BrainStorm Call for Updated FDA Approaches for Rare Disease Therapies in Journal Article

Rare Daily Staff

BrainStorm Cell Therapeutics’ CEO has escalated the company’s long‑running dispute with the U.S. Food and Drug Administration over how emerging ALS and regenerative medicine therapies should be evaluated, arguing that regulators are still judging 21st‑century science with 20th‑century tools.

In a new perspective article in the Journal of the Academy of Public Health, BrainStorm President and CEO Chaim Lebovits and board member Peter Pitts, a former FDA associate commissioner, argue that advances in biomarkers, genomics, artificial intelligence, regenerative medicine, and precision therapeutics have transformed what is scientifically possible, while many FDA review practices still reflect older models built around large, homogeneous trial populations and traditional drugs.

They frame ALS as a “stress test” of whether U.S. regulators can adapt to fast‑moving science in small, heterogeneous, rapidly progressive diseases, where disease trajectories vary widely and therapeutic signals may be confined to specific subgroups or disease stages.

The authors note that Congress and FDA have, on paper, embraced tools meant to create regulatory flexibility, such as special designations, the Regenerative Medicine Advanced Therapy pathway, adaptive trial designs, real‑world evidence, and patient‑focused drug development. Nevertheless, they argue that implementation remains uneven, especially for autologous cell therapies and other regenerative products with individualized manufacturing and complex mechanisms of action. They describe a persistent gap between leadership‑level commitments to flexibility and more conservative instincts within review divisions.

BrainStorm’s experience with NurOwn in ALS serves as the article’s central case study. The company’s biologics license application was initially met with a Refusal to File letter in 2022, prompting BrainStorm to “file over protest,” which forced the agency to conduct a full review and convene a Cellular, Tissue and Gene Therapies Advisory Committee meeting in September 2023. FDA staff argued that the BLA was “scientifically incomplete,” citing manufacturing deficiencies and missing biomarker data, and external advisers voted overwhelmingly that existing evidence did not demonstrate efficacy in mild to moderate ALS.

Against that backdrop, Lebovits and Pitts highlight FDA’s decision to grant a Special Protocol Assessment (SPA) for BrainStorm’s planned phase 3b NurOwn trial as a critical marker of regulatory legitimacy, describing an SPA as a “scientific contract” that follows extensive negotiation over trial design, endpoints, and statistical methods.

They contend that once such a framework is formally agreed upon, later criticisms questioning a program’s scientific validity raise concerns about internal consistency and erode confidence among investors, clinicians, and patients. Lebovits presents the SPA‑backed Phase 3b trial as evidence of what is possible “when a sponsor and regulator work together in good faith,” and as a path to relaunch NurOwn’s development after its earlier regulatory setbacks.

The article calls for broader use of Bayesian statistical approaches and integrated evidence models in ALS, arguing that regulators should synthesize signals from multiple datasets—including prespecified subgroups, biomarker trajectories, and expanded‑access or long‑term survival data—rather than treating each trial in isolation.

In NurOwn’s case, they argue that long‑term survival and functional outcomes from the company’s Expanded Access Program could reasonably serve as informative priors when interpreting subgroup findings from its completed phase 3 study, framing this not as a lowering of standards but as a better fit for biologically complex, iterative evidence generation in neurodegenerative disease.

The authors also point to FDA’s 2023 Accelerated Approval of Biogen and Ionis’s Qalsody (tofersen) for SOD1‑mutant ALS, which the agency approved primarily on the basis of reductions in neurofilament light chain (NfL) rather than a positive primary clinical endpoint, as evidence that the agency is willing to rely on biomarker‑driven inference in ALS. They argue that once FDA accepts a biomarker‑centered framework for one ALS therapy, principles of administrative consistency require comparable flexibility for similarly situated programs, warning that biomarker‑based latitude cannot be reserved for selected sponsors while others, implicitly including BrainStorm, are held to more rigid evidentiary standards.

“Future policy decisions will determine whether American regulatory institutions can evaluate these therapies using standards aligned with contemporary biomedical science rather than frameworks inherited largely from another era,” they write. “The future of rare disease innovation may very well depend on the answer.”