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BY MO HEIDARAN, VP TECHNICAL AND STEVE WINITSKY, VP TECHNICAL, REGULATORY CONSULTING, PAREXEL
The FDA released a draft guidance1 that outlines regulatory considerations for INDs that study multiple versions of a cellular or gene therapy (CGT) product in a single trial. There are some important things to keep in mind about the scope of the draft guidance. Importantly, this draft guidance applies only to early-phase clinical trials of CGT products, and the FDA explicitly states the guidance is not applicable to vaccines intended to prevent infectious diseases, bacteriophage products, live biotherapeutic products, fecal microbiota for transplantation (FMT) products, or allergenic products. The guidance provides the FDA’s best thinking as to how to use a master protocol to evaluate different versions of a CGT product for a specific indication, but it does not lower the bar for needing to sufficiently characterize CMC and safety/bioactivity of a given version of a product prior to studying it in patients. Also, keep in mind this guidance is not applicable to basket trials, which study one product for multiple indications.
Specifically, this guidance focuses on a certain type of clinical study, often referred to as an umbrella trial, where the products are multiple versions of a CGT product being studied as therapeutics for a single disease indication. A central question for this type of development program is whether changes in the product would require a new IND, or issues introduced by the proposed changes can be addressed under an existing IND as amendments. This guidance reinforces FDA’s historical stance that different iterations of a product that the FDA considers to be distinct products should be the subject of separate INDs.
Primary and Secondary INDs
The guidance points out that it’s possible to submit a primary IND that houses the clinical content for a multi-product development program (i.e., a master protocol, informed consent document, and Investigators’ Brochure) for a clinical trial of a specific cell and gene therapy product, with cross-referencing of secondary INDs, which describe the new version(s) of the product that will be studied under the master protocol. This approach can create efficiency primarily in clinical conduct of the study, since an umbrella trial could use a single concurrent control arm as opposed to conducting side-by-side comparisons of treatment versus control if each iteration of the product is studied in a separate clinical trial under different INDs. Any changes to the master protocol should be reported as an amendment to the primary IND, and the secondary INDs can cross-reference that amendment.
It’s important to note that if the FDA places the entire study on clinical hold, then all of the primary and secondary INDs will be also be placed on clinical hold, or if applicable partial clinical hold, as per 212 21 CFR 312.42(a). If only one of the study arms (i.e., an arm in which a specific Product Y) will be placed on hold, then the primary IND (e.g., for a three-arm study in which Products X, Y, and Z are being studied) will be placed on partial hold (i.e., the Product Y study arm will be on hold), and the relevant secondary INDs (i.e., the IND for Product Y) will be placed on clinical hold. To get a clinical hold removed, sponsors need to submit detailed information addressing all of the hold comments; however, the detailed Response to Clinical Hold does not need to be submitted to all of the INDs. For example, if a primary IND is placed on partial hold due to CMC issues related to a product that’s the subject of a secondary IND, the sponsor should submit the Response to Hold to the secondary IND, and the primary IND can just cross-reference the detailed Response to Hold information that was submitted to the Secondary IND.
With regard to safety reporting, sponsors must follow 21 CFR 312.32. Safety reports need to be submitted to all INDs relevant to the product for which the hold issue was identified, so safety reports should be submitted to both the primary IND and any relevant secondary INDs in which the detailed CMC non-clinical information for that product are included. When a safety report has information that’s important to understand the safety of multiple versions of a product, the sponsor needs to submit the safety report to all of the relevant secondary INDs for the different versions of the product (21 CFR 312.32(c)).
Summary and Perspectives
In summary, the FDA’s draft guidance provides advice on organizing primary and secondary INDs for multiple versions of a CGT product that will be studied under an umbrella trial master protocol. Conducting an umbrella trial, as described in the draft guidance, can promote efficiency in clinical development (e.g., through the use of a common control group). However, the FDA’s issuance of the draft guidance is not indicative of the Agency lowering the bar for adequate characterization of CMC and non-clinical evidence of safety/bioactivity for different product iterations. The guidance states that there are other options for organizing primary and secondary INDs that may be acceptable; however, it would be important for the sponsor to discuss any alternative strategies with the FDA.
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1Draft Guidance for Industry: “Studying Multiple Versions of a Cellular or Gene Therapy Product in an Early-Phase Clinical Trial”
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