Rare Disease Development: Navigating Small Populations and Complex Protocols

Each rare disease may affect only a few thousand, or even a few dozen, people worldwide. Yet together, rare conditions impact millions of patients and families. Developing effective therapies for these populations is one of the most complex and meaningful challenges in clinical research.

At Veristat, approximately 25% of our work supports clinical programs for rare and ultra-rare diseases. In the past five years, our teams have contributed to more than 390 clinical trials and consulting projects and supported 26 regulatory approvals for rare disease therapies. From this experience, we know that success depends on strategic foresight, flexible scientific design, and meaningful collaboration among researchers, regulators, and patient communities.

This high-level guide is intended to help sponsors anticipate the unique scientific, operational, and regulatory considerations that define rare and ultra-rare disease development and to provide practical insight drawn from Veristat’s extensive experience in this field.

Start With a Deep Understanding of the Disease

Every successful program begins with knowledge. Before designing a study, sponsors must understand how the disease manifests across patients, including genetic and phenotypic variability that may influence response to therapy. Even with a well-defined genetic cause, the clinical presentation can differ widely. Recognizing these differences early informs patient selection and endpoint strategy.

Equally important is understanding what matters most to patients and caregivers. Engagement with advocacy groups provides insight into symptom burden, meaningful outcomes, and barriers to participation. These conversations can reveal what makes a protocol feasible or too demanding for a small population spread across regions.

Consider This: What do patients and caregivers identify as the outcomes that would most improve quality of life, and how can those shape study endpoints?

Design for Flexibility and Feasibility

In rare disease development, there is no standard model. The study design must fit the population. Traditional randomized controlled trials may not be possible when only a few dozen eligible patients exist worldwide. Sponsors must consider alternative designs such as adaptive, crossover, or single-arm trials.

Natural history studies and real-world data (RWD) collection are essential tools in this setting. They provide baseline information about disease progression and, if designed correctly, may serve as external comparators when control groups are not feasible. In slowly progressing diseases, biomarkers can provide early insight into treatment effect if validated as predictors of clinical benefit.

Selecting endpoints also requires balance. They must be measurable, clinically meaningful, not lead to undue burden on the patient, and achievable within the trial's timeframe. In some programs, composite or patient-reported outcomes capture change more effectively than a single clinical measurement.

Consider This: Given the disease’s natural history and rate of progression, which endpoints or biomarkers best demonstrate a clinically meaningful impact within a feasible timeframe?

Work Collaboratively With Regulators From the Start

Regulators worldwide share the same goal: to make effective therapies available for patients as quickly and safely as possible. Agencies such as the FDA, EMA, MHRA, Health Canada, and PMDA all encourage early dialogue on study design, endpoints, and nonclinical requirements.

Because rare disease programs often involve small datasets, regulators apply a flexible, science-based approach. Early agreement on safety requirements, statistical methodology, and evidence standards helps prevent unnecessary delays. Sponsors should also evaluate opportunities for accelerated pathways such as Breakthrough Therapy, RMAT, PRIME, Fast Track, or Priority Review/Accelerated Assessment, and align their evidence generation accordingly. While Orphan Drug Designation (ODD) is not an accelerated review pathway, early pursuit can provide important development incentives such as fee reductions, regulatory support, and longer market exclusivity that may influence overall program planning.

Global planning is essential. Most rare disease studies require multinational participation to reach sufficient enrollment, so sponsors should coordinate interactions with multiple agencies to ensure consistency across regions.

Consider This: Have you engaged each relevant agency early enough to identify shared expectations and reduce divergence later in development?

Prioritize Patients Through Coordination That Simplifies Complexity

Rare disease trials may be small in size but are often complex. Sponsors often collect genomic, imaging, functional, and patient-reported data across a small, geographically dispersed cohort. Managing that data requires both precision and adaptability.

Operationally, site and visit models such as centralized sites, hybrid or virtual visits, and at-home data collection can expand access while reducing the burden on patients and families. Close collaboration between clinical operations, data management, and biostatistics teams ensures that quality is maintained across every site and vendor.

Consider This: How can participation for patients be simplified without compromising data quality or regulatory expectations?

Plan Globally, Execute Cohesively

Because patients are dispersed worldwide, rare disease programs inherently require a global footprint. Sponsors that align study design, regulatory interactions, and submission strategy under a unified plan gain efficiency and consistency.

Regulators are increasingly coordinated in their approach to rare disease review, but regional nuances remain. Planning for convergence early—through parallel discussions with the FDA, EMA, and other authorities—helps ensure that evidence packages meet global expectations while avoiding duplication.

Consider This: Have you designed your clinical and regulatory strategy to meet the expectations of multiple agencies within a single, coherent framework?  See our recent blog on this topic here.

Learn From Every Program

Each rare disease study expands collective understanding of how to run small, complex trials successfully. Sponsors that document and share lessons learned on design feasibility, data integration, and patient engagement strengthen future programs.

At Veristat, we analyze outcomes across hundreds of rare disease projects to refine study strategies, streamline execution, and anticipate emerging regulatory expectations. This continuous learning loop allows each new program to build on what came before.

Consider This: How will your team capture and apply what you’ve learned to strengthen future decision-making?

Veristat's Perspective

Each rare disease program is a contribution to knowledge that shapes future innovation and brings hope to patients that have waited too long to realize the potential of a promising therapy. With over 25% of our work dedicated to rare and ultra-rare disease programs, Veristat brings proven experience across therapeutic areas including oncology, neurologic, and pediatric indications. Our integrated teams align clinical design, statistical strategy, and regulatory guidance to help sponsors create feasible studies, manage complex data, and deliver clear, defensible submissions to global agencies. To discuss how early, integrated planning can accelerate your rare disease development program, connect with Veristat’s experts.