“Explore FDA guidance on evaluating multiple versions of cellular and gene therapies in early-phase trials. Learn about IND submission efficiency and CBER’s umbrella trial approach.”
Introduction: The Need for Streamlined Evaluation of Cellular and Gene Therapies
Under many traditional clinical trial conditions, a single investigational product requires an individual Investigational New Drug (IND) application whenever the product is altered, leading to possibly duplicative IND submissions of like information among numerous INDs. That process not only creates extra work for sponsors, but it also takes precious time and resources from regulators and researchers. Realizing that there has to be a more streamlined approach to testing several iterations of cell or gene therapy products in the same clinical trial, Center for Biologics Evaluations and Research (CBER) is taking charge with a broad new guidance platform.
This guidance intends to facilitate evaluation, promote innovation and support the development of potential therapies while maintaining appropriate regulatory requirements. The framework aims to implement a clear structure and consistent classification of IND submissions that will allow sponsors to pursue umbrella trials of several whole/parts versions of these products for the most efficient evaluation of these therapies in one study.
Among the most promising novel treatments in the field of cellular and gene therapy are approaches for various diseases and medical conditions. Yet, assessing different versions of such therapies in early-phase clinical studies poses challenges for sponsors and researchers. In light of these difficulties and in an effort to develop a more streamlined, adaptable approach to assessing multiple iterations of CGT products in one clinical trial, the Center for Biologics Evaluations and Research (CBER) recently released guidance on this issue.
Efficiency-Based Evaluation: The Need
Traditionally, when studying more than one version of the same investigational product in clinical trials, each version required its own IND submission. INDs quickly pivoted from paper-based submissions to submissions in electronic form but often, providers submitted similar information across INDs redundantly and continuously, representing consumer burden by channels with different aspects of workload and utilization. This new draft guidance is intended to facilitate the evaluation process by allowing sponsors to evaluate multiple product versions under a single umbrella trial.
Scope and Limitations:
This guidance is limited to early-phase studies of cellular or gene therapy products under investigation for a single disease. This guidance is intended to apply for situations in which the IND sponsor manufactures all of the cellular or gene therapy product versions and has adequate chemistry, manufacturing, and controls (CMC) and pharmacology/toxicology (P/T) information available for submission as part of the INDs or through cross-reference.
This guidance does not cover every type of trial, including “basket” trials, which test the same cell or gene therapy product in numerous populations. Sponsors wishing to conduct such studies should arrange for a pre-IND meeting with the Office of Tissues and Advanced Therapies (OTAT) at CBER to discuss the proposed design of their clinical trial.
A More Efficient Framework:
At the heart of this guidance is the classification of IND submissions as “Primary” or “Secondary” INDs. Specific terminology is utilized to clarify which INDs will contain clinical information regarding the umbrella trial (e.g., Primary INDs), and which INDs will not include clinical information (e.g., Secondary IND).
For example, a clinical study comparing two versions of the investigational product (e.g., Product A and Product B) should have 2 INDs submitted by the sponsor: One for each product (IND A and IND B), with IND A designated as the “Primary” IND containing CMC and P/T information for Product A, plus full clinical data for the umbrella trial. Thus IND B will be termed as a Secondary IND, containing CMC and P/T information for Product B, whereas the clinical studies between three different product versions (Products A, B & C) should include CMC and P/T info and Product C in Secondary IND.
Cross-Referencing to Prevent Duplicate Submission:
Sponsors using this framework can check for overlap of information shared between the Primary and Secondary INDs to reduce duplicate submissions and increase efficiency. The Primary IND, for example, should reference the Secondary IND(s) concerning CMC and P/T information about the secondary products; conversely, the Secondary IND(s), with respect to clinical information about a primary or combination product, should reference that of the Primary IND, etc.
Also, if some of the CMC or P/T data is the same across versions, sponsors can file it just to the Primary IND and cross-reference into the Secondary IND(s).
Cover letters and electronic submissions:
Like any regulatory submission, electronic submission in the required format is also foundational. Note: For IND submissions, sponsors should consult FDA’s Guidance for Industry: Providing Regulatory Submissions in Electronic Format..
It is suggested that the cover letter for both Primary IND and Secondary IND indicates their classification. The cover letter for the Primary IND must indicate that this is a Primary IND and include the Secondary IND number(s). On the other hand, any Secondary IND cover letter should also identify itself as a Secondary IND and include the Primary IND number. It is advisable to request these IND number for pre-assigned numbers before the submission to ensure appropriate cross-referencing and cover letter.
Adding More SKU Versions:
Sponsors also may create other versions of a product after submitting an IND. An amended IND should be submitted to the existing IND if the sponsor wants to evaluate both original and additional versions of a product together under an umbrella trial. The amendment should indicate that it is a Primary IND, and the actions described in the guidance and the steps to submit Secondary IND(s) and append arm(s) to the study.
Conclusion
This guidance provides a promising approach to increasing efficiency and flexibility of early-phase trials by streamlining clinical evaluation of breakthrough cellular or gene therapy products with multiple versions. To enable rapid and efficient evaluation of INDs, a framework will be developed to classify IND submissions as Primary and Secondary such that by cross-referencing the information contained in each submission, sponsors can lessen redundant IND submissions. This guidance will provide a resource for researchers and sponsors of cell and gene therapy who would like to develop and test several versions of this new bio-therapeutics technology in one clinical evaluation as the field matures.
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