I recently attended the World Orphan Drug Congress in Boston, and one of the things I appreciated most was that many of the conversations were less about commercialization and more about how we continue to evolve the science behind developing therapies for rare and ultra-rare diseases.
At Egeria, we spend a great deal of time talking with patients, caregivers, and physicians. One thing we hear repeatedly is that two people with the same rare disease can have remarkably different experiences. Symptoms vary. Severity varies. The aspects of the disease that have the greatest impact on daily life can vary. That reality isn’t new. What was interesting was seeing how clinical trial thinking is beginning to catch up with it.
Several sessions focused on moving beyond singular endpoints toward composite measures that better capture the overall burden of disease. Rather than relying on one assessment, such as a six-minute walk test or a single measure of lung function, researchers are increasingly asking how to evaluate improvement across the many ways a disease can manifest. It seems like a subtle shift, but it has significant implications. If we’re measuring what truly matters to patients, we’re more likely to demonstrate meaningful benefit in a way that reflects the reality of living with these conditions.
That same willingness to rethink convention extended to trial design itself.
In ultra-rare diseases, every patient enrolled in a clinical trial is incredibly valuable. Several discussions explored alternatives to traditional control arms, including the possibility of using carefully curated historical data as an external control instead of assigning patients to standard of care when they could potentially benefit from an investigational therapy. These approaches are not without challenges, but they reflect a broader willingness to think creatively about how to generate rigorous evidence in very small patient populations.
Of course, innovation in trial design also depends on regulators being willing to evolve alongside the science. As our understanding of rare diseases grows, the frameworks we use to evaluate meaningful evidence need to evolve as well.
Another fascinating topic was the idea of N-of-1 therapies, where a treatment is developed for a single patient with an ultra-rare genetic condition. It’s hard to imagine a more personalized approach to medicine, and it raises important questions about development, regulation, and access. While these cases are uncommon, they offer a glimpse into where precision medicine may be headed.
Finally, one theme was impossible to miss throughout the conference: advocacy. Patients, caregivers, and advocacy organizations are increasingly becoming partners from the earliest stages of product development, not just participants once a clinical trial begins. They are helping researchers understand which outcomes matter most, how disease truly affects daily life, and ultimately how therapies should be evaluated.
For me, the common thread running through many of these discussions was a willingness to challenge long-held assumptions. Whether it was rethinking clinical endpoints, exploring new trial designs, or bringing patients into development earlier, the underlying question was the same: How do we generate evidence that better reflects the realities of rare disease?