FDA firstly advises industry on submission of a research, or noncommercial, IND versus a commercial IND.

In November 2024, the U.S. Food and Drug Administration (FDA) issued draft Guidance responding to frequently asked questions about developing cellular and gene therapy (CGT) products. This draft Guidance supplements existing finalized and draft Guidance on CGT products.

The draft Guidance covers four main areas:

1. Interactions with FDA, including investigational new drug application (IND) submission;
2. Product development considerations such as product characterization and quality attributes;
3. Conducting nonclinical studies; and
4. Conducting human trials.

Interacting with FDA

FDA firstly advises industry on submission of a research, or noncommercial, IND versus a commercial IND. The draft Guidance explains that the former is an application for a product that is not intended for commercial distribution and should be submitted in electronic common technical document format. Alternatively, commercial applications must follow Section 745A(a)(2) of the Food Drug & Cosmetics Act for submission. FDA additionally advises on information to include in an original IND submission, including clinical investigation history and pharmacology/toxicology information. Importantly, the draft Guidance explains the distinction between INTERACT meetings and pre-IND meetings. INTERACT meetings occur when a sponsor has not progressed to designing or conducting toxicology studies but has identified an investigational product and conducted preclinical proof-of-concept studies. Pre-IND meetings, by contrast, offer feedback on product development programs, such as nonclinical and clinical study design, product manufacturing and targeting particular populations. If sponsors require guidance as to no more than three to five total questions, they may request a Type D meeting to focus on specific, critical issues relating to development. The draft Guidance contains additional advice regarding rolling biologics license application (BLA) reviews and the timeline for IND feedback.

Product Development

To guide CGT product development, the draft Guidance distinguishes between requirements for autologous and allogeneic donor eligibility, including the requirement that allogeneic donor material be found eligible by testing donor specimen and screening donor medical records. The draft Guidance additionally differentiates characterization testing (for product information) from release testing (for product safety, purity, potency), noting that release test results must be reported on the product certificate of analysis, but both must be included in a BLA or IND application. FDA recommends that when conducting characterization testing, industry test both the drug substance and the drug product. It is further recommended that sponsors reach out to FDA regarding the effect of manufacturing changes on comparability of pre- and post-change products. The draft Guidance also elaborates on chemistry, manufacturing and controls considerations in preparation of BLA submission.

Conducting Nonclinical Studies

In the nonclinical study context, FDA’s draft Guidance advises on considerations for selecting proper animals for studies. The draft Guidance also recommends that sponsors provide scientific justification in both pre-IND and IND submissions for the animal model selected for pharmacology studies. Such justification should include data supporting each animal model’s biological relevance, description of animal anatomy as compared to human anatomy, comparison between the animal model and proposed patient population, and model lifespan. If there is no possible animal model to evaluate the product with, the draft Guidance suggests that supporting data be derived from other sources such as in vitro and in silico studies. In response to the question of whether sponsors can submit INDs without conducting nonclinical toxicology studies for particular products, FDA emphasizes the importance of toxicology studies in an IND. FDA directs sponsors who believe that no further toxicology studies are required for a particular product to include in an IND submission a description of the scientific rationale for this choice.

Conducting Human Trials

The draft Guidance explains important considerations for CGT clinical trial design. FDA views it necessary for there to be substantial evidence of effectiveness to support biological product licensure, usually in the form of two adequate and well-controlled clinical investigations. However, FDA clarifies that it will sometimes consider data from one adequate, well-controlled clinical investigation paired with confirmatory evidence to be sufficient. An adequate, well-controlled study may include bias-mitigating measures, appropriate assignment to treatment and control groups, and valid comparison with a control. FDA considers multiple factors to decide whether one study is appropriate, including:

1. If the study has robust confirmatory evidence;
2. How serious the disease is;
3. If it is practicable or ethical to conduct two studies;
4. How persuasive the single trial is; and
5. Patient population size.

Given CGT products are often administered a single time, the draft Guidance recommends intensive safety monitoring during and for weeks and months post-admission. FDA also advises that depending on the product, sponsors observe subjects for delayed adverse effects in long-term follow-up trials for up to 15 years post-exposure.

To provide input before finalization of this draft Guidance, individuals may submit comments until February 18, 2025.

For More Information

If you have any questions about this Alert, please contact Frederick R. Ball, Kelly A. Bonner, Victoria (Tori) Hawekotte, any of the attorneys in our Life Sciences and Medical Technologies Industry Group or the attorney in the firm with whom you are regularly in contact. 

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