Drugmakers suggest tweaks to FDA’s neurodegenerative disease gene therapy guidance

Regulatory NewsRegulatory News | 06 April 2021 |  By 

Several drugmakers and Health Canada are suggesting changes to the US Food and Drug Administration’s (FDA) recently released draft guidance on developing gene therapies for neurodegenerative diseases.
Released in January, the draft guidance provides recommendations for the development, testing and clinical study of gene therapies for neurodegenerative diseases. The guidance also discusses considerations for chemistry, manufacturing and controls (CMC) and offers an overview of the regulatory pathway and opportunities for engagement with FDA for such products. (RELATED: FDA offers first thoughts on neurodegenerative disease gene therapies, Regulatory Focus 7 January 2021).
While supportive of the agency’s effort to develop the guidance, each of the industry commenters had their own suggestions for how FDA should change the guidance before issuing a final version.
“While this guidance serves as a useful overview of high-level recommendations in existing gene therapy guidance, we believe more detailed recommendations are necessary to help guide sponsors as they navigate development. For instance, the document does not often distinguish between a rare, rapidly progressing versus a chronic, slow progressing neurological disease, although the considerations and rationale may be very different between these two settings,” Biogen writes, pointing to the agency’s recent guidance on gene therapies for retinal disorders as a model.
The company also calls on FDA to develop disease-specific guidance for neurodegenerative diseases that offer recommendations for clinical development, including study design, dose selection, safety considerations and study endpoints.
Cognizant of resource constraints at the Center for Biologics Evaluation and Research (CBER), something that both FDA and industry are seeking to address in the ongoing Prescription Drug User Fee Act negotiations, Biogen notes that sponsors have faced challenges securing meetings with the agency through the channels suggested in the guidance.
In its comments, Passage Bio seeks additional flexibility around characterizing manufacturing processing prior to early-stage trials, specifically with regard to determining critical quality attributes (CQAs) and critical process parameters (CCPs).
“Passage Bio believes this is challenging for manufacturing processes for [first in human] FIH studies considering the limited amount of development material for characterization and testing, the limited experience with the manufacturing process and the complexity and variability of the gene therapy manufacturing process at this stage of development and the state of the analytical method robustness,” the company writes, adding that it may be difficult to identify or confirm CQAs at such an early stage and instead recommends using representative clinical gene therapy product in appropriate nonclinical and toxicology studies to provide evidence of safety and efficacy before launching FIH trials.
Passage Bio also points out that manufacturing processes and methods continue to be refined during clinical development, which may impact both CPPs and CQAs. “Prior knowledge with similar products and similar processes along with representative development lots should allow the establishment of early-stage process controls for the manufacture of the clinical grade product.”
Additionally, Passage Bio, Biogen and Lonza suggest that FDA adopt a risk-based approach for determining limits for residual product-related impurities, rather than setting a specific limit.
“The guidance should provide a recommendation where a total residual DNA level should be strictly controlled and kept at a minimum without the 10ng/dose limit. Instead, examples of risk assessment elements should be included with justification of individual viral vector residual host cell DNA limits for specific gene therapy programs,” Biogen writes.
On the clinical side, Passage Bio suggests FDA be more flexible on the use of innovative trial designs and the types of biomarkers that may be used to support accelerated approval. “Treatment-related changes in biomarkers that reflect alterations in the targeted disease pathophysiology, especially when multiple biomarkers reflect similar directional changes in different pathophysiological manifestations of the disease, should also be considered acceptable surrogates for accelerated approval, pending eventual confirmation of effects on clinical outcomes.”
Novartis also recommends that FDA leverage its experience with small molecule drugs, biologics and other cell and gene therapies to develop a platform that would allow developers to reduce redundancies across development programs.
“Well characterized common attributes shared across programs can facilitate the use of a common data set without unnecessary redundant studies. There are not enough resources to sustainably develop gene therapies for rare and ultra-rare diseases if full development programs are required for each therapy,” Novartis writes. The company also requests numerous clarifications throughout the guidance and proposes FDA incorporate several different risk assessments in its CMC recommendations.
In its comments, Health Canada suggests that FDA modify its recommendations regarding species selection. As written, FDA suggests that “animals with larger brains or spinal columns, such as pigs or nonhuman primates may provide additional safety information and facilitate dose extrapolation.”
However, Health Canada says that, “Previous experience with gene therapies (GT) for neurodegenerative diseases have demonstrated that adeno-associated virus-based vectors that biodistribute to CNS tissues can cause neurodegeneration in [nonhuman primates]. The neurotoxicity is believed to be immune-mediated and species specific (i.e., does not occur in rodents),” and suggests that FDA clarify the immune function aspect in species selection.


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