Held on 7Feb2023, the OTAT Town Hall was interesting in that it was only Q&A on Gene Therapy with no presentations. It started with 15 questions that had been submitted prior to the webinar and then followed with questions from the audience. Note that the following is based on my interpretation of the responses to the questions by the FDA speakers and is not the FDA's position.
Several questions were about choosing the study population in early trials vs later trials. The FDA's response for adults and pediatric studies was pretty consistent - it is benefit-risk based optimization and that must include the patient’s ability to provide consent. This tended to mean patients with more advanced diseases (including those who cannot take any existing therapies due to side effects or are refractive to those therapies). Patients should, however, be chosen as those without other co-morbidities that would reduce the patient’s ability to handle side effects. In pediatric trials, this also means starting with older children. For pediatric trails, the concept of "prospect of direct benefit", where the risks can be mitigated to some extent through animal testing and preferably adult testing - i.e., ensures that the risk is minimized in favor of the benefit (see 21 CFR 50 subpart D)
Other questions explored the appropriate control arms of studies and the FDA noted 5 different approaches to control arms with the least favored being open trials followed by externally controlled trials. The concept of externally controlled trials, which were the focus of a recently released draft guidance, was felt best applied to well-characterized diseases but in general were not favored since they could not include blinding or randomization. Both of which were noted as important for rare diseases. Additionally, externally controlled trials may not be adequately controlled for a variety of factors (e.g., disease status, progression, supervision of the external control arm of study).
On the question of "how can biomarker endpoints be best used in gene therapy clinical trials?" Efficacy is typically measured based on minimizing morbidity and reduction in the clinical signs of the disease. Biomarkers may help characterize the status of disease. Start a natural history study early to identify the most appropriate biomarker(s). Use of Biomarkers relies on validated biomarkers or when the biomarker shows relative change that aligns with a change in disease status (i.e., an intermediate gene therapy endpoint is predictive of population efficacy endpoint). In this case, the FDA would still like to see reduction in morbidity, but the biomarker may help accelerate the approval.
Overall, a good opportunity to hear and understand the FDA thinking on implementing gene therapy clinical trials in adults and children.
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