Clinical development in rare and orphan indications is often defined by urgency, unmet need, and an extraordinary level of complexity. While scientific innovation continues to drive therapeutic breakthroughs, many rare disease studies struggle to meet one fundamental milestone: patient enrollment and retention.

At Confidence Pharmaceutical Research, we’ve supported trials in more than a dozen rare and ultra-rare indications. Our experience makes one thing clear: success in rare disease trials is not about scaling the usual recruitment strategies—it’s about tailoring every element of the study to the reality of the patient population.

This blog series, Patient Enrollment and Retention in Rare Disease Studies, will explore the operational, strategic, and human-centered approaches that enable sponsors to effectively recruit and retain rare disease patients across all study phases. In this first installment, we introduce the series, examine the diverse nature of rare patient populations, and present an overview of the specialized toolkit required to reach, engage, and support them.

Understanding the Rare Disease Landscape

Rare diseases, by definition, affect a small percentage of the population—but their collective impact is immense. With more than 7,000 identified rare conditions and over 300 million people affected globally [1], there is both an urgent need and a growing opportunity to bring treatments to these underserved patients.

Yet, rare disease trials are consistently more difficult to enroll than those for more common conditions. On average, enrollment timelines are three times longer, and screen failure rates can reach up to 50% [2]. Several factors contribute to these challenges:

• Patients are often geographically dispersed across regions or countries
• Many individuals remain undiagnosed or misdiagnosed for years [3]
• There are limited sites with prior experience or infrastructure to support rare indications
• Study designs tend to be more complex, with narrowly defined eligibility criteria
• Caregiver involvement is essential and must be factored into both recruitment and retention strategies [4]

These realities frequently lead to underestimated timelines, higher dropout rates, and operational strain. Protocols built for general populations may prove unworkable when applied to rare disease settings without significant adaptation.

That’s why this series focuses not just on what makes rare disease enrollment hard—but how to overcome those barriers through smart planning, specialized partnerships, and deep operational insight.

Types of Rare Patient Populations

Understanding your target population isn’t just important—it’s foundational. Rare diseases span a vast range of clinical, social, and logistical realities, and each category of patient population introduces its own enrollment and retention implications.

Here are just a few types you may encounter:

1. Undiagnosed or Misdiagnosed Patients

In diseases where diagnostic tools are lacking—or symptoms overlap with common conditions—patients may remain unrecognized for years. Studies in conditions like ATTR-CM or BED often rely on raising diagnostic awareness at the site level and working closely with referring physicians to capture the right population [5, 6].

2. Pediatric Populations

Children with rare conditions require special consideration: consent and assent processes are more complex, visit structures must accommodate caregivers and schools, and the emotional toll on families is significant. Pediatric studies demand site staff with child-specific training and strong retention support for parents⁴.

3. Rapid Progression Populations

In ultra-rare and life-limiting conditions, patients may decline rapidly. For these studies, time is of the essence, and eligibility windows are narrow. Protocols must be streamlined and site activation accelerated to avoid losing potential participants before enrollment.

4. Patients in Medically Underserved or Isolated Regions

Patients may be spread across wide geographies, far from major medical centers. Without thoughtful site selection and support tools, these patients remain unreachable. Remote visit models, concierge services, and digital consent options can be game-changers here. Identifying your rare population is only the beginning. Understanding how they live, access care, and make medical decisions is what turns feasibility into enrollment.

The Rare Disease Enrollment & Retention Toolkit

At Confidence, we’ve developed a flexible, multi-layered toolkit specifically designed to address the unique demands of rare disease trials. While not every tool is needed for every study, the following elements form a solid foundation for building a viable recruitment and retention strategy:

1. Early Feasibility Modeling

We go beyond incidence and prevalence to include real-world diagnosis rates, referral patterns, site capabilities, and geographic access. This helps sponsors avoid overpromising on timelines or selecting non-viable regions.

2. Tailored Site Selection & Education

Selecting sites with experience in rare disease research is essential—but experience alone isn’t always enough. It’s equally important to ensure that investigators and site staff are aligned with the protocol’s diagnostic definitions and enrollment criteria, particularly in conditions where symptoms may resemble more common diseases. In these cases, a shared understanding of the study’s clinical focus, along with tools to support patient identification and referral pathways, can make the difference between steady enrollment and prolonged delays. Confidence supports sites through targeted materials, clear communication, and collaborative feasibility processes that enable early alignment without overburdening teams.

3. Caregiver-Inclusive Protocol Design

From scheduling flexibility to travel stipends, retention depends on supporting not just the patient—but their ecosystem. That’s especially true in pediatric and degenerative conditions.

4. Customized Recruitment Materials

Generic outreach doesn’t resonate in rare communities. We collaborate with sponsors to create disease-specific, culturally sensitive, and visually accessible materials that build trust and drive engagement.

5. Ongoing Retention Support

There’s no single formula for keeping rare disease patients engaged in a study. What works for one group might not work for another. That’s why we work closely with sponsors to develop practical, personalized strategies—whether that means flexible visit scheduling, regular check-ins, or small gestures that acknowledge a patient’s commitment along the way.

What’s Next in the Series?

In our next post, we’ll explore the vital role of patient support organizations and networks in rare disease trials—highlighting how strategic collaborations can help sponsors not only identify eligible patients but retain them throughout the study.

Whether you’re initiating your first rare disease trial or looking to improve enrollment in an ongoing study, Confidence can help you design for success—starting with the patients you aim to serve.

References

1. Rare Disease Day. (n.d.). What is a rare disease? Retrieved from https://www.rarediseaseday.org/article/what-is-a-rare-disease
2. Global Genes & Tufts Center for the Study of Drug Development. (2019). Orphan Drug Trials in Rare Disease Research: A 2019 Benchmark Report. Retrieved from https://globalgenes.org/wp-content/uploads/2019/08/2019-Tufts-Report.pdf
3. Rare Disease UK. (2020). The Rare Reality – An insight into the patient and family experience of rare disease in the UK. Retrieved from https://www.raredisease.org.uk/news-policy/the-rare-reality-report-2020/
4. U.S. Food & Drug Administration. (2020). Enhancing the Diversity of Clinical Trial Populations – Guidance for Industry. Retrieved from https://www.fda.gov/media/127712/download
5. Maurer, M. S., Elliott, P., Merlini, G., et al. (2016). Diagnosis and management of transthyretin cardiac amyloidosis in the era of noninvasive imaging. Journal of the American College of Cardiology, 68(3), 283–285. https://doi.org/10.1016/j.jacc.2016.03.596
6. Udo, T., & Grilo, C. M. (2018). Prevalence and correlates of DSM-5-defined binge eating disorder in a nationally representative sample of U.S. adults. Biological Psychiatry, 84(9), 627–635. https://doi.org/10.1016/j.biopsych.2018.03.014