The FDA has spent years trying to fit rare disease drug development into regulatory models that weren't designed for rare diseases. Its new Framework for Rare Disease Review suggests the agency is finally prepared to confront the consequences.
It's also an exciting beginning for Karim Mikhail, the new director of the FDA's Center for Biologics Evaluation and Research (CBER). Mikhail takes charge of a center responsible for evaluating some of the most complex medical technologies ever developed. He has an early opportunity to demonstrate that scientific flexibility is an essential part of rigorous regulatory review, not a special favor granted when patients and their families become sufficiently desperate.
The framework deserves strong support. Whether it succeeds will depend on how the FDA handles the next difficult application, not how enthusiastically it announces a new approach.
Randomized, controlled clinical trials remain indispensable to modern medicine. But insisting on conventional trial designs when patient populations are small, disease progression is variable, and recruitment is difficult can make it harder to determine whether a treatment works. The problem isn't randomization. It's the assumption that the same evidentiary approach is appropriate for every disease, regardless of its biology or the practical limitations of studying it.
Amyotrophic lateral sclerosis (ALS) makes the problem painfully clear. Patients lose motor function, speech, swallowing, and ultimately the ability to breathe. Progression varies substantially, and opportunities for meaningful intervention narrow as the disease advances. Yet developers must frequently work within evidentiary expectations established for much larger, more homogeneous populations. Familiarity with a particular clinical trial design doesn't necessarily make it the right design.
In my recent Journal of Clinical Investigation article, "Do the Math," I describe this problem as denominator collapse. As medicine becomes more precise, the populations most likely to benefit from targeted therapies become smaller. Molecular diagnostics, genetic characterization, and biomarkers allow researchers to identify biological distinctions that were previously invisible. That's a major scientific achievement, but it also challenges statistical assumptions developed when patients were routinely grouped into broad diagnostic categories.
We cannot demand precision medicine while refusing to modernize the methods used to evaluate it. When the denominator shrinks, the evidence must be assessed with greater attention to biological plausibility, clinically meaningful outcomes, and the limitations of small populations. This isn't an argument against statistical rigor. It's an argument against statistical ritual.
The FDA's proposed framework recognizes the problem and offers a sensible response: fit-for-purpose evidence, innovative trial designs, more sophisticated statistical methods, outside scientific expertise, and greater consistency across review divisions. None of these concepts is particularly new. Much of the necessary flexibility already exists under current law. What's been missing is the institutional discipline to apply it consistently.
Developers shouldn't encounter materially different evidentiary expectations simply because their application lands in a different review division. Nor should the agency agree to a scientifically justified development strategy early in the process only to introduce fundamentally different expectations after the trial is completed. Special Protocol Assessments and other formal mechanisms for early agreement should provide meaningful predictability, subject to legitimate new scientific information. Regulatory expectations should change when the science changes, not when the decision becomes politically or institutionally uncomfortable.
For ALS patients, these are consequential issues. Consider neurofilament light chain (NfL), a biomarker of neuronal injury that has become increasingly important in ALS research. Changes in NfL may provide valuable information about disease activity and biological responses to treatment. They don't automatically establish clinical efficacy, but they can contribute to a broader assessment of whether a therapy is having a meaningful effect.
The FDA should evaluate such evidence in context. Does the biomarker response support the proposed mechanism of action? Are clinical observations consistent with the biological findings? Are natural-history comparisons reliable? What uncertainties remain, and can they be addressed through additional studies or appropriate post-approval commitments? These questions require experienced scientific judgment, not the mechanical application of a preferred statistical template.
The agency must reject applications that fail to meet the statutory standard for safety and effectiveness. Patients deserve protection from ineffective therapies and false promises. But requiring another lengthy trial carries consequences of its own. For someone with ALS, another year of regulatory uncertainty can mean the permanent loss of functions that no subsequent approval can restore. Regulatory delay is not a scientifically neutral act.
Karim Mikhail takes the reins at CBER at an important moment for regulatory science. The agency has put the right principles on paper. Now comes the harder part: making them matter in actual regulatory decisions. Cell therapies, gene therapies, and other advanced biological products frequently present scientific questions that cannot be resolved through conventional development models.
CBER can demonstrate how rigorous, fit-for-purpose evidence should be evaluated without compromising its responsibility to protect patients. That will require leadership willing to defend sound scientific decisions, including difficult ones. It will also require administrative consistency and parity across CBER and the Center for Drug Evaluation and Research. Patients shouldn't face different interpretations of the same scientific principles depending on which center has jurisdiction over a therapy.
ALS patients aren't asking the FDA to suspend scientific judgment. They're asking the agency to exercise it. That means understanding the difference between uncertainty that can be responsibly managed and uncertainty that genuinely prevents approval.
The FDA has identified the problem. Now it needs to prove that it can solve it. The agency has the luxury of debating regulatory reform. ALS patients don't have the luxury of waiting for it.
Peter J. Pitts, a former FDA Associate Commissioner, is Executive Chairman of Brainstorm Cell Therapeutics, a company developing an investigational treatment for ALS.
