FDA finalizes neurodegenerative disease gene therapy guidance
The US Food and Drug Administration (FDA) last week finalized guidance to assist sponsors developing human gene therapy (GT) products for neurodegenerative diseases. In the final version, FDA acceded to industry’s requests to modify its language on the use of crossover trials, provided more detail on the use of comparability studies in assessing the effect of post-approval manufacturing changes on products and eliminated limits for residual product-related impurities.
The document finalizes a draft version issued in January 2021. (FDA guides on Covid considerations in cell and gene therapy, Regulatory Focus 20 January 2021). Industry stakeholders requested changes to the draft guidance in comments submitted to the public docket.
“Changes to the guidance include clarifications to the recommendations regarding use of tumorigenic cell lines, comparability studies, and crossover designs for clinical trials. In addition, editorial changes were made to improve clarity,” said FDA’s announcement.
The final version deletes the recommendation that residual host cell-DNA impurity levels be set to less than 10 ng/dose to avoid unwanted immunogenic reactions in study subjects. Instead, it states 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 presence of tumorigenic sequences) and limit residual host cell-DNA levels and DNA size.”
The final guidance also refers readers to FDA’s standalone guidance on CMC considerations for gene and cell therapy guidance for assessing impurities. The Alliance for Regenerative Medicines (ARM) was among those requesting FDA eliminate the 10 ng dose limit, stating that “it may be unattainable for gene therapies delivered with a viral vector such as AAV. This challenge is due to the fact that inevitably during production of AAV vectors, using either the mammalian/plasmid transfection or baculovirus/Sf9 production platforms, some level of host cell DNA can become encapsulated and will not be able to be removed during purification process.”
The limit is also “inconsistent with the 2020 FDA CMC for GT Guidance and the rationale for a different policy for neurodegenerative disease gene therapies, i.e., not allowing the use of tumorigenic cell lines, is unclear. We request that FDA aligns policy across gene therapy guidances.”
Some companies and groups, including Biogen and ARM, requested more detail on how sponsors should assess comparability of products after making post-approval manufacturing changes. The guide states that “the extent of comparability studies should depend on the manufacturing change, the ability of analytical method to detect changes in the product, and the stage of clinical development. After discussing the proposed comparability protocols and manufacturing changes with FDA, sponsors should be prepared to perform the comparability study. It is critical that that sufficient samples are retained (such as such in-process materials, drug substance (DS), drug substance intermediates, and drug products (DP). After the comparability study is conducted, sponsors should submit the data from the cpampantity studies as an amendment to the IND.”
The final guidance also modifies its recommendation on the use of crossover designs in gene therapy clinical trials, in responding to industry comments that crossover trial design models are not appropriate for gene therapy trials. It states that “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.” The draft had recommended that crossover studies be considered in such trials “when disease progression can be clearly identified.”
Biogen, Pfizer, and Novartis and ARM had requested this modification. Biogen wrote that “crossover designs are mainly relevant to diseases where there is fast progression (e.g., leber congenital amaurosis or amyotrophic lateral sclerosis) versus slower, chronic neurodegenerative disease, which limits the applicability of this design.”
ARM similarly requested that “FDA clarify what is meant by a crossover trial in the context of a one-time gene therapy product (e.g., is the intention similar to a delayed start or delayed treatment design?) and what expectations there are for sponsors to demonstrate that disease progression can be clearly identified.”
Read more »The US Food and Drug Administration (FDA) last week finalized guidance to assist sponsors developing human gene therapy (GT) products for neurodegenerative diseases. In the final version, FDA acceded to industry’s requests to modify its language on the use of crossover trials, provided more detail on the use of comparability studies in assessing the effect of post-approval manufacturing changes on products and eliminated limits for residual product-related impurities.