Traditional randomized trials are often impractical for treatments in the rare and ultra rare disease space.
Earlier this year, FDA issued draft guidance that allows for a wider range of data to be used in clinical trials. This includes the incorporation of real-world data (RWD) with study data. For patients with rare diseases, this shift may help solve a serious problem these communities face.
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Due to the small patient populations, rare diseases can be difficult to collect sufficient data for. As a result, patients can often be left waiting while drug makers work their way through a difficult approval process. However, even with this the addition of RWD, the approval process for rare diseases is still long and difficult, which can be frustrating for patients and the doctors treating them.
Pharmaceutical Executive spoke with Dr. Patricia Greenstein, a neurologist and geneticist at Beth Israel Deaconess Medical Center. She has more than 30 years of experience in clinical medicine and research and is an advocate for raising awareness for rare neurological diseases.
PE: What is the FDA's stance on real-world data (RWD)?
Dr. Patricia E. Greenstein: The FDA's stance on RWD has undergone a meaningful shift in early 2026. Rather than treating RWD solely as supplemental or post-marketing evidence, the Agency is now integrating it more formally as a core evidentiary component of drug evaluation––particularly in rare and ultra-rare diseases where traditional randomized trials are often impractical.
At the center of this shift is the FDA's increasing acceptance of a "single pivotal trial plus confirmatory evidence" model, where high-quality real-world evidence can serve as confirmatory support, reducing or even eliminating the historical expectation for a second Phase 3 trial. The emphasis is not on volume of data, but on validity––RWD must be transparent, reproducible, and able to withstand rigorous statistical scrutiny comparable to conventional clinical trials. For certain ultra-rare conditions, the Agency has also shown greater openness to natural history data as an external control arm, where demonstrating outcomes meaningfully different from the expected disease course may be sufficient to support approval even without a randomized control group.
PE: How would the acceptance of RWD impact approval timelines?
Greenstein: For patients waiting on new therapies, the acceptance of RWD can meaningfully shorten the time between scientific discovery and treatment availability. One of the biggest impacts is the reduced need for duplicate late‑stage clinical trials. Allowing a single pivotal trial supported by real‑world evidence can eliminate years that would otherwise be spent designing and conducting an additional Phase 3 study.
This is particularly important in rare diseases, where recruitment itself can be a major bottleneck. When real‑world data or natural history cohorts can be used as external controls, patients are less likely to be placed in placebo groups, and far fewer patients are needed overall. That not only reduces timelines but also lessens the burden placed on patient communities that may already be small and over‑studied.
In addition, newer FDA processes––such as rolling submissions supported by ongoing real‑world data collection––allow regulators to review evidence as it emerges rather than waiting for a complete dataset at the end. For patients, this can translate into earlier regulatory decisions and, ultimately, earlier access to therapies that address serious unmet needs.
PE: What avenues do pharmaceutical companies have to speed up approval timelines for rare disease treatments?
Greenstein: Pharmaceutical companies pursuing rare disease therapies have several regulatory avenues to expedite development. The Plausible Mechanism Pathway allows the FDA to approve therapies targeting a known biological cause based on biomarker confirmation and clinical plausibility, even from a single-patient study. Accelerated Approval (Subpart H) permits approval based on a surrogate endpoint rather than direct clinical benefit, though it is now increasingly paired with mandatory post-launch RWD collection to confirm real-world effectiveness. Master Protocols allow multiple related therapies or indications to be evaluated under a single regulatory framework, avoiding the need for a completely new application for every genetic variation. Finally, Breakthrough Therapy and Regenerative Medicine Advanced Therapy (RMAT) designations offer intensive FDA guidance and eligibility for priority review––Breakthrough Therapy for drugs showing early substantial improvement over existing options, and RMAT as a specialized fast-track for cell and gene therapies.
FDA Issues Guidance on Modernizing Statistical Methods for Clinical Trials. FDA. January 12, 2026. Accessed April 21, 2026.
