FDA officials offer advice on gene therapy trials

Regulatory NewsRegulatory News | 08 February 2023 |  By 

FDA's Lei Xu, Elizabeth Hart, and Melanie Blank

Officials from the US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) Office of Tissues and Advanced Therapies (OTAT) asserted that the duration of clinical trials for gene therapies depends on the nature of the disease being treated, and that diseases that are more progressive and have a rapid onset may involve shorter trials.
This was one of the learnings imparted by officials during a 7 February virtual town hall meeting to answer stakeholder questions on the clinical development of gene therapies for rare diseases outside the hematology and oncology space. The town hall is part of a series to address questions from stakeholders on topics under OTAT’s remit.
The town hall addressed the factors sponsors should consider when determining the study population for early phase gene therapy trials; the office’s criteria for allowing single arm, externally controlled trial to provide the primary evidence of effectiveness for approval; and the agency’s guidelines for determining the duration of gene therapy clinical trials.
“It’s a very exciting time in gene therapy. We are seeing one or two new applications coming in every week for new gene therapies for different diseases … We are working very hard to expedite gene therapy development so that all of these programs can be successful,” said Melanie Blank, clinical team leader for the general medicine branch at FDA’s Division of Clinical Evaluation and Pharmacology/Toxicology (DCEPT) at the outset of the town hall.
Duration of trials
Elizabeth Hart, branch chief, General Medicine 1 in DCEPT, asserted that there is no one-size-fits-all approach to determining the necessary duration of clinical trials, instead the length of time varies based on the type of disease that the therapy is intended to treat.
“In general, for diseases that are rapidly progressive, a shorter time will be needed to demonstrate efficacy compared to a disease that is more heterogenous,” she said, adding that for such diseases, it may be possible to demonstrate a clinically meaningful effect with valid biomarkers “in a shorter period of time than demonstrating a clinical meaningful effect.”
Factors in understanding study populations
Blank said that sponsors should conduct a benefit-risk analysis to ensure that patients that would benefit the most from the therapy are given enrollment preference.

“In terms of benefit-risk, we want to enroll patient population who is most likely to benefit... We really want to be sure that those who are first enrolled will have the greatest potential benefit. We also want to ensure that they are otherwise healthy because of toxicity.”
The ability to give informed consent is also another important factor in determining the study population, Blank said in response to a question on what factors sponsors should use when determining the study population for early phase gene therapy trials.
Blank said that older patients who can give consent are preferable to patients that cannot give such consent.
“An adult is able to provide consent whereas the pediatric population at best can provide assent and the youngest children cannot either provide consent or assent. When possible, if the disease affects the adult population we like to go first in adults and make sure that there is some preliminary safety data before going to children. And then it is best to go first in those that can assent, the older before the younger.”
Conditions for allowing single arm studies
Officials were asked to specify whether the agency will allow the use of single-arm, externally controlled studies in lieu of two well-controlled randomized studies to evaluate the efficacy of new gene therapies.
Lei Xu, branch chief, General Medicine 2 within DCEPT, said that for gene therapies, regulatory approval hinges on “substantial evidence of efficacy from an adequate and well-controlled study.
Yet the agency will permit external controls, such as a natural history controls or concurrent controls for gene therapy trials to treat rare and serious conditions under certain conditions. These would include cases involving diseases with “a well understood underlying pathogeneses, and the disease course is well documented and highly predictable and can be objectively measured and verified.”
Xu noted that Novartis’ Zolgensma (onasemnogene abeparvovec-xioi) was the first systemically administered gene therapy approved treatment for patients under two years of age with spinal based atrophy based on substantial evidence of two single-arm externally controlled studies in children with infantile onset of SMA.
FDA recently issued a guidance on criteria it will use to allows eternal controls to substitute for two well controlled randomized clinical trials, though the guidance does not specifically address rare diseases. (RELATED: FDA draft guidance addresses use of external controls to assess effectiveness of new drugs and biologics, Regulatory Focus 2 February 2023).
The idea for the town hall series was first announced by outgoing OTAT Director Wilson Bryan at a meeting last year to improve communications with sponsors and to widen its messaging. (RELATED: FDA explains plans to bolster cell and gene therapy approvals through wider messaging, Regulatory Focus 19 May 2022).
OTAT town hall on gene therapies


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Tags: FDA, gene, OTAT, therapy

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