Why Progress for Rare Diseases Is So Hard to Capture in Clinical Trials
For people living with progressive neurological diseases, the only certainty is worsening over time. Improvement is not the expectation. Stability, or simply stalling the disease, can be a big win. Slowing decline can mean the difference between walking independently for another year or needing assistance sooner than expected.
But proving that kind of benefit is one of the hardest problems in rare disease drug development.
That challenge has been especially visible in recent efforts to develop treatments for spinocerebellar ataxia, or SCA, a group of rare neurological conditions that affect balance, coordination, speech, and independence. While patients and families often describe changes they feel in their own bodies, translating those experiences into evidence that meets regulatory standards is far more complex.
Why Progression Is So Hard to Measure
Spinocerebellar ataxia is made up of about 50 different genotypes and worsening of the disease does not follow a straight line. Some people decline steadily. Symptoms can fluctuate day to day, and progression can look different across genetic subtypes.
Because the disease is rare, clinical trials tend to include small numbers of participants, making it difficult to establish clear patterns or averages, especially over short time periods. Traditional trial designs, which often look for improvement compared to a placebo group, can struggle to capture whether a treatment meaningfully slows decline rather than reverses it.
Researchers have long acknowledged this problem in progressive neurological diseases. When decline is gradual and uneven, detecting change requires sensitive tools and long follow-up periods that are not always feasible in rare disease trials. Regulators have also recognized these challenges and have regulations that allow for flexibility in such circumstances.
In a rare disease workshop, the FDA noted, “Rare disease drug development is complex; there can be limitations in our understanding of the natural history of a disease; challenges with endpoint selection; and the fact that small populations can also lead to challenges with trial design and interpretation.”
Why Slowing Decline Matters to Patients
For patients, the value of slowing progression is not theoretical. It shows up in everyday life. Being able to stand without support for longer. Holding onto clear speech a bit more. Delaying the need for mobility aids or full-time care.
Advocacy organizations have consistently emphasized that what matters most to people with progressive diseases is not dramatic improvement but preserving function for as long as possible. In surveys and public statements, patients have described time as their most limited resource, noting that abilities lost to progression cannot be regained.
This is where patient experience and clinical measurement often diverge. A person may feel steadier on their feet or notice fewer falls, even if that change does not register strongly on a standardized scale over the course of a trial. What feels meaningful to a patient can be hard to quantify in a way that satisfies scientific and regulatory expectations.
When Real World Experience Meets Trial Endpoints
To bridge that gap, drug developers and researchers increasingly turn to real-world data, natural history studies, and externally controlled comparisons. These approaches aim to show how a person’s disease trajectory compares to what would typically be expected without treatment.
In describing its SCA program, Biohaven pointed to evidence it believes supports this approach. The company said that “compelling data from troriluzole’s drug application included a three-year real-world evidence study showing slowing of SCA disease progression by 50-70% in troriluzole-treated patients compared to matched untreated external controls.”
Regulators have acknowledged that real-world evidence can play a role when traditional trials are impractical, while also emphasizing the need for data that can be interpreted with confidence.
Taken together, this raises a recurring question in progressive diseases with no approved treatments: whether and how regulatory flexibility should be considered when safety is not the primary concern, yet evidence of benefit remains difficult to quantify.
The Weight of Waiting Without Clear Answers
For families following treatment development, this measurement gap can be emotionally taxing. When evidence is inconclusive or disputed, the result is often delay rather than resolution. Time continues to pass and disease progression continues alongside it.
Advocacy groups have said that uncertainty itself becomes a burden when regulatory processes stretch on. Patients are asked to wait while questions about data and design are debated, even as their bodies change in ways that are deeply personal and irreversible.
After the FDA declined to approve Biohaven’s experimental treatment for SCA in November, the National Ataxia Foundation responded, writing that while it respects the FDA’s role, “the experiences and priorities of people living with Ataxia must play a larger role in these decisions,” and that when no approved treatments exist, “regulatory flexibility and consideration of patient risk tolerance are not just important, they are essential.”
Biohaven has said it is appealing the FDA’s decision, a process that could extend the timeline as questions about evidence and measurement continue to be debated.
The challenge facing researchers and regulators is real. So is the challenge facing patients who are trying to make sense of a system that struggles to measure what matters most to them.
As work continues to improve how progression is measured and how patient experience is incorporated into evidence, many families say they are watching closely and waiting. Not for guarantees, but for a clearer path that recognizes both the complexity of the science and the reality of living with a disease that does not pause.