How to Design a Cell or Gene Therapy Clinical Trial: Advice from the FDA

Advancing new cell and gene therapies (CGTs) from the laboratory into early-phase clinical trials has proven to be a complex task even for experienced investigators. About 20 years ago, the US Food and Drug Administration (FDA) held discussions with representatives from the CGT field on what regulatory approach would best fit such products. Two types of regulation were available: similar to that used for blood banks and similar to that used for small-molecule pharmaceuticals. The pathway eventually chosen by the FDA was originally developed for small-molecule drugs, which do not resemble CGT products. The subsequent attempts to force a square peg into a round hole have been frustrating. For example, maximum-tolerated-dose determination is relatively straightforward when using a small molecule, but for CGT products the considerations are more complex and wide-ranging, and starting doses have often been tiny. Problems such as this have usually required extensive discussions between investigators and the agency's Office of Cell and Gene Therapies.

In an attempt to clarify the factors that should be evaluated during design of a phase I/early phase II CGT trial, the FDA's Center for Biologics Evaluation and Research published a guidance for industry in July 2013 entitled “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products.”¹ This document describes some of the FDA's major concerns relating to trials of CGT products—specifically, the potential for substantial risks due primarily to (i) the possibility of prolonged biological activity, after even a single administration of the product; (ii) the high potential for inducing immunogenicity; and (iii) the need for relatively invasive procedures (sometimes involving devices) for administration of certain types of CGT products. To support the concerns, the guidance cites three publications on severe adverse events that have been reported.^2,3,4

Additional concerns related to gene therapy products focus on the possibility of uncontrolled expression of the delivered gene following integration into the DNA, resulting in interference with normal pathways in the recipient, and the potential for activation or inactivation of neighboring genes, giving rise to benign or malignant tumors. Viral or bacterial shedding is also mentioned as a possible source of transmission to other individuals.

Additional concerns pertaining to cellular therapy products involve possible changes in the cells after administration. These range from alterations in membrane composition to differentiation into undesired cell types. The potential for cell migration to unintended organs is also mentioned.

For gene-modified cell therapy products, both sets of the abovementioned concerns apply. The guidance then discusses how these issues can be considered when designing early-phase clinical trials. It covers factors such as manufacturing considerations, preclinical data packages, trial design, dose selection, monitoring and follow-up, and stopping rules. In each section the FDA describes its particular areas for concern and how these may be addressed in the investigational new drug (IND) application. It also recognizes particular properties of CGT products that clearly differentiate them from small-molecule drugs and how the application can be successfully modified to accommodate these differences.

Many of these concerns are already well known to the CGT community, but the guidance provides a useful and comprehensive listing of these issues, as well as recommendations as to how these can be addressed. Importantly, it provides strategies to deal with areas in which the traditional small-molecule regulatory model does not work for CGT products. Although the guidance information is descriptive rather than prescriptive, some concrete suggestions are included, e.g., advice on incorporating risk–benefit considerations into CGT trial design.

For the new investigator, this guidance provides valuable insight into how the FDA deals with an issue that it believes requires its attention. FDA draft guidance documents such as this one are intended as an initial snapshot of the agency's thinking; they are responses to questions asked by investigators struggling to develop a CGT clinical trial. This guidance includes a useful section on the types of meetings that an investigator can have with the FDA while developing an IND and lists the various topics that are usually discussed at such meetings. It also provides advice on filing an IND and cross-references other guidance documents that are of value (e.g., “Gene-Therapy Clinical Trials—Observing Subjects for Delayed Adverse Events”⁵).

The CGT community is encouraged to submit written or electronic comments on this draft guidance by 22 November 2013. Guidances are often the first step in developing regulations, and it is important that the FDA receive feedback on these documents so that it can evaluate the response to the proposals and consider this information when developing future policies, recommendations, and requirements.