Running a clinical trial for rare diseases is very different from trials in more common conditions. Small patient numbers, limited data, and complicated rules make every part of the process more careful and more creative. Instead of going over the basics, this article focuses on advanced but practical things that experienced sponsors need to think about—from choosing the right countries and trial sites to designing studies that actually work in rare disease populations.

Let’s walk through five key considerations in this space: Feasibility, Study Design, Approvals and Policies, Trial Execution, and Site Selection. Each step builds on the other, and how you handle one directly affects the next.

1. Feasibility planning for rare disease trials

The first step is figuring out where and how the trial can work. This is more than just asking if patients are available—it’s about understanding the environment you’re stepping into.

Country-level planning: Rare disease patients are often spread across many countries, and most of them may not even be diagnosed yet. You need to understand where patients are likely to be, but also where healthcare systems can support the trial. Some countries have good incentives for rare disease studies, while others might have long approval timelines or no experience with these conditions.

Site-level reality: Even within the right countries, not every site will work. Traditional databases might show high recruitment numbers, but that doesn’t mean those sites know how to handle rare conditions. You need to assess whether they have the right diagnostic tools, the right specialists, and, ideally, connections with local patient groups.

Using data and tools: Technology can help here. Platforms that use real-world data and patient registries can help you find clusters of patients and newer investigators with real disease knowledge—even if they haven’t run trials before. Mentorship programs between experienced and new investigators are also proving valuable.

As you finish feasibility, you’ll have a better picture of what kind of study design will actually work on the ground.

Would you like to learn more about feasibility in rare disease clinical trials? Click here to find out more.

2. Study design choices for rare diseases

In rare diseases, traditional randomized trials aren’t always possible. You’re often working with very few patients, high variability, and limited historical knowledge of the disease.

Flexible study models: Advanced sponsors often use adaptive trial designs, which let you change parts of the study—like the number of patients or treatment arms—based on what early data is showing. This makes the most of limited data without needing to restart the trial.

Creative structures: Umbrella and basket trials help group patients in smarter ways. Umbrella trials test different treatments in one disease with different subtypes. Basket trials look at one treatment across different diseases that share a genetic marker. Both save time and patients.

Avoiding placebo when needed: Placebos can be ethically tricky in rare diseases. In those cases, synthetic or external control groups, created using historical data or real-world evidence, are helpful. But the quality of that data has to be strong and similar to your patient group.

Advanced stats, simple goals: Bayesian and other model-based statistical methods are often used when patient numbers are small. These models help you get reliable answers without needing huge sample sizes.

Would you like to learn more about clinical trial phases and study designs? Click here to explore.

Once your design is in place, the next big task is aligning it with regulators.

3. Approvals and policies

Approval in rare disease trials isn’t just about paperwork. It’s about building long-term conversations with regulators and taking full advantage of available incentives.

Using orphan drug benefits: Getting orphan drug designation early gives you benefits like fee waivers, market exclusivity, and special support from agencies like the FDA or EMA. But to qualify, your data has to clearly show that the disease is rare and that the treatment idea is solid.

Faster approval pathways: Rare disease studies often use fast-track or breakthrough therapy pathways. These let you use early or surrogate endpoints, sometimes including real-world evidence, to speed up approvals. But you still need to show regulators that the data is meaningful.

Grants and tax breaks: Many governments offer help—grants, tax credits, and support for natural history studies. Smart sponsors factor these into planning to reduce costs and make projects more attractive to funders and partners.

Staying flexible with regulators: Rules and expectations change, especially in rare diseases. Sponsors need to stay in close touch with agencies and be ready to adjust protocols and submission packages.

Once approvals are in motion, the next major task is getting the trial off the ground and keeping patients engaged.

Interested in learning more about regulatory incentives for rare diseases? Click here to explore.

4. Running the trial and keeping patients

Running a clinical trial for rare diseases often means going above and beyond standard operations. Every patient is critical, and the dropout of even one participant can affect results.

Making trials easier for patients: Rare disease patients may live far from trial sites or have mobility issues. Sponsors are increasingly offering services like home visits, travel coordination, or even digital visits. Remote monitoring tools and electronic diaries also reduce the need for clinic visits and help keep data flowing.

Keeping patients informed and involved: Trust matters. Sponsors who work with patient advocacy groups from the start—on materials, consent forms, and communication—see better retention. Patients who feel part of the process are more likely to stay involved.

Spotting issues early: Real-time data dashboards and monitoring tools help site teams catch problems fast. This prevents missing data and reduces the chances of needing to redo parts of the study.

Interested in learning how engagement influences patient retention in clinical trials? Click here to learn more.

Keeping patients leads into the next step: making sure sites are equipped to handle all of this.

5. Choosing the right sites

Site selection isn’t just about geography—it’s about trust, experience, and readiness.

Targeting patient-rich regions: Using disease registries and AI-based tools, sponsors can find regions with the most likely eligible patients. Choosing the right locations means fewer barriers to recruitment and better overall trial performance.

Checking site readiness: Not all hospitals are equipped for rare disease trials. Sponsors assess sites on whether they have the right equipment, trained staff, and past experience with complex studies. On-site visits and deep-dive questionnaires help verify this.

Using networks wisely: Centers of excellence and rare disease networks are valuable. Sponsors who partner with them early gain faster startup times, better quality data, and more reliable patient access.

Maintaining quality across all sites: Digital tools for central monitoring and regular training ensure that protocols are followed and data is consistent—especially important when patient numbers are low and every data point matters.

Want to learn more about Key Aspects To Consider While Selecting A Site for clinical trials? Click here.

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Do you have any questions about challenges in clinical trials for rare diseases? 

Hope you found these key considerations in rare disease clinical trials helpful. If you have any questions or would like to discuss your specific trial needs, feel free to reach out—just fill out the form below to connect with our experts.

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