Gene Therapy Trials – A Word of Advice From FDA Officials

Representatives from the US FDA Center for Biologics Evaluation and Research Office of Tissues and Advanced Therapies have said that the gene therapy clinical trials depend on the nature of the disease being treated and that the diseases that happen to be more progressive or that have a rapid onset may have shorter trials.

This was one of the many learnings which was imparted by the officials during the virtual town hall meeting on February 7 so as to answer the questions from the stakeholders on the clinical development of gene therapy for rare diseases that were outside the scope of oncology and hematology. The town hall happens to be a part of the series to answer questions from the stakeholders on the topics that fall under the OTAT umbrella.

The town hall session addressed the factors that should be considered by sponsors when gauging the study population for early phase gene therapy trials, which happens to be the office’s yardstick for allowing single-arm and externally controlled trials so as to provide primary evidence related to effectiveness for approval, and also the guidelines from the agency to determine the gene therapy clinical trial duration.

According to clinical team leader from the general medicine branch of FDA division of clinical evaluation and pharmacology and toxicology, Melanie Blank, They are working hard to fasten the development of gene therapy and it is indeed a very time in this segment. They are witnessing either one or two applications coming in every week pertaining to different diseases’ need for gene therapies.

Trial Duration

Branch Chief in General Medicine 1 at DCEPT, Elizabeth Hart, said that there isn’t any one-size-fits-all approach that determines the necessary clinical trial duration, but instead the time length varies based on the disease type that the therapy is known to treat.

A shorter time is going to be needed for diseases that happen to be rapidly progressive so as to demonstrate their efficacy as compared to those that are known to be more heterogeneous. She added that for such diseases, it can be a possibility to showcase a clinically meaningful effect with biomarkers that are valid.

Study Populations And The Factors That Determine Them

As per Blank, the sponsors must do a benefit-risk analysis to make sure that the patients who happen to be most benefited from the therapy are given the preference of enrolment. When it comes to benefit-risk, they are looking to enrol patients who are most likely to get benefited and that they really want to make sure that whosoever enrols ought to have the greatest potential benefit.

The capacity to give informed consent is another significant factor when it comes to determining the study population, said Blank in response to a question on what elements the sponsors must use when looking into the study population for gene therapy trials across every phase.

According to Blank, the older patients who give consent happen to be more favourable than those who cannot give consent. An adult patient is able to provide consent, while the paediatric population provides assent and for that matter, the youngest of all cannot provide either. Blank adds that when the disease is likely to affect the adult population, they go ahead with adults first just to ensure that some preliminary data on safety is available before going ahead with children and thereafter to go into those who can assent, again in that case older before approaching the younger.

Single-Arm Studies: The Conditions

The officials were asked to specify if the agency is going to allow the single-arm use of externally controlled studies in place of two well-directed randomised studies to gauge the new gene therapies’ efficacy.

The branch chief of General Medicine 2 in the DCEPT, Lei Xu, opined that the regulatory approval of gene therapies hinges on efficacy evidence which is substantial from a study that is well-controlled and adequate.

That said, the agency shall approve the external controls like the history as well as the concurrent controls for the gene therapy in order to treat the conditions that happen to be serious and rare. This includes cases pertaining to well understood underlying pathogeneses of diseases, the course of which is well documented and is also pretty much predictable, and can also be verified and measured objectively.

FDA has recently come up with a guideline based on criteria that will be used to allow external controls that shall substitute for two well-controlled randomised trials, although the guidance does not specify rare diseases. Apparently, it was Wilson Bryan, the outgoing OTAT director, who first announced the idea to have a town hall series during a meeting in 2022 so as to enhance the communication done with sponsors and thereby widen the scope of messaging.