FDA Guidance Offers New Flexibility to Biotechs in Cell and Gene Therapy

The Food and Drug Administration (FDA) recently released new guidance regarding cellular and gene therapy products, one of which may significantly impact early-phase clinical trials of such products.

This guidance particularly addresses biotech companies’ interest in “umbrella” trials—trials designed to evaluate multiple investigational drugs administered as single drugs or as combination drugs in a single disease population. In addition, the guidance document includes recommendations for organizing and structuring investigational new drugs (INDs), submitting new information, and reporting adverse events (AEs).

This article explores the implications of this guidance, including new approaches for studies focused on cellular or gene therapies.

The Benefits of the Umbrella Trial

There are many potential benefits to the umbrella trial. Most important for sponsors—and a public eagerly awaiting new therapies—is the opportunity to reduce a therapy’s total development and review/approval time to market. For example, instead of taking the traditional iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which might serve to speed the identification of the versions of a product potentially more safe or effective. Randomization between the study arms, where feasible, and sharing of the control group can also add to improved efficiencies.

On Structuring an IND

The new guidance is especially useful for sponsors. The document details the main requirements for organizing and structuring an IND and submitting new information. There are also details on how to capture and report AEs. In all cases, it’s evident the FDA’s interest is in providing sponsors with greater flexibility and improved efficiency in research.

The FDA notes sponsors may find it challenging to determine how to structure and organize INDs for a single clinical study for different versions of an investigational product where each version is submitted in a separate IND, as well as how to submit changes or new information as the study progresses. Accordingly, the new guidance minimizes the need to submit the same information in multiple INDs by facilitating cross-referencing to shared information within the INDs.

To this end, the Agency suggests INDs be distinguished as Primary or Secondary. The Primary IND will include complete clinical information about the umbrella trial. Secondary INDs will not need to repeat this information. Instead, they will focus on information specific to that product version.

When an arm is added to the study, the guidance suggests adding a tertiary IND to represent it.

Regarding the Master Protocol

Of particular importance for biopharma companies are the recommendations for drawing up a master protocol to evaluate different versions of a cell or gene therapy product. The master protocol should focus on both the safety of the product and an assessment of the bioactivity of each version of the product. This is to ensure a sufficient level of scientific and clinical understanding is developed prior to Phase I trials.

An important part of protocol development is identifying and characterizing potential risks primarily due to the concern over adverse events that may not occur until 10-15 years following gene therapy.

Holds and Safety Concerns

According to the guidance, if one arm of a study is placed on hold, the Primary IND must move to a partial hold phase. When such a partial hold is in place, the sponsor must submit to FDA a response to each IND involved.

Safety reports must be created for an investigational product in relation to all sponsor INDs relevant to the product, including all versions of the product.

On Early Phase Trials

FDA noted while early-phase studies are not appropriate for demonstrating efficacy that might support a marketing application or demonstrating statistically significant differences in efficacy between study arms, they may be useful in evaluating multiple versions of the product with an eye to further development in later-phase studies.

The regulatory landscape is complex and perpetually changing. Keeping abreast of it is no easy task. Achieving a detailed understanding of the implications is even more difficult. Sponsors who want to minimize every risk and leverage every advantage are well advised to work with experienced partners who can help them achieve safer, smarter, and faster clinical research.

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