Developing gene therapies for neurodegenerative diseases: FDA finalizes guidance
Biopharma companies debating whether or not to start developing new gene therapies for neurodegenerative diseases — a historically tricky field to crack — will now have more advice from the FDA to help with preclinical testing and clinical trial design, among other topics. The final FDA guidance, building off a draft from Jan. 2021, includes new clarifications on the recommendations regarding the use of tumor-forming cell lines, comparability studies, and crossover designs for clinical trials.
Under the CMC portion of the 16-page final guidance, for instance, the FDA notes, “we recommend that sponsors carefully consider characteristics of the cell lines used in the manufacture of viral vectors that may impact the safety of the final product (such as the presence of tumorigenic sequences) and limit residual host cell-DNA levels and DNA size.” Previously, the draft recommended that gene therapy vectors used to treat neurodegenerative diseases “not be grown in tumorigenic cell lines and the residual host cell-DNA levels be set to less than ten ng/dose, if possible.”
The change in the final version followed comments from Swiss contract manufacturer Lonza and biopharma heavyweights Novartis and Pfizer, which questioned the initial guidance. Pfizer noted in its statement from April 2021, “Given the abundance of evidence showing this is not feasible for AAV production, we suggest modifying the text to exclude a fixed number and encourage sponsors to specify and justify an appropriate level.”
Under considerations for clinical trials, the final guidance also includes a new section on follow-up duration that was not in the draft, with the FDA noting: The length of follow-up necessary to provide sufficient information regarding the safety and efficacy of the GT product depends on many aspects of a GT product, including vector persistence, genome integration, and transgene activity, and the goal of the follow-up (e.g., safety vs. durability of clinical effect). In addition to monitoring for safety, long-term follow-up is recommended to evaluate the durability of the clinical impact.
In terms of the changes around crossover designs, the draft explains how “Crossover designs may also be considered in such trials when disease progression can be clearly identified.” But the final guidance is further watered down. It does not include that sentence, instead noting: When appropriate, crossover designs may also be considered in concurrent-controlled trials to allow patients in the control group to receive the GT product after completion of the randomized, controlled portion of the trial. To qualify for additional prespecified effectiveness assessments, we recommend that patients, investigators, site personnel, and site monitors remain blinded to treatment group assignment from the randomized treatment period during the open-label extension period.
https://endpts.com/developing-gene-therapies-for-neurodegenerative-diseases-fda-finalizes-guidance/
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