FDA finalizes umbrella trial guidance for cell and gene therapies

The US Food and Drug Administration (FDA) laid out its recommendations for sponsors to study multiple versions of a cellular or gene therapy in a clinical trial for a single disease. The agency said its final guidance should help sponsors conduct umbrella trials of similar products for the same disease more efficiently to bring cell and gene therapies to market sooner.

While clinical trials typically evaluate a single product, umbrella trials use a single-trial infrastructure, design and master protocol to simultaneously evaluate multiple products for a disease or condition, which can be more efficient. (RELATED: For gene therapies, FDA drafts trial guidance, finalizes "sameness" for orphan exclusivity, Regulatory Focus 30 September 2022)

“Sponsors have expressed interest in gathering preliminary evidence of safety and activity using multiple versions of a cellular or gene therapy product in a single clinical trial,” FDA said. “Although multiple versions of a product can be studied together in a single clinical trial, each version of the product is distinct and is generally submitted to FDA in a separate investigational new drug application (IND). The objective of these early-phase clinical studies is to guide which version(s) of the product to pursue for further development in later-phase studies.”

The agency noted that early-phase studies are not meant to provide primary evidence of effectiveness to support a marketing application and are not sufficient to show statistically significant differences in efficacy between the study arms. However, they can be used to evaluate multiple versions of the therapies a sponsor is developing to better understand how to organize and structure the INDs, submit new information and report adverse events, which FDA said should help sponsors identify the most promising therapies for a particular disease.

“The potential benefits of this type of umbrella trial include flexibility and efficiency in product development,” said FDA. “Instead of an iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which may streamline early clinical development by expeditiously identifying alternative versions of a product that may be safer or more effective.”

The agency said such comparisons should be achieved by randomization between the study arms, if doable. It also notes that umbrella trials may allow sharing of the control group between the study arms, which may help alleviate enrollment issues and could simplify the study.

FDA stressed that the guidance only applies to early-phase studies of multiple versions of a cellular or gene therapy product being studied in a single disease. If sponsors want to apply the same type of umbrella trials to other types of products, they should speak with CBER first.

“This guidance applies to studies where the IND sponsor is responsible for manufacturing all versions of the cellular or gene therapy product (either directly or through a contract manufacturer) and the IND sponsor is able to provide the required chemistry, manufacturing, and controls (CMC) and pharmacology/toxicology (P/T) information for those products either in the IND submissions or through cross-reference,” the agency added. “Situations where the IND sponsor does not have complete access to proprietary information for those products being studied raise additional considerations beyond those described in this guidance.”

FDA also emphasized that the guidance does not apply to trials conducted outside the narrow scope of umbrella trials discussed in the document by the agency and noted that the guidance does not apply to basket trials, in which a single therapy is tested in different populations. If a sponsor is interested in conducting such studies, the agency says they should talk to CBER and request a pre-IND meeting to discuss potential clinical trial designs.

The guidance addresses how sponsors can submit information in their INDs about the umbrella trials, add additional study arms, addresses clinical holds, submitting safety reports and how to complete study arms.

“For a single clinical study of different versions of an investigational product where each version is submitted in a separate IND, it may be challenging to determine how to structure and organize the INDs, and how to submit changes or new information as the study progresses,” said FDA. “The framework described here is intended to provide clarity on these topics and, as feasible, to minimize submission of the same information to multiple INDs by facilitating cross-referencing to shared information in the INDs.”

FDA finalizes umbrella trial guidance for cell and gene therapies

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