During a recent congressional hearing on rare disease drug approvals, doctors described watching patients deteriorate while therapies remained stalled in regulatory review. As a neurologist and geneticist who has treated spinocerebellar ataxia (SCA) for three decades, and as a principal investigator in clinical trials of a promising therapy, I recognize that testimony not as advocacy, but as clinical reality.
Now, with the recent departure of Vinay Prasad from the Food and Drug Administration (FDA), the agency finds itself at a moment of transition. Dr. Prasad brought a deep commitment to scientific rigor and patient safety – principles that must remain central to the FDA’s mission. But leadership changes also create an opportunity to reconsider how that rigor is applied in the context of rare diseases, where small patient populations and irreversible progression make traditional evidentiary standards difficult to meet.
Congress has already granted the FDA flexibility in evaluating therapies for rare diseases, including the use of real-world evidence and natural history data when traditional large-scale trials are not feasible. The question before the FDA now is not if those tools can be applied – they can – but if the agency has the courage to use them before more patients lose their autonomy, and ultimately, their lives, to this disease.
SCA is a fatal neurodegenerative disorder that progressively destroys the cerebellum, the structure responsible for balance, coordination, posture and speech. When cerebellar Purkinje cells die, those functions do not return.
I began caring for patients with SCA in the mid-1990s. In those early years, every patient I enrolled in research ultimately died from complications of the disease – most commonly aspiration pneumonia or injuries from repeated falls. Many were under 50. For decades, there were no disease-modifying therapies to offer them.
That changed with the development of troriluzole, a therapy designed to reduce damage to vulnerable cerebellar neurons. By regulating glutamate in the brain, the therapy may help preserve Purkinje cell function. In a relentlessly progressive disease, even partial preservation matters.
Since 2019, I have served as a site principal investigator in clinical trials of this therapy. More than 20 of my patients have participated. In SCA1 – one of the more aggressive subtypes – patients typically worsen by one to two points annually on the f-SARA scale, with steep decline often within five years. Most require wheelchairs within a decade.
In our trials, patients who entered ambulatory remained so years later. We have observed a more than 50% reduction in fall risk. Some individuals have now been on therapy for as long as seven years.
Yet, last year, the FDA issued a Complete Response Letter declining approval and citing the need for more “statistical certainty.” This is puzzling to the ataxia community. Troriluzole is a prodrug of riluzole, a drug approved in 1995 and still actively marketed today for ALS patients. Troriluzole is quickly converted to riluzole in the body with safety and dosing advantages.
Previously, the FDA allowed expanded access to troriluzole for SCA patients outside clinical trials in response to more than 300 Right to Try requests. Now, the FDA’s Complete Response Letter means patients who were hoping to access the drug through pending requests – and some who are already receiving it – may lose access.
The FDA’s role in ensuring safety and efficacy is essential. At the same time, rare diseases pose challenges that traditional drug development wasn’t built to handle. Congress has created regulatory flexibility for rare diseases within the FDA’s review framework, and many patients and advocates feel that flexibility is not being applied here.
SCA is uncommon and genetically heterogeneous. Large, prolonged, double-blind trials are difficult to execute, and natural history data already demonstrate consistent decline. Waiting for perfect trial symmetry can mean more patients going the way of their parents and grandparents: rapid degeneration and early mortality.
Investigators have accumulated substantial longitudinal data. Real-world evidence shows a consistent divergence between treated and untreated trajectories. Yet such data have not always been fully integrated into regulatory decision-making.
This creates a profound clinical tension physicians confront directly: how to balance statistical certainty with the reality of irreversible neurological loss.
In SCA, delay has measurable consequences. Without intervention, patients accumulate what I describe as “progression debt” – annual losses of motor function that are rarely regained. Once Purkinje cells are lost, they do not regenerate. A year of delay can mean permanent loss of mobility for patients nearing wheelchair dependence.
If funding collapses and expanded access programs end, patients will decline from their current level of function. As a physician, presiding over that predictable regression poses moral distress.
The congressional hearing underscored what clinicians already know: in progressive neurodegenerative disease, time is not neutral. The regulatory framework has the flexibility to account for rarity. Now it must be used with both rigor and urgency.
Author bio:
Dr. Patricia Greenstein is a neurologist and geneticist with more than 30 years of experience in clinical medicine and research. She specializes in the diagnosis and treatment of complex neurological disorders, with particular expertise in neurogenetic diseases. For the past three decades, Dr. Greenstein has treated patients with spinocerebellar ataxia (SCA), working closely with families affected by these rare, progressive conditions.
Dr. Greenstein is also a principal investigator in clinical trials studying promising new therapies for SCA, helping advance research aimed at slowing or preventing disease progression. She earned her medical degree from the University of the Witwatersrand Medical School in 1984 and is affiliated with Beth Israel Deaconess Medical Center and Beth Israel Deaconess Hospital in Boston, where she is the Program Director for the Neurology Residency Training program and continues to see patients and conduct research. In addition to her clinical work, Dr. Greenstein advocates for greater awareness of rare neurological diseases and the importance of continued investment in innovative treatments.
Photo: wikimedia commons
