The U.S. Food and Drug Administration (FDA) recently released its final guidance on umbrella trials of cellular or gene therapies in early-phase clinical trials. The guidance focuses on studying multiple versions of a therapy to treat a single disease.
Umbrella trials are one type of master protocol trial. These trials “have the potential of increasing efficiency in modern drug development,” write Xiaoyun Li and fellow researchers in a 2022 article in Annals of Translational Medicine. Their additional complexity must be managed carefully to maximize benefits while minimizing risks.
The FDA guidance seeks to offer recommendations for performing more effective umbrella trials of cellular and gene therapies. By understanding the nuances of the FDA’s recommendations, CROs can more thoughtfully select eTMF software to support umbrella trial efforts.
FDA Guidance Regarding Umbrella Trials for Gene Therapies
Most clinical trials evaluate a single version of a single product to treat a single condition. Umbrella trials, on the other hand, evaluate multiple versions of one product simultaneously to see how the versions differ in their treatment of a single condition, writes Ferdous Al-Faruque in Regulatory Focus. Examining multiple versions of a cellular or gene therapy in one clinical trial setting for their effect on one condition can be more efficient than setting up a separate trial for each version.
In its introduction to its final guidance document released in November 2022, the FDA explains that its guidance focuses on the early phases of clinical trial research for cellular and gene therapies. The guidance seeks to help researchers gather “preliminary evidence of safety and activity” by examining multiple versions of a product at the same time.
The guidance applies to trials in which “two or more versions of a cellular or gene therapy product would be studied for one specific disease using just one trial design, shared infrastructure, and a master protocol,” writes Kari Oakes in Regulatory Focus. Each version has its own investigational new drug application, but the applications may cross-reference each other — making consistency in shared data essential.
By studying multiple versions of a therapy at the same time, clinical trial teams can compare versions more effectively. Researchers can identify which version is most likely to provide maximum benefit to patients and devote resources to developing that version, rather than pursuing a version that ultimately turns out to be fruitless, writes Tim Sandle in a guest column in Clinical Leader.
The FDA’s Guidance: Insights for CROs
Cellular and gene therapy research “is at a significant turning point,” notes Amy Raymond in Applied Clinical Trials. The FDA estimates that 10 to 20 new cellular and gene therapy trials will be approved per year as early as 2025. To take advantage of this change, CROs will need to adhere to the FDA’s guidance — which means rethinking their approach to clinical trials.
In its guidance document, the FDA provides recommendations on several topics, including:
- How to organize and structure investigational new drug applications (INDs) for each version of a cellular or gene therapy under study.
- How to submit new information related to one or more versions of the therapy under study.
- How to report adverse events related to one or more versions of therapy.
Rethinking the approach to INDs is essential, writes Raymond. The FDA guidance recommends that sponsors request both primary and secondary IND numbers for umbrella trials in advance. This means deciding in advance which versions of a treatment will be studied and how the study will be structured. Similarly, clinical holds should be seen not as hindrances but as necessary safeguards.
The FDA noted several potential benefits to umbrella trials for gene therapies. One is the ability to share control groups, which may help clinical trial teams reduce enrollment burdens.
Umbrella trials for cellular and gene therapies can also pose challenges, writes Vann Parker in Precision for Medicine. Potential risks include:
- Delays in disseminating safety information that may lead to dangerous consequences.
- Risks of exposing participants to doses that are too low or too high.
- Including more participants than a single trial, which potentially exposes more participants to side effects and other potential issues.
- Increased chances of misinterpreting preliminary results when multiple treatments are studied at the same time.
The FDA’s guidance seeks to help clinical trial teams manage or reduce these risks with more focused and clear study requirements and protocols. Thus, while the FDA seeks to provide guidance for umbrella trials, its guidance has limits. The FDA notes that its guidance document does not apply to:
- Studies that aim to gather evidence of effectiveness to support a marketing application.
- Studies that fall outside the scope described in the document.
- Basket trials, which study a single therapy applied to different populations.
The FDA recommends that sponsors who want to conduct these studies speak to CBER and request a pre-IND meeting to talk about clinical trial design options. Also, the FDA notes that the umbrella studies discussed in its guidance are not sufficient to demonstrate statistically significant differences in efficacy among versions of a cellular or gene therapy.
As new trial designs become feasible, new tools are needed to ensure the efficient and accurate execution of these trials, says Vivek Subbiah in an article in Nature Medicine. Choosing the right software can help CROs build umbrella trials that provide the complete, accurate data necessary to meet regulatory requirements and provide a clear understanding of how different versions of a therapy may perform.
Choosing Software to Align Umbrella Trials With FDA Guidance
Umbrella trials offer significant opportunities to bring new cellular and gene therapies to market more efficiently and to produce more effective treatments. Yet high quality design and reporting in umbrella trials is essential to maximize their benefits, write Luke O. Ouma and fellow researchers in a 2022 article in Frontiers in Medicine.
One primary goal of the FDA’s guidance is to offer clarity in setting up and cross-referencing INDs for multiple versions of the same therapy. Choosing robust eTMF software, like Anju’s eTMF Master solution, can make it easier to make sure shared information is consistent across documents generated in an umbrella trial. An eTMF with automated data options, for example, can ensure that information is the same across documents when necessary — eliminating the risk of errors mistakenly introduced during manual data entry.
The right eTMF can even help clinical trial teams whose studies span both the U.S. and the EU. Although terminology in cell and gene therapy studies differs between the two regions, the steps required to create a complete marketing application are the same, writes Michael Cooper, a senior consultant at NDA.
The FDA’s guidance offers recommendations, not requirements. These recommendations are the result of intensive study. They represent the agency’s attempt to offer recommended best practices to CROs and others involved in the design and execution of umbrella studies of gene therapies.
By understanding the FDA’s information and recommendations, CROs can make software choices that align with these identified best practices. By doing so, CROs equip their clinical trial researchers, Medical Affairs teams, and other involved parties with the tools they need to carry out more effective studies and produce deeper insights.
In search of the ideal software systems to accelerate the execution and management of their clinical trials, CROs can rely on Anju’s partnership program to leverage our clinical data management experience and best-of-class eClinical solutions.
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