“Learn how to incorporate arms into gene & cell therapy clinical trials, and navigate the FDA IND filing process for regulatory compliance and safety.”
Cell and gene therapy clinical trials are undoubtedly among the most exciting areas of modern medicine, but they also hold the potential for unprecedented therapies for a broad range of diseases and chronic conditions. But the flexible nature of these trials also needs prudent management, especially when it comes to ordering new arms or altering randomization. This article provides greater detail about how arms can be added to clinical trials in the context of cellular and gene therapies, and how changes and new information should then be submitted to regulators.
Introduction:
The rise of cellular and gene therapy has been one of the most significant advancements in medical research, opening up an exciting new realm of curative possibilities for a range of diseases. This novel class of therapies harnesses the potential of genetic and cellular engineering to tackle the underlying causative factors for a diverse array of debilitating diseases. The field of cellular and gene therapies is rapidly growing, and the clinical trial process that supports the development of these innovative therapies must also evolve to keep pace with their ever-changing nature.
Yet the specificity and newness to cellular and gene therapy trials require care in planning, as well as compliance with a number of regulatory aspects. A significant feature of these trials is the addition of new arms, that is, introduction of more treatment groups or change in the design (protocol) of study. In fact, beyond that initial information, sponsors are required to submit further amendments or updates as the trial progresses for safety and efficacy as well as regulatory compliance. Improvement of these processes will be fundamental in making cellular and gene therapy clinical trials more accessible and rigorous.
Therapy Product:
New Versions of the Product Add Arms to Randomized Model
However, when a clinical trial sponsor wishes to add an arm to evaluate a new version of the investigational cellular or gene therapy product (e.g., Product C), certain considerations in regulatory filings and/or assessments are needed to streamline this process and ensure patient safety.
First, the sponsor files a Secondary Investigational New Drug Application (IND C) with the U.S. Food and Drug Administration (FDA). It should incorporate Chemistry, Manufacturing and Controls (CMC) data and Pharmacology/Toxicology (P/T) information for Product C into this application; the Secondary IND C will also need to state explicitly that it is a secondary IND and citation of primary IND number for clinical information.
Handling Extensions of Arms Without New Therapy Products
At the same time, the sponsor needs to also revise and submit the Primary IND (IND A) with the revised clinical protocol that now includes a new arm for Product C. The cover letter for this amendment should indicate that it is a Primary IND and list out all Secondary IND number(s), including IND C. Finally, the Primary-individuals should update their own Primary-individual to include a cross-reference to Secondary-Individual CMC and secondary –individual presentation registration in-product c.
Importantly, an application for new Secondary IND C cannot become effective until 30 days after the FDA is notified of the application unless a notification is given earlier. In addition, Product C cannot be administered to subjects in the clinical trial until IND C has become effective and an amendment to the protocol has been approved by an institutional review board (IRB).
Extensions of Arms without Novel Therapy Product:
If the new arm does not represent a different form of the investigational therapy, that process is made somewhat simpler but is still regulated (though slightly less so).
If the new arm studies an association of Product B with a marketed product or from investigational Products A and B, together, then its sponsor will need to file an amendment to the Primary IND (IND A) associated with such product. This amendment should be accompanied by the revised clinical protocol which includes the new arm details.
Also, if the new arm is supported by any further P/T information, they would need to provide this in a relevant IND(s). This will ensure that the FDA and other regulators have a complete picture of the proposed changes and can evaluate their clinical safety and efficacy impact.
Other changings or brand-new information to submit:
In addition to adding arms to the clinical trial, sponsors may need to file multiple other categories of a change or new clinical information while the trial is ongoing. The sponsor should submit a revised umbrella trial clinical protocol (with or without adding a new arm) or any other requisite new clinical information to the Primary IND (IND A). In these cases, the information does not need to be submitted to the Secondary INDs thus increasing efficiency.
Changes to Chemistry, Manufacturing, and Controls (CMC) or Pharmacology/Toxicology (P/T) Information:
Since there is a continuous evolution of the CMC or P/T information, and repeated interactions between regulators and developers during the life cycle of cellular and gene therapy products (CGTP), it may happen that new information appears over time during the course of a trial. To efficiently deal with such transformations:
Only CMC or P/T information for the specific product (e.g., Product B) should be filed in the relevant IND (IND B).
If the new information is applicable to multiple products (e.g., Products A and B), it should be filed with each affected IND (INDs A and B). Or IND A can submit the information to be cross-referenced by IND B, as previously described.
The sponsor should also submit an IB update to the Primary IND if there is new P/T information. It guarantees that the team conducting the research, health care providers, and patients are all kept up to date with novel treatment-related information.
Clinical Holds and Responses to Hold:
Essential to regulating clinical trials, clinical holds allow a regulatory body to pause an arm or the whole study if safety issues are detected. As a reminder, the process for responding to clinical holds involves circling back and coordination between Primary and Secondary INDs.
If just one arm is placed on hold (e.g., the arm studying Product B), then Primary IND will be placed on partial hold, and appropriate Secondary IND will be placed on hold (or partial hold if applicable). This is done for patient safety while still allowing other arms to progress.
If the FDA were to issue an order placing the entire study on clinical hold (for example if there was a safety issue that would affect all versions of the products), then 21 CFR 312.42(a) allows for all Primary and Secondary INDs to be placed on hold (or partial hold as appropriate).
To ensure their release, the sponsor needs to submit one response per IND that was put on hold. Nevertheless, specific responses to individual hold comments do not have to be submitted in their entirety to several INDs so as not to be redundant.
For example, if a product in a Secondary IND that is subject to the Partial Hold was placed on a Partial Hold due to concerns raised in CMC regarding the Primary IND, the sponsor should submit CMC information specifically responding to Hold comments for consideration directly into the Secondary IND. The Primary IND can then reference the Secondary IND for specifics in its response to hold, thus simplifying communication.
Conclusion: Streamlining Gene and Cell Therapy Clinical Trial Workflows
Cellular and gene therapy clinical trials have the potential to change how we treat diseases which means that it is important for sponsors of these types of trials to maneuver through the regulatory landscape smoothly. The comprehensive protocols for such trials here must be developed in alignment with established FDA guidelines to enable organizations to add arms to or submit changes/new information. Coordination between Primary and Secondary INDs allows for clinical trial workflow while assuring patient safety and research integrity.
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