The FDA’s Center for Biologics Evaluation and Research (CBER) plans to finalize a guidance document in 2022 focused on recommendations for companies studying multiple versions of a cellular or gene therapy product in early-stage clinical trials, the center announced today.
- Early in the clinical development process, companies may still be trying to determine which of several products should be advanced into later-stage testing. To do this, some companies will test multiple iterations of a product, either as part of one trial or a series of trials.
- This approach can be especially helpful for developers of cell and gene therapy products (CGTs), where a sponsor may not be sure which vector to use to administer the product, for example, or which exact transgene to use.
- But this approach also raises an important regulatory question: If sponsors of CGT products want to test multiple versions of the product, how should they comply with FDA regulations? Could they test all products under the same Investigational New Drug Application (IND), or would they need to submit multiple INDs covering each respective product?
FDA’s existing guidance
- According to a draft guidance document issued in September 2021 by the FDA, multiple versions of a product can be studied in one trial, but each product version requires its own IND. Developers of CGT products may want to investigate several versions of their potential product in one trial to save time and cost of initiating several trials. Although one clinical protocol and one control arm may be sufficient for this type of trial, a separate IND is needed for each CGT version since each product may have subtle differences and a different development history.
- What does the FDA mean by “different versions” of a cellular or gene therapy product? Changes to a CGT product that would result in a “new version” could include changing from bulk tumor-infiltrating lymphocytes to a purified CD8+ subpopulation, changing the transgene, or adding a transgene and changing the promotor, enhancer or another control element in a gene therapy expressing the same transgene. It is important that any change still addresses the same disease to fall within this guidance. Manufacturing process changes and optimizations (e.g., change from serum-containing to serum free media, scaling up, or adding new manufacturing sites) will not generally result in a product characteristic changes sufficient to create new versions.
- Rather than focus on traditional clinical studies, the FDA’s guidance focuses on a type of clinical trial known as an “umbrella trial” in which multiple products are compared head-to-head against the same control group and disease. Umbrella trials are used to evaluate multiple potential drug candidates, with the aim of determining which of the products are most effective or safe. The guidance only addresses early-phase trials to provide safety and preliminary activity information for all versions. The selected promising candidates will then need to be studied in further later phase studies.
- Studying multiple versions of cellular or gene therapy products in parallel could expedite early clinical development. This parallel trial design is sometimes more efficient than similar iterative approaches since it can reduce the time needed to conduct subsequent studies. According to the FDA’s draft guidance document, “this trial design may facilitate sharing of the control group, potentially facilitating investigator participation and subject enrollment, and may simplify study management, relative to conducting a separate clinical trial for each product version.”
- The point of these early-phase studies is not to establish evidence of effectiveness for marketing authorization applications. Rather, the studies addressed in the guidance only support the selection of the most promising candidates for further study. They are “generally are not adequately powered to demonstrate a statistically significant difference in efficacy between the study arms,” the FDA explains in its guidance.
- While the products are different and require separate INDs, sponsors won’t need to completely duplicate efforts, according to the FDA. The guidance explains how sponsors can cross-reference information about related product versions between a primary IND and secondary INDs.
- [ Read AgencyIQ’s comprehensive analysis of FDA’s draft guidance document from September 2021 here.]
While CBER published the draft guidance in September 2021, there was no mention of plans for a final document in its guidance agenda for 2022.
- CBER publishes a guidance agenda every calendar year to inform the public of all the guidance documents (both draft and final) that it plans to publish that year. This document is typically updated throughout the year as appropriate. Compared with other FDA centers, CBER is especially diligent in updating its agenda – and in following through with publishing most of the documents it says it will publish.
- When CBER published its guidance agenda in January 2022, there was no mention of the multiple versions guidance. CBER also updated its guidance agenda in May 2022, which also lacked any mention of the guidance.
Now, in an updated guidance agenda, CBER says it plans to release a final version of the guidance in the latter half of this year.
- The latest guidance agenda, updated on June 22, 2022, includes the guidance as part of the “tissues and advanced therapies” section. It is the only guidance document that was added or changed in the latest update.
- The final guidance is likely to reflect several changes asked for by industry during a comment period that closed in December 2021. Among the many issues raised in comments: How does the FDA define an early-stage study? How might studies evolve over time? Should clinical holds apply to all trial arms, or just a few? (Alliance for Regenerative Medicine) Will this approach have an effect on the difficulty of obtaining FDA assent to proceed with an IND? How will safety data from each individual arm be considered for collective purposes? (International Society for Cell & Gene Therapy) When is the best time to discuss clinical plans for such a study with the FDA? Are there ways to reduce duplication when cross-referencing the Primary and Secondary INDs? At what point might the addition of further trial arms be detrimental to the study? (American Society of Gene & Cell Therapy) Could the FDA expand the scope of the guidance to basket trials in addition to the umbrella trials it now supports? Can data obtained from studies that are not pursued for development support the development of the candidate that is selected to advance? (GSK) What constitutes a “version” of a product, and would it include different vectors from the same viral group or a new CAR transgene targeting a different antigen? What types of safety issues would result in broader clinical holds across the entire “umbrella” of studies? As the study progresses past the initial umbrella approach and into the study of just one or two therapies, will a change in the IND be required, or may it remain the same? Will FDA considered therapies to be “different” if they are respectively made by a sponsor and a contract manufacturer? (PhRMA)
Featuring prior analysis by AgencyIQ’s Kirsten Messmer
To contact the author of this article, please email Alec Gaffney ( [email protected])
To contact the author of this article, please email Kari Oakes ( [email protected])