Stakeholders seek clarity on FDA cell and gene therapy draft guidance

Regulatory NewsRegulatory News | 13 January 2022 |  By 

Industry, medical societies and other stakeholders have weighed in on draft guidance from the US Food and Drug Administration (FDA) detailing how sponsors that want to study multiple versions of cell and gene therapies could combine them in a single “umbrella” trial.
The draft guidance, released in September 2021, outlined FDA’s proposed thinking for how this process would work. For cell and gene therapies intended to treat a single disease, sponsors would typically submit separate investigational new drug (IND) applications, but these INDs could cross-reference one another, and the therapies could be evaluated within the same early phase clinical trial, the agency said. (RELATED: For gene therapies, FDA drafts trial guidance, finalizes ‘sameness’ for orphan exclusivity, Regulatory Focus 30 September 2021)
“The potential benefits of this type of umbrella trial include flexibility and efficiency in product development. Instead of an iterative approach to clinical studies, multiple versions of a cellular or gene therapy product can be studied in parallel, which may expedite early clinical development by expeditiously identifying alternative versions of a product that may be safer or more effective,” FDA wrote in the draft guidance.
General comments
Overall, stakeholders who commented on the draft guidance applauded the agency for its efforts to make the development pipeline for cell and gene therapies more flexible and efficient. The non-profit Biocom California largely agreed with FDA’s draft guidance and noted the framework “will be particularly helpful for sponsors in the oncology space.”
Some stakeholders offered general comments on FDA’s draft guidance. Biotechnology company Transgene SA suggested FDA add more examples to FDA’s list of cell and gene therapy versions in the appendix of the draft guidance.
In their comment, the advocacy group Alliance for Regenerative Medicine (ARM) asked for more detail on what FDA considered an early-phase trial and a single disease under the framework and questioned why a basket trial was deemed as out of scope for the guidance. “We recommend the Agency clarify whether an umbrella trial could include studying multiple versions of a product of a cell or gene therapy in a basket trial studying multiple cancer populations,” ARM wrote.
The Pharmaceutical Research and Manufacturers of America (PhRMA) commented that the current framework of an umbrella trial “provides an overly narrow scope” for the process outlined in the draft guidance.
“Particularly in the field of cell and gene therapy, the ability to study multiple versions and/or multiple populations would result in significant development efficiencies,” they wrote. “PhRMA believes that the IND structure outlined in the draft guidance should be broadly applicable to clinical trial designs for cell and gene therapy products in early stages of clinical development and requests that the Agency consider expanding the scope of this guidance to facilitate use of these alternative approaches.”
GSK, which contributed to a comment made by PhRMA but also wrote to FDA separately, advocated for including basket studies, the need for more clarify from the agency on the parent-child IND approach and the use of targeted safety actions for multiple versions of therapies.
The International Society for Cell & Gene Therapy (ISCT) suggested in their comment that a risk assessment be required for cell and gene therapy (CGT) products to determine whether the product fits this or other guidances released by FDA, such as “Considerations for the Design of Early-Phase Clinical Trials of Cellular and Gene Therapy Products” or “Establishment and Operation of Clinical Trial Data Monitoring Committees.”
“Before undertaking a study of multiple versions of a CGT product, the data monitoring arrangements should be assessed to ensure they are appropriate for all versions of the CGT products envisaged and enhanced if warranted,” ISCT wrote. “In evaluating this, the expertise and independence of monitors to assess the impact of the changes on patient safety should be considered.”
ISCT also questioned whether the draft guidance would affect the difficulty of seeking IND approval of these CGT products.
When do changes become a new version of a product?
Most stakeholders wrote to FDA wanting more details and direction for clinical trials and specific cell and gene therapy product changes. ARM asked FDA for more guidance on when manufacturing changes across multiple products would be considered a process improvement as opposed to a new version of a product.
“While the examples provided in the Appendix are helpful, they focus on minor process changes and do not speak to the extent to which the underlying manufacturing processes could be changed. One could conceive of process changes that might exceed those described and would be considered by the Agency to result in a new version of the product,” they wrote.
PhRMA also raised this concern, and requested the agency clarify whether specific instances, such as changing the viral vector in a therapy to one from the same viral group or adding a new chimeric antigen receptor (CAR) transgene, would result in FDA considering the therapy a new version.
Additionally, PhRMA asked the FDA how they would apply safety issues to cell and gene products that fall under this purview. “PhRMA recommends that FDA set forth its thinking regarding how individual differences in versions may impact the decision-making process for safety reports or clinical holds for different versions of the same product,” they wrote.
Members of a review group from the biopharmaceutical collaboration group BioPhorum noted that FDA should include examples of what would not be considered a change that would differentiate a product as a new version. “The examples provided in the Appendix involve determinations based on differences in mechanism, source of cells, subset of cells etc., but the review group consider that the principles are unclear and therefore the utility of the guidance limited, as in each case FDA interaction would be required,” they said.
The American Society of Gene & Cell Therapy (ASGCT) wrote to FDA and recommended the agency allow discussions of what constitutes multiple products at either a pre-IND stage or INTERACT meeting, as “the pre-IND meeting is ideally preserved for discussing the detailed plans, and not solely the conceptual approach.”
How do versions progress to later trial phases?
Both ARM and PhRMA raised questions about what needs to occur when cell and gene therapy products with multiple versions advance to later clinical trial phases.
ARM sought clarify on if the umbrella trial is allowed to continue if a lead candidate is advanced and is the primary IND. “When one version of a product is advanced to later-phase studies this should not preclude the sponsor from continuing the umbrella trial for the other versions,” they said.
“[T]he Agency outlines the procedure for submitting a Phase 3 protocol to a specific IND but does not provide additional clarity on whether the resulting IND structure needs to change,” PhRMA noted. “[A]s individual versions progress to later-stage clinical trials, it would be helpful for the Agency to confirm that new potential versions can be added to the original primary and secondary IND structure and clarify if this would necessitate a change in the IND structure.”
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