Guidance Breakdown: FAQs on Developing Potential Cellular and Gene Therapy Products
The agency offers more guidance on developing cell and gene therapies. We break it down.
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The FDA has released new draft guidance aimed at helping drugmakers navigate the complexities of developing and submitting applications for new cell or gene therapies. The 40-page guidance addresses several important aspects, from pre-IND meetings to long-term safety monitoring. A lot of the guidance seems to be based on advice it has previously provided to the industry at its monthly town halls hosted by the CBER’s Office of Therapeutic Products.
The guidance was developed as part of the FDA’s commitments under the latest user fee agreement and reflects the agency’s wider efforts to enhance the efficiency of cell and gene therapy development.
This draft builds on previous recommendations regarding the development of cell and gene therapies, outlining the key elements that should be included in quality Investigational New Drug (IND) submissions. It also advises when the FDA recommends scheduling a pre-Biologics License Application (BLA) meeting and what information should be included in a request for such a meeting.
The guidance specifies conditions under which a surrogate endpoint can support accelerated approval, highlighting the factors for evaluating a biomarker's effectiveness as a surrogate. The use of biomarkers as surrogates has been established for over two decades; for instance, Sanofi’s Fabrazyme received accelerated approval in 2003 based on this approach.
In conjunction with a 2020 guidance on Chemistry, Manufacturing, and Controls (CMC) for gene therapies, this new Q&A guidance outlines key CMC considerations for sponsors submitting a BLA. It clarifies that safety testing data must be provided before Phase 1 studies, along with essential product and process characterization data.
The guidance also emphasizes the importance of both short- and long-term safety monitoring in investigational cell and gene therapy trials, advising sponsors to track participants for delayed adverse events for up to 15 years after exposure.
Regarding the amount and type of proof-of-concept data appropriate before initiating a clinical trial, the agency stresses that “the adequacy of the nonclinical data to support the administration of the investigational CGT product in the proposed clinical trial is determined based on the review of the [proof-of-concept] and safety data in the IND.”
Here's a quick distillation of the critical details addressed in each of the FAQs.
IND submission and quality (Q1-Q5)
Q1: What should sponsors know about submitting an Investigational New Drug application? Commercial INDs must be submitted in eCTD format through the FDA's Electronic Submission Gateway; noncommercial (research) INDs have an optional eCTD format.
Q2: What is important for inclusion in an original IND submission? Original IND submissions require Form FDA 1571, a cover letter, detailed CMC information, pharmacology/toxicology data, and clinical protocols. All documents must be in English.
Q3: What regulatory forms are included in original INDs and IND amendments? Form FDA 1571 is required for IND submissions, must be signed by a sponsor/authorized representative, and includes an overview of submission contents.
Q4: What is the general process for evaluating original INDs for CGT investigational products? The 30-day IND review process involves administrative review, discipline reviews (CMC, pharmacology/toxicology, clinical), and determination if it is safe to proceed or if a clinical hold is needed.
Q5: What should sponsors know about submission tracking numbers for applications submitted through the Electronic Submission Gateway? Tracking numbers are pre-assigned by CBER for eCTD submissions and must be requested via email to cberrib@fda.hhs.gov.
Meeting types (Q6-Q9)
Q6: What are the differences between INTERACT and pre-IND meetings? INTERACT meetings are for early development discussion before toxicology studies; pre-IND meetings are for feedback before IND submission.
Q7: How should sponsors prepare briefing packages for and request INTERACT and pre-IND meetings? INTERACT and pre-IND meetings have specific requirements for briefing packages and timing of submissions.
Q8: What is a Type D meeting and how do sponsors request one? Type D meetings focus on narrow issues (max 2 topics) requiring input from no more than 3 disciplines.
Q9: Does the FDA recommend a pre-BLA meeting, and what should be included in the briefing package if sponsors choose to request one? Pre-BLA meetings are strongly recommended to ensure complete application and avoid review delays.
IND amendments and expedited programs (Q10-Q11)
Q10: What is the FDA's timeline for feedback on new or revised information submitted to an active IND? Manufacturing changes affecting product quality must be submitted as amendments before implementation; new protocols can be implemented after submission to FDA and IRB approval.
Q11: When does rolling review begin for qualifying BLAs and what is the timing of module submission? Rolling review for qualifying BLAs allows the FDA to review portions before complete submission; the review clock starts when the final module is received.
Product development (Q12-Q20)
Q12: What are some differences between autologous and allogeneic donor eligibility considerations? Autologous products don't require donor eligibility determination; allogeneic products require full donor screening and testing.
Q13: What is the difference between product characterization testing and release testing? Product characterization provides information about the product; release testing demonstrates acceptable quality with predefined acceptance criteria.
Q14: What information should be submitted regarding critical quality attributes? CQAs should be established early, particularly for manufacturing changes.
Q15: How should analytical methods be shown to be fit for purpose for first-in-human trials? For first-in-human trials, analytical methods must be shown fit for purpose with performance characteristics evaluated.
Q16: At what scale should process characterization and validation be executed? Process validation should use commercial-scale batches; scaled-down models can be used for process design and characterization.
Q17: How many process performance qualification lots are recommended for process validation? No fixed number of Process Performance Qualification lots is required; the number should be based on risk assessment.
Q18: How should manufacturers evaluate comparability of pre- and post-change products? Refers to separate guidance for evaluating comparability of pre- and post-change products.
Q19: What stability information is needed to support first-in-human studies? Stability data is needed at all stages; Phase 1 can use data from nonclinical/engineering lots.
Q20: What CMC issues should sponsors consider as they prepare to submit a BLA? CMC development should progress with clinical development; BLA requires validated processes and methods.