FDA offers first thoughts on neurodegenerative disease gene therapies
The FDA has issued draft guidance on the development, testing, and trial design for human gene therapies for neurodegenerative diseases. The document, released on Tuesday, also highlights approval pathways for these novel products.
The draft guidance, which applies to products for both adult and pediatric populations, emphasizes the importance of early communication with FDA before the submission of an investigational new drug (IND) application. The agency pointed to INTERACT meetings, which can be used to discuss issues in a product’s early preclinical program, and pre-IND meetings, which occur later in development but prior to the submission of an application.
Early interaction with FDA’s Office of Tissues and Advanced Therapies (OTAT), part of the Center for Biologics Evaluation and Research, may include product-specific considerations related to the evaluation of drug product purity, identify, potency, and strength.
FDA also recommends that sponsors evaluate the effect of manufacturing process changes on the product’s critical quality attributes (CQAs). In cases where the effect is not immediately identifiable, sponsors should consider conducting a two-part risk analysis prospectively looking at pre- and post-change product, as well as retrospectively analyzing post-change product samples that have been preserved.
When developing preclinical studies for gene therapy products, the agency recommends focusing on five overall objectives:
1、Identification of a biologically active dose range
2、Recommendations for an initial clinical dose level, dose-escalation schedule, and dosing regimen
3、Establishment of feasibility and reasonable safety of the proposed clinical route of administration
4、Support of patient eligibility criteria
5、Identification of potential toxicities and physiologic parameters to guide clinical monitoring
When considering pediatric, first-in-human clinical trials where there is “more than a minor increase over minimal risk,” the agency is calling on sponsors to design a preclinical program that includes studies showing the potential for direct benefit of the gene therapy. “Preclinical evidence to support a prospect of direct benefit is most important when clinical evidence of effectiveness is not available from adult subjects with the same disease,” FDA wrote.
FDA suggested that innovative clinical designs — not only randomized, placebo-controlled trials (RCTs) — could be used for clinical development for monogenic disorders with a well-characterized pathogenesis and pathophysiology, such as infantile spinal muscular atrophy due to mutations in the survival motor neuron 1 gene. However, traditional RCTs are likely more appropriate for neurodegenerative diseases with a poorly understood etiology and a variable natural history, such as sporadic amyotrophic lateral sclerosis or sporadic Alzheimer’s disease.
But sponsors are advised to at least consider innovative trial designs — adaptive designs, enrichment designs, dose-controlled studies, or historical controls — for any neurodegenerative disorder.
When planning pediatric trials, FDA recommends that sponsors first obtain preliminary safety and effectiveness data in adults. If no prior adult data is available, sponsors should provide a rationale as to why adults studies are not ethical or feasible.
In any clinical trials that are intended to support a marketing application, FDA advises that the primary efficacy endpoints should be either clinically meaningful endpoints or surrogate endpoints that are “reasonably likely” to predict a clinical benefit.
An effect on a clinically meaningful endpoint would generally be used to support a marketing application under the traditional approval pathway, while surrogate endpoints could be used to support accelerated approval. “Use of a surrogate endpoint may be appropriate when a [gene therapy] product directly targets an underlying, well-understood and well-documented monogenic change that causes a serious neurodegenerative disorder,” the agency wrote. “In these cases, the [gene therapy] product could alter the underlying genetic defect and thereby treat or cure the disease.”