The rapid progress in cellular and gene therapy has sparked great excitement and hope for revolutionizing the treatment of various diseases and medical conditions. These cutting-edge therapies offer the potential to address previously untreatable or challenging-to-treat ailments, and their immense therapeutic potential has garnered significant attention from researchers, clinicians, and patients alike. As cellular and gene therapies move from preclinical investigations to early-phase clinical studies, new challenges arise, particularly when multiple versions of the investigational products are being studied for the treatment of a single disease.
In conventional clinical trial settings, each version of an investigational product necessitates a separate Investigational New Drug (IND) submission, resulting in potential redundancies in the submission of similar information across multiple INDs. This process not only places additional burdens on sponsors but also consumes valuable time and resources for both regulatory authorities and researchers. Recognizing the need for a more efficient and flexible model for evaluating multiple versions of cellular or gene therapy products within a single clinical trial, the Center for Biologics Evaluations and Research (CBER) has taken a proactive step in issuing a comprehensive guidance framework.
The aim of this guidance is to streamline the evaluation process, foster innovation, and facilitate the development of promising therapies while adhering to rigorous regulatory standards. By offering a clear structure and a standardized categorization of IND submissions, this framework seeks to enable sponsors to conduct umbrella trials encompassing multiple versions of their investigational products, thereby optimizing the assessment of these therapies in a single comprehensive study.
In the field of cellular and gene therapy, the development of innovative treatments has shown great promise for addressing various diseases and medical conditions. However, the evaluation of multiple versions of these therapies in early-phase clinical studies can present unique challenges for sponsors and researchers. To address these challenges and create a more efficient and flexible model for evaluating multiple versions of cellular or gene therapy products within a single clinical trial, the Center for Biologics Evaluations and Research (CBER) has issued a new guidance framework.
The Need for Streamlined Evaluation:
Traditionally, when multiple versions of an investigational product are being studied in clinical trials, each version required a separate Investigational New Drug (IND) submission. This process often led to redundant submissions of similar information across INDs, which could be time-consuming and resource-intensive for both the regulatory authorities and the sponsors. The new guidance aims to streamline the evaluation process by enabling sponsors to assess various product versions within a single umbrella trial.
Scope and Limitations:
The scope of this guidance is limited to early-phase studies of cellular or gene therapy products being studied in a single disease. The guidance applies to scenarios where the IND sponsor is responsible for manufacturing all versions of the cellular or gene therapy product and can provide the necessary chemistry, manufacturing, and controls (CMC) and pharmacology/toxicology (P/T) information either in the IND submissions or through cross-referencing.
It's important to note that this guidance does not apply to certain types of trials, such as "basket" trials, where a single cell or gene therapy product is evaluated in different populations. Sponsors interested in conducting such studies should request a pre-IND meeting with the Office of Tissues and Advanced Therapies (OTAT) at CBER to discuss their proposed clinical trial design.
A More Efficient Framework:
The core of this guidance revolves around the categorization of IND submissions as "Primary" or "Secondary" INDs. This nomenclature aims to distinguish which INDs will include clinical information about the umbrella trial (Primary INDs) and which INDs will not include such clinical information (Secondary INDs).
In practical terms, for a clinical study involving two different versions of the investigational product (Product A and Product B), the sponsor should submit two separate INDs, namely IND A and IND B. IND A will be considered the "Primary" IND, containing CMC and P/T information for Product A, as well as complete clinical information for the umbrella trial. On the other hand, IND B will be considered a "Secondary" IND, containing CMC and P/T information for Product B. For clinical studies involving three different product versions (Products A, B, and C), the CMC and P/T information for Product C should be provided in Secondary IND C.
Cross-Referencing to Minimize Redundant Submissions:
To minimize redundant submissions and promote efficiency, sponsors adopting this framework should cross-reference shared information between the Primary and Secondary INDs. For instance, the Primary IND should cross-reference the Secondary IND(s) for the CMC and P/T information specific to the secondary products, while the Secondary IND(s) should cross-reference the Primary IND for clinical information.
Furthermore, if certain CMC or P/T information is identical between the different product versions, sponsors can submit that information solely to the Primary IND and incorporate it into the Secondary IND(s) by cross-reference.
Electronic Submissions and Cover Letters:
As with any regulatory submission, electronic submission in the appropriate format is essential. Sponsors should refer to FDA's Guidance for Industry on providing regulatory submissions in electronic format for IND submissions.
For both the Primary and Secondary INDs, it is recommended that the cover letter clearly indicates their categorization. The cover letter for the Primary IND should state that it is a Primary IND and specify the Secondary IND number(s). Conversely, the cover letter for any Secondary IND should identify it as a Secondary IND and specify the Primary IND number. Pre-assigned IND numbers should be requested prior to submission to facilitate proper cover letter and cross-referencing.
Incorporating Additional Product Versions:
In some instances, sponsors may develop additional versions of a product after submitting an IND. If the sponsor wishes to evaluate the original and additional versions of a product together in an umbrella trial, an amendment to the existing IND should be submitted. The amendment should specify that it is a Primary IND, and the steps outlined in the guidance (section IV.B) should be followed to submit Secondary IND(s) and add arm(s) to the study.
The guidance on streamlining the evaluation of multiple versions of cellular or gene therapy products in clinical studies offers a valuable approach to enhancing efficiency and flexibility in early-phase trials. By categorizing IND submissions as Primary and Secondary, and through effective cross-referencing of shared information, sponsors can significantly reduce redundant submissions and expedite the evaluation process. As the field of cellular and gene therapy continues to advance, this guidance will serve as a valuable resource for researchers and sponsors seeking to develop and assess multiple versions of these innovative therapies within a single clinical trial.