FDA Issues “Cliffs Notes”-style Guidance on Cell and Gene Therapy; What Questions Did They Answer? (Part 1)
December 6, 2024On November 19, 2024, FDA released a draft guidance titled “Frequently Asked Questions – Developing Potential Cellular and Gene Therapy Products.” As much of the content of this draft guidance for cellular and gene therapy (“CGT”) products is articulated elsewhere, this document serves as a one-stop shop or “Cliffs Notes” for the numerous guidance documents now covering CGT product development. However, as your high-school literature teacher warned you—to ace the test, you need to read the book, ahem, source regulations, guidance, or other policy documents.
CBER’s approach here was to take FAQs from across sponsor interactions, public workshops, email requests, etc. and create a new guidance to help CGT sponsors more efficiently find their way to the correct answers. The draft guidance includes FAQs covering topics from across disciplines: regulatory review; chemistry, manufacturing, and controls (“CMC”); nonclinical and pharmacology/toxicology (“PT”); clinical; and clinical pharmacology. Because this guidance covers such a breadth of information, for Part 1 of our coverage, we will focus on the non-CMC topics and summarize our top takeaways from each section, something of a Cliffs Notes for the Cliffs Notes.
Section #1: FDA Interactions
Given the wide range of sponsors (i.e., academic to industry) involved in developing CGTs, the guidance starts by summarizing some of the fundamentals of opening an IND. This summary covers everything from format and contents of INDs to their submission and use of the Electronic Submissions Gateway to cross-referencing other applications to FDA’s review of the IND and the associated timelines. While this section is emblematic of the breadth of coverage of this guidance, it is particularly helpful for any sponsor who is looking to submit an IND for the first time, academic sponsors, and entities who partner with academic sponsors.
Interestingly to us, the draft guidance attempts to again clear up a common source of confusion by describing the differences between INTERACT and pre-IND meetings. Here, the draft guidance states that the appropriate timing for an INTERACT meeting should be when a sponsor has identified a specific product and has conducted some preliminary proof-of-concept (“POC”) studies but has not yet designed and conducted definitive toxicology studies. CBER had previously, as recently as July 2024 in its SOPP on regulatory interactions with sponsors (SOPP 8101.1), described that an INTERACT meeting may be appropriate when a sponsor has identified a “specific investigational product or product-derivation strategy to evaluate in a clinical study before requesting an INTERACT meeting” (emphasis added). In contrast to the scope for INTERACT meetings, the draft guidance describes an example of when a pre-IND meeting would be appropriate as being when the sponsor has completed POC and possibly some preliminary nonclinical safety/toxicology studies and desires to move to the definitive toxicology studies. The distinction between the INTERACT and pre-IND meeting and the potential narrowing of the scope for INTERACT meetings appears to have moved these two meeting types closer together on the continuum of product development timelines. It also appears to have continued to shift the focus away from degree of CMC-readiness, although our experience tells us that this continues to be a consideration in CBER’s review of INTERACT meeting requests.
The draft guidance also describes pre-BLA meeting considerations, noting that FDA “strongly recommends” scheduling one. The draft guidance states that only one 90-minute pre-BLA meeting will typically be granted for a specific product or indication planned for an original marketing application. Such meetings should also be multi-disciplinary, not discipline-specific. The draft guidance states that a pre-BLA meeting request should be submitted at least 4 months before the anticipated BLA submission. The draft guidance recommends that no more than 15 questions are included in the briefing package. CBER will not commit to reviewing packages greater than 250 pages.
For the many CGT programs intended for rare disease indications, we have found there is immense value in “socializing” pivotal data (whatever “phase” of study they may come from) prior to a pre-BLA meeting. This could occur during an End-of-Phase 2 (“EOP2”) meeting if a Phase 2 study is expected to provide primary evidence of safety and effectiveness. Even if an EOP2 meeting has occurred, it may help to have a focused clinical/statistical discussion of study results following Phase 3, as an “EOP3” meeting. This highlights the opportunities that exist for engaging with FDA beyond the opportunities explicitly acknowledged in guidance.
Section #2: Nonclinical Studies
As CBER has indicated in other guidance documents regarding considerations for nonclinical investigations, designing a nonclinical program is highly product and indication specific, which makes uniform design recommendations difficult. Instead, this guidance highlights questions about species, animal model, and product selection for nonclinical programs as well as several aimed at helping to understand the purpose and importance of POC, toxicity, and biodistribution studies. There is even a tip of the hat to alternative (non-animal) test methods, which have become powerful methods for the assessment of the potential for off-target toxicity and unintended genome editing. To us, some of the most helpful information provided pertains to selection of animal species and the design of pharmacology and toxicology studies, with the discussion of considerations that are unique to either cellular products or gene therapies.
The draft guidance enumerates key considerations for selecting an animal species for both pharmacology and toxicology studies. These considerations consist of (1) whether the investigational CGT product is pharmacologically active in the species, (2) the technical feasibility of using the intended clinical delivery device or procedure, (3) comparability of the physiology and anatomy, and (4) the sensitivity of the selected species to potential toxicities. Additional specific considerations for cell therapies include the ability of the species/strain to support survival and engraftment or availability of an appropriate analogous animal product. Specific considerations for gene therapies include the susceptibility of the species to the vector, the vector transduction profile, and the pharmacological response to the vector and expressed transgene.
