FDA releases draft guidelines on genome editing and CAR-T therapies
The US Food and Drug Administration (FDA) has issued draft guidance on the development of gene therapy products that incorporate genome editing of somatic cells and chimeric antigen receptor (CAR) T-cell products. The two draft guidance documents discuss the incorporation of genome editing and CAR-T product development.
Within the draft on human gene cell therapy products, FDA makes recommendations on information that should be included within an application for an investigational new drug (IND). This includes information on component design, manufacture and testing, product manufacture and testing, and preclinical and clinical studies. The classification of the drug status of these products was also clarified, whereby in vivo administration of DNA, RNA and/or protein via nanoparticles are considered to be active pharmaceutical or drug substances.
“FDA evaluates human [genome editing] products using a science-based approach weighing the benefits and risks of each product,” the agency wrote. “The benefit-risk profile for each product depends on the proposed indication and patient population, the extent and duration of therapeutic benefit achieved, and the availability of alternative therapeutic options. Some of the specific risks associated with [genome editing] approaches include off-target editing, unintended consequences of on- and off-target editing, and the unknown long-term effects of on- and off-target editing.”
Further recommendation for product sponsors is also included within the draft guidance: “We recommend sponsors optimize the [genome editing] components to reduce the potential for off-target genome modification, to the extent possible”.
In the CAR-T draft guidance document, FDA offers insight on chemistry, manufacturing and control (CMC) elements; pharmacology and toxicology; clinical study design and specific recommendations for autologous and allogeneic CAR-T products. In the document, they stated: “The emphasis for CMC in all phases of development is product safety and manufacturing control. We recommend that CAR T cells be developed following a life cycle approach where information may be gathered over the course of product development and submitted in a stage-appropriate manner.”
FDA also noted that sponsors will change the CAR-T design and manufacturing process or manufacturing facility during development, or after approval. However, if changes result in the transition from an autologous to allogenic product, this would generally mandate a new IND application. Any changes made will be assessed on a case-by-case basis and should be communicated with the agency through an IND amendment requesting advice or a formal meeting request.
Final considerations within the guidelines outlines for preclinical and early-phase clinical studies. For preclinical testing, the considerations mentioned include vector and cellular component of CAR-T and testing that may be required for modified CAR-T cells. The early-phase clinical development of CAR-T cells in cancer patients is highlighted also, whereby considerations include safety, determination of optimal dosage, pharmacokinetic/pharmacodynamic studies, evaluation of efficacy, and selection of an appropriate population for future clinical studies.
