed antigen or immunomodulator and other relevant characteristics of the cells.

Cell viability is also an important potency-related CQA and should be considered as part of the overall potency assessment.

When different cell populations contribute to product activity, the appropriate approach may depend on whether their contributions are interdependent or independent.

Potency Considerations for Cellular and Gene Therapy Products

The FDA's CGT development guidance highlights potency as an important consideration during development of cellular and gene therapy products.

During early clinical development, sponsors should evaluate product characteristics that may be relevant to clinical performance to help identify and understand CQAs.

Analytical methods used to assess product quality should be appropriate for their intended development stage. For gene therapy products, assays used to determine dose should be qualified before clinical studies begin, with appropriate information supporting assay performance.

Regulatory Interaction During Development

The FDA also describes opportunities for sponsors to obtain feedback during development.

A pre-IND meeting can be used to discuss topics such as nonclinical study design, initial clinical studies, manufacturing and quality controls, and other development considerations.

For later development, a pre-BLA meeting can help sponsors prepare the information, data, and analyses needed for review of a marketing application. These interactions can help identify unresolved issues and discuss the presentation of supporting data.

A Science- and Risk-Based Potency Strategy

The FDA recommendations emphasize that potency assessment should be linked to the product's mechanism of action and relevant potency-related CQAs.

The appropriate approach can differ depending on whether the product is peptide- or protein-based, vectored, personalized, or cell-based. Depending on the product, potency may be assessed using bioassays, physicochemical methods, or multiple complementary approaches.

For cellular and gene therapy products more broadly, analytical methods, CQAs, manufacturing controls, and regulatory interactions are also important parts of development.

Overall, early consideration of potency, appropriate assay development, and continued assessment during development can help sponsors establish that active immunotherapy and cellular or gene therapy products consistently meet their intended quality and potency expectations.