North America Legal and Regulatory Affairs
Mo Heidaran, PhD
Head of Translational and Regulatory Strategy,
Joseph (Yossi) Schwartz, MD, MPH
Professor of Pathology, Molecular and Cell Based Medicine,
Mount Sinai Health System
The Watchdog Focus:
The FDA had recently released a draft guidance on studying multiple versions of cell and gene therapy (CGT) products. The guidance outlines regulatory considerations for INDs that study multiple versions of a CGT product in a single trial.
Important general notes regarding this guidance:
- It applies to early-phase clinical trials of CGT products only.
- It is not applicable to vaccines intended to prevent infectious diseases, bacteriophage/live biotherapeutic/fecal microbiota for transplantation products, or allergenic products.
- It provides the FDA’s current thoughts on using a master protocol to evaluate different versions of a CGT product for a specific indication. However, sufficient characterization of CMC and safety/bioactivity is still required for a given version of a product prior to studying it in patients.
- Lastly, it is not applicable to trials that study one product for multiple indications.
- The guidance focuses on clinical studies, in which multiple versions of a CGT product are investigated as therapeutics for a single disease indication (‘umbrella trial’).
- Separate versus single IND: This guidance reinforces the FDA’s long time stance which considers different iterations to be distinct products; thus, requiring separate INDs.
- Primary and Secondary INDs: It is 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 CGT 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 would increase efficiency for the 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.
- Study hold:
- If entire study is on clinical hold: then allINDs (primary and secondary) will also be placed on clinical hold, or if applicable partial clinical hold, as per 21 CFR 312.42(a).
- Partial hold: If only one of the study arms (e.g. specific Product B arm) is on hold, then the primary IND (e.g., for a three-arm study in which Products A, B, and C are being studied) will be placed on partial hold (i.e., the Product B study arm will be on hold), and the relevant secondary INDs (i.e., the IND for Product B) will be placed on clinical hold.
- Hold removal: Sponsors will need to submit detailed information addressing all the hold comments; however, a detailed response to clinical hold will not be needed for all the INDs. For example, if a primary IND is placed on partial hold due to CMC issues related to a product that is the subject of a secondary IND, the sponsor should submit the response to hold to the secondary IND, and the primary IND can cross-reference the information from the response to hold submitted to the Secondary IND.
- Safety reporting: Safety reports are required for all INDs relevant to the product for which the hold issue was identified. Thus, 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. 21 CFR 312.32 apply.
This FDA’s draft guidance provides advice on organizing primary and secondary INDs for multiple versions of a CGT product studied under an umbrella trial master protocol. While the proposed approach promotes efficiency in clinical development (e.g., using a common control group), the requirements for adequate characterization of CMC and non-clinical evidence of safety/bioactivity for different product iterations are upheld. Other options for organizing primary and secondary INDs may be acceptable, it would be advisable for the sponsor to discuss any alternative strategies with the FDA to achieve the best pathway for a specific clinical trial.
This report includes links to issues and activities that might be of interest both on the Health Canada as well as the FDA websites. Please note that you can follow HC and FDA on Facebook and Twitter. You can also subscribe to receive emails from the FDA at https://www.fda.gov/about-fda/contact-fda/get-email-updates
What’s new in Biologics, radiopharmaceuticals and genetic therapies can be found at: https://www.canada.ca/en/health-canada/services/drugs-health-products/biologics-radio-pharmaceuticals-genetic-therapies/what-new-biologics-radiopharmaceuticals-genetic-therapies-health-canada.html
Information for health product manufacturers and distributors in relation to COVID-19: https://www.canada.ca/en/health-canada/services/drugs-health-products/covid19-industry.html
What’s new for Biologics including Approval and Determination Letters:
COVID-19 Information and Resources:
Updated Approvals and Listings:
Complete List of Licensed Products and Establishments
Complete List of Substantially Equivalent 510(k) Device Applications
Complete List of Currently Approved Premarket Approvals (PMAs)
Complete List of Currently Approved NDA and ANDA Application Submissions
2021 Biological Approvals