Navigating the landscape of cell and gene therapy development: Insights from the FDA’s new FAQ

The U.S. Food and Drug Administration (FDA) recently released a draft guidance titled “Frequently Asked Questions — Developing Potential Cellular and Gene Therapy Products.” This 40-page document, while not legally binding, offers insights into best practices for common questions received by the Office of Therapeutic Products (OTP). While each question is answered in brief, the document includes nearly 40 references to other FDA content, indicating that further research is needed for a deeper understanding. This summary highlights key points from the draft and underscores the importance of the agency’s efforts in addressing these questions.

Maximize engagement

Effective interactions with regulators are crucial during drug development, particularly in the innovative and ever-changing cell and gene therapy (CGT) field. The FAQ outlines key meeting types, their differences, and when to schedule them. Type D meetings, for instance, are informal and focus on scientific issues, regulatory policies, or product development strategies. The agency advises that discussions be limited to two topics across a maximum of three disciplines, concentrating on critical issues rather than an entire development strategy. A type D meeting allows for rapid feedback on new development ideas without detailed analysis. A somewhat similar consultation is an INTERACT meeting, designed to facilitate early dialogue between sponsors and FDA regulators that enables prompt decision-making. Both meeting types are designed to give sponsors rapid feedback on specific topics. The initial FDA meetings are crucial for CGTs and having an experienced team member involved can significantly enhance the chances of success.

Ensuring quality and safety

The agency outlines screening and testing requirements for allogeneic donor material, as fully described in 21 CFR §§ 1271.50, 1271.75, 1271.80, and 1271.85. Properly screening donors for medical risk factors and communicable disease is not only crucial for donor and recipient safety but will directly affect the quality of the donated tissue and may have significant impact on critical attribute assessment during manufacturing. It was pointed out that screening requirements under the referenced regulation is not necessary for autologous drugs. The donor requirements—like medical history to ensure tissue or cells can be safely collected, and donor testing and screening for infectious agents—are relevant for allogeneic therapies to negate the transmission of disease and ensure donor safety. 

While FDA does indicate that screening requirements under the regulation are not required for autologous products, the package inserts of some approved CGTs do indicate that patient screening should be performed for certain infectious agents like CMV, HBV, and HCV. This ensures patient safety and protects against risking viral reactivation from latency or a quiescent state if the patient’s immune system is compromised during treatment. Determining screening requirements is a necessary step from clinical study design through assembling a Biologics License Application (BLA) and should be carefully considered. Leveraging expert advice can help ensure patient safety and product efficacy.

In Chemistry, Manufacturing, and Controls (CMC), it is crucial to differentiate between characterization testing and release testing. Characterization testing defines the identity, quality, and biological properties of a cell or gene therapy product, providing insights into its mechanism of action, purity, and stability. An effective characterization strategy is vital for supporting development and regulatory submissions. A “characterization assay” for a BLA provides detailed information about a biological product’s structure and composition. In contrast, “assay validation” ensures that the method used to evaluate the BLA is reliable and accurate. A “release assay” assesses the quality attributes of a drug product—pharmaceutical or biological—before its release, confirming that it meets specifications for purity, potency, and identity. This critical step in quality control ensures the product’s safety and efficacy. Release assays are regulated by agencies like the FDA and must follow Good Manufacturing Practice (GMP) guidelines1,2.

Critical Quality Attributes (CQAs) related to safety, purity, identity, quantity, potency, and stability are essential for both biological products and CGTs. The principles of CMC inform the development of analytical strategies for these CQAs. With CAR T-cells, as an example, the vector copy number is assessed, which correlates to efficacy and reveals consistency in manufacturing. In general, the strategies for evaluating product purity depend on the product and process, highlighting CQAs related to quantity and potency. AAV-based gene therapies, for example, may use digital droplet PCR and ELISA to quantify genomic and capsid titers, while flow cytometry may measure cell quantity and viability for a cell-based therapy. Final product testing requires specific assessments, such as evaluating replication-competence when using viral vectors.

To address these challenges, researchers and manufacturers are developing new analytical techniques, utilizing advanced cell characterization methods, and working with regulatory agencies to establish clear guidelines for monitoring CQAs in CGT products. While these therapies have complex biological activities and varied mechanisms of action, similar potency assessment strategies are often used. However, for more complex cell therapy products, a single assay may not suffice. Instead, multiple complementary assays are typically developed to measure different attributes related to potency.

From bench to bedside

The agency highlights key differences in preclinical and clinical research. While drug developers focus on human physiology, animal studies can be included in evidence packages, but they must consider anatomical and physiological differences between species that may affect therapy delivery and target sites. The agency recognizes that suitable animal disease models may not always be available, so alternative methods like in vitro or in silico studies are recommended. In the field of CGT, in vivo models are essential for preclinical studies, enabling researchers to assess the efficacy and safety of therapies within living organisms. Researchers create animal models that closely mimic human diseases to study disease progression and test therapeutic interventions. They evaluate various viral and non-viral delivery methods to ensure efficient gene delivery to target tissues while assessing tissue tropism and expression levels. Important information includes safety assessments, biodistribution studies, and viral shedding studies for CGT products. Studies using disease models and safety models are often paired with pharmacokinetic (PK) or biomarker studies, as well as biodistribution and viral shedding assessments, particularly when the tested CGT products are AAV or viral vector-based.

Finally, there is a need for extensive long-term follow-up for CGTs, sometimes up to 15 years, especially for gene therapies that may integrate into the genome. Long-term studies are also important in animal studies, but the follow-up duration and monitoring focus may differ based on the study design and objectives. Monitoring animal health and conducting tissue analyses are essential for identifying adverse effects of CGT products. Tracking the distribution of therapeutic cells also assesses treatment effectiveness and potential off-target effects. These animal models provide valuable insights into disease progression and delivery mechanisms before clinical trials begin. They inform actions and inspire advancements in preserving the natural world: the connection between animal models and human studies is mutually beneficial, enhancing our understanding of biology and behavior. This model helps develop preventative measures, diagnostic targets, treatment strategies, and potential cures for devastating diseases.

Collaboration is key to success

The FDA’s draft guidance on developing potential cellular and gene therapy products is crucial as it provides valuable insights and best practices for navigating the complex and evolving landscape of CGT development, underscoring the necessity of collaborating with experts to effectively address the myriad challenges presented throughout the entire process.

Louis Cicchini, Ph.D., is director of scientific affairs, cell & gene therapy at Cencora, and Cori Gorman, Ph.D., is senior director of biopharmaceutical CMC and regulatory affairs at PharmaLex (a part of Cencora).