Brainstorm leaders urge FDA to update treatment review process
Company officials say scientific advances call for new regulatory tools
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Two leaders at Brainstorm Cell Therapeutics, which is developing the experimental cell-based therapy NurOwn (debamestrocel) for people with amyotrophic lateral sclerosis (ALS), have published a paper calling on the U.S. Food and Drug Administration (FDA) to modernize its review process for experimental therapies for ALS and other rare diseases.
The paper argues that the FDA has not consistently implemented modern tools aimed at speeding the development and approval of important new therapies for rare and heterogeneous diseases, and instead often falls back on frameworks that were developed decades ago and are not well suited for more complex disorders such as ALS.
The paper, “Restoring Regulatory Fairness and Reclaiming Biomedical Leadership: ALS, Rare Disease Regulation, and the Future of Regenerative Medicine,” was co-authored by Chaim Lebovits, Brainstorm’s president and CEO, and Peter J. Pitts, a company board member and former FDA associate commissioner. It was published in the Journal of the Academy of Public Health.
“We’re asking regulators to evaluate 21st-century science with the most up to date tools,” Pitts said in a company press release. “The Agency now has these tools, including Accelerated Approval, adaptive trial design, Bayesian statistics, and biomarker qualification. In this paper we discuss how those tools can be applied more consistently in ALS and regenerative medicine.”
Process ill suited to rare, variable conditions, authors say
The FDA is a government agency that has final say over approvals of new medical treatments in the U.S. Traditionally, FDA approvals have relied on well-designed clinical trials, usually involving many people with a disease who are given either a treatment or a placebo, to test whether an experimental therapy is safe and effective.
This same framework is still largely used to assess investigational ALS therapies. But Pitts and Lebovits argue that it falls short in ALS for several reasons. For one, the disease is highly variable: In some people, it leads to paralysis and death within months, while others will live for decades. This means datasets are inherently noisy, and it can be difficult to tease out the effects of a treatment from all the variability. And ALS is a rare condition, so there are logistical constraints on the number of patients who can be included.
“Existing approval structures were largely designed around traditional pharmaceuticals, large populations, and relatively uniform disease models. ALS is none of those things,” Pitts and Lebovits wrote. “The disease progresses unevenly, patient populations are small, and therapeutic effects may emerge differently across stages of illness.”
The authors also noted that, under traditional frameworks, a long delay in obtaining approval is generally considered a neutral factor, allowing decisions to be made with scientific rigor. But in fast-progressing diseases such as ALS, they argue, there are additional ethical issues to consider.
“In ALS, time is a clinical variable. Patients who deteriorate during prolonged review cycles may never live long enough to benefit from eventual approvals,” they wrote, noting that this reality “does not eliminate the need for scientific rigor, but it does change the ethical calculus.”
‘Persistent institutional conservatism’
Over the past two decades, the FDA and lawmakers have established several structures to speed drug development. These include designations to fast-track development and a mechanism called accelerated approval, in which the FDA can allow a therapy to be conditionally brought to market based on early positive data, while further studies to prove efficacy are ongoing.
Pitts and Lebovits said the modernization agenda is clear on paper, but actual application of these tools has been inconsistent, revealing what they called “persistent institutional conservatism.”
They contend that the FDA has tended to fall back on established frameworks and has been reluctant to adopt cutting-edge techniques such as modern statistical models and computational analyses. These types of analyses are especially important in variable and rare diseases such as ALS, they said.
“Regenerative medicine, biomarker-driven approvals, adaptive statistical methodologies, and individualized therapeutics are no longer speculative concepts,” the authors wrote. “They are becoming central features of modern medicine.”
“Future policy decisions will determine whether American regulatory institutions can evaluate [ALS] therapies using standards aligned with contemporary biomedical science rather than frameworks inherited largely from another era,” they said. “The future of rare disease innovation may very well depend on the answer.”
Brainstorm had sought FDA approval of NurOwn for ALS, but ultimately abandoned its application because the agency said available data were insufficient to prove the therapy’s effectiveness. The company is now working on a new Phase 3b clinical trial to further test NurOwn.
The FDA collaborated with Brainstorm on plans for the upcoming study. Under a Special Protocol Assessment, the agency said, the design is generally adequate to support a future regulatory application of NurOwn.
“When science advances, the system has to advance with it,” Lebovits said. “Our Special Protocol Assessment, the first ever granted in ALS, is a good example of what is possible when a sponsor and regulator work together in good faith.”
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