The draft guidance also directs sponsors to consider the biological relevance of a particular animal or disease model for pharmacology studies. Factors related to the relevance of an animal or disease model to a target patient population include (1) progression of the disease phenotype or injury, (2) the lifespan of each model, (3) the similarities and differences between the animal model and the proposed patient population, (4) the timing of product administration relative to disease onset and progression, and (5) the relevant anatomy and physiology related to the delivery method and target anatomic site(s). If there is no available animal model, the sponsor should provide supporting data from other sources, which can include in vitro studies, in silico studies, in vivo studies using an analogous animal product, and relevant data from studies evaluating a related product or indication.
Shifting from pharmacology, the draft guidance offers input on design of toxicology studies. Because many CGT products are single-dose administration products, the duration for pivotal toxicology studies evaluating such a product should be informed by the biodistribution and persistence profile of the investigational product. The draft guidance describes various methods to assess either cell distribution for cell therapy products or vector biodistribution for gene therapy products. For cell therapy products, the draft guidance notes that in vivo imaging techniques provide certain advantages. For gene therapy products, the use of quantitative and sensitive assays such as qPCR are recommended. Where vector presence is detected, transgene mRNA and/or protein expression levels should also be measured.
Section #3: Human Trials
Finally, the guidance provides a quick overview of clinical study recommendations. Here, CBER focused on high-level questions about study design, providing substantial evidence of effectiveness, endpoint selection (including differences between clinical and surrogate endpoints), and assessing safety in CGT clinical programs. The draft guidance recommends, when feasible/ethical, the use of a placebo/sham concurrent control, active concurrent control, or dose-ranging concurrent control, as opposed to no-treatment concurrent control or external control, though no guidance is offered as to when such controls are feasible or ethical. Next, sponsors should consider no-treatment control. However, the draft guidance notes that in some cases, such as with rare diseases that have a natural history that does not spontaneously improve, a well-conducted natural history study may serve as an acceptable external control.
Consistent with both previous guidance and CBER’s approval decisions and recommendations to sponsors, the draft guidance recommends that for rare diseases, sponsors should consider designing their FIH study to be an adequate and well-controlled clinical study so that it may contribute to meeting the substantial evidence of effectiveness standard or even “serve as a pivotal study to support approval.” The draft guidance also notes that clinical outcomes in early phase studies could provide confirmatory evidence of effectiveness.
The discussion of endpoint selection, especially with respect to accelerated approval, caught our attention. It was quite notable to us that, while the guidance mentions both surrogate endpoints and intermediate clinical endpoints, the latter received little attention. The discussion focused almost entirely on distinguishing clinical and surrogate endpoints, explaining considerations for selection of biomarkers as surrogate endpoints, and the strength of evidence needed to support a surrogate endpoint. On the other hand, CBER provided no additional guidance as to when a clinical endpoint would be appropriate as an intermediate clinical endpoint to support accelerated approval. However, CBER just recently granted (to our knowledge for the first time) an accelerated approval based upon an intermediate clinical endpoint (see the November 13, 2024 approval of the gene therapy, Kebilidi).
For safety, the draft guidance emphasizes that close monitoring of subjects immediately after product administration is critical to capture early safety signals for CGT products. FIH studies should generally employ staggered enrollment and treatment to identify potential safety issues before dosing the next subject. The staggering interval should be long enough to monitor for acute and subacute adverse events based on observations in animal studies or previous human experience with related products. Clinical studies of CGT product should have well-designed stopping rules to assure that risks remain reasonable. Such stopping rules should specify the number of adverse events, as well as the nature/severity of these events, which would trigger such a determination.
Our Concluding Thoughts
While much of this new FAQ guidance reiterates policies and interpretations of FDA’s legal and regulatory authority that are described elsewhere, sponsors will likely find this document helpful for its effective summation of a large breadth of information. Perhaps, this guidance is best used as a first step before searching across the many and various documents it aims to summarize. The draft guidance contains a lengthy references section citing to 39 other guidance and procedure documents, not to mention the numerous statutory and regulatory provisions cited throughout, indicating the breadth of sources summarized in this one document. While the much of the benefit of the guidance comes from its utility as one-stop source of information, its discussion of topics like the narrow distinctions between pre-IND and INTERACT meetings may still be helpful to sponsors, even if this new discussion seem, to us, to push further into development the potential first window during which a CGT product sponsor could interact with CBER.
It is also worth noting that the draft guidance reinforces CBER’s view that sponsors should consider how to maximize the potential for early phase studies to contribute to substantial evidence of effectiveness as one of two adequate and well-controlled studies, as confirmatory evidence, or even as the pivotal study to support a marketing application. As such, particularly for rare diseases, it is important for sponsors to assess efficacy in these studies, even if only pharmacodynamic measures can be adequately measured. All the while, this efficiency in clinical development requires accelerating CMC by having early-stage studies serve as large stage studies. However, as we noted above, the CMC topics covered in this draft guidance will be covered in Part 2 of this blog coverage. Stay tuned for the next iteration of the Cliffs Notes to the Cliffs Notes.