Rare Disease Trial Recruitment: The Role of Patient Registries

Giulia: When trials compete for the same patient population, or when no established patient network exists in a given rare condition, traditional recruitment collapses back onto two narrow levers: center-of-excellence reach and the sponsor’s capacity to fund patient mobilization programs. Some rare disease indications are already highly saturated. A couple of examples that come to mind are myasthenia gravis, Duchenne muscular dystrophy, spinal muscular atrophy, sickle cell disease, and certain hemophilias. In these settings, multiple sponsors converge on the same handful of expert sites and the same already-diagnosed patients. Washout periods and exclusion criteria can further lock each enrolled patient out of competing studies. This is a saturation problem no site-execution fix can solve.

Most of the 7,000-plus rare diseases have no registry, no center of excellence, no advocacy organization, no natural history dataset. So in low-infrastructure indications, the sponsor has no entry point at all. Even when centers of excellence are available, many rare disease patients do not have a formal diagnosis for their cluster of symptoms. In our experience, this makes EMR-based identification structurally impossible.

Reliance on a few academic centers compounds the problem. This is because their patient panels are finite and often exhausted, their catchment does not reach community-treated or geographically distant patients, and the limited pool of expertise and sites with research experience in a specific rare disease creates geographic and socioeconomic barriers.

Giulia: Joining a rare disease trial could be blocked by many factors. Two major barriers are awareness and geography. Many patients never hear about studies from their treating clinicians, and geographic distance to trial sites represents one of the most significant barriers, particularly for rare disease patients who may find only a handful of trial locations across the country or even globally.

Layered on top are restrictive eligibility criteria built around homogeneous populations and screening criteria designed for common diseases, which screen out the real-world rare disease patient with comorbidities or atypical presentations. There is also the emotional weight of consenting to an unproven therapy when less than 10% of rare diseases currently have an available treatment approved by the FDA.

The financial and logistical hurdles are equally burdensome. Nearly two-thirds of patients and caregivers say travel has stopped them from participating in a clinical trial, with childcare, including for siblings, lost wages, and upfront out-of-pocket costs disproportionately excluding lower-income families.

Jennifer: I believe that the greatest value comes when a registry includes contact information for potential participants and the appropriate consent for patients to be contacted about clinical trial opportunities. In those cases, the registry can support more targeted outreach, help identify potentially eligible patients earlier, and create a more efficient path from awareness to prescreening.

Even when a registry does not include patient contact information or consent for direct outreach, it can still provide important strategic value. For example, registries based on site-entered data or secondary data sources can help identify geographies with higher concentrations of eligible patients, inform site selection, and support referral planning.

Giulia: We saw that for patients and families, a well-designed registry could be a powerful instrument for reducing the personal burdens that accompany rare disease, starting with the burden of finding the right trial. Registries that prospectively profile diagnosed patients can match them to studies for which they are genuinely eligible, coordinate site selection and patient recruitment in advance across geographies and countries, and surface cross-border participation options that would otherwise remain invisible to a family or their treating physician.

Registries can also dissolve isolation by connecting families to one another, to advocacy organizations, and to expert clinicians, and they generate knowledge that flows directly back into day-to-day disease management. Registries ensure the patient voice remains central to research, championing patient-reported outcomes and shaping research priorities around what matters most in real life.

Finally, patients retain ownership of their data and gain a tangible sense of contribution. This can be a form of agency that survey after survey identifies as one of the most powerful motivators for sustained engagement in the rare disease community.

Jennifer: A well-designed rare disease registry starts with a clear understanding of how the data will be used and who the registry is meant to serve. Ideally, it should allow for direct engagement with patients, including appropriate permissions to contact them for follow-up, research updates, or potential study opportunities.

It is also important to build the registry in partnership with a trusted organization, such as a nonprofit patient advocacy group, when one exists. These organizations often have deep relationships with the patient community and can help ensure that the registry is designed in a way that feels credible, respectful, and valuable to participants.

In our experience, another essential component is selecting the right measures. This is often more complex than it appears. Many patient organizations include research as part of their mission, but designing a registry that produces data that can be meaningfully used in research requires substantial methodological expertise. The choice of clinical, patient-reported, and longitudinal measures needs to be thoughtful, scientifically sound, and aligned with the registry’s intended research goals.

Long-term engagement and retention are also critical. Registries only become more valuable over time if patients continue to participate, update their information, and feel that their contribution matters. When possible, incentives can help support participation, but sustained engagement often depends on whether patients see the registry as meaningful.

Jennifer: I am convinced that one of the most important early decisions is how patients will be involved in shaping the registry. Patients should be engaged from the beginning to help ensure the registry is designed in a way that feels valuable, accessible, and worth participating in over time.

In Alira Health’s experience, it is also important to involve researchers early, particularly those with expertise in the specific disease area. Validated outcome measures should be included when available and fit for the research purpose. Researchers with experience using registries, natural history studies, or other real-world data sources can help ensure that the data being collected will be scientifically meaningful and useful to the broader research community. A scientific advisory committee or steering committee can provide regular oversight and help guide decisions around study design, data elements, endpoints, and future research use.

Consent, governance, and privacy also need to be addressed upfront, not treated as operational details later in the process. Privacy and legal experts should be involved early to ensure that patient consent, data access, and data management processes comply with applicable laws and regulations, such as HIPAA and GDPR.
This early planning is critical because mistakes in consent language, governance, or data management can create major barriers later. A successful registry needs to be built with patient trust, scientific utility, and responsible data stewardship in mind from day one.

Jennifer: In many cases, the strongest approach is to embed a natural history study within a registry rather than treat the two as completely separate efforts. This can reduce cost and decrease the burden on participants, sites, and research teams by avoiding the need to run two separate observational studies.

Ideally, the registry is designed from the beginning to support the types of analyses required for a natural history study. That means collecting the right information on the patient journey, disease burden, disease progression, treatment history, outcomes, and other variables that may be important to understanding the condition over time.

Even when a registry was not originally designed with a natural history study in mind, it may still be more efficient to build on the existing registry than to create a new study from scratch. Missing domains can often be added prospectively, while the registry may already contain historical data that can support natural history analyses.

This is especially important in rare disease, where access to patients is often one of the greatest barriers to completing research. An existing registry may already have an engaged participant population that can be invited to contribute additional data or participate in a more structured natural history component. In that sense, a registry does not necessarily replace a natural history study; rather, it can provide the foundation that makes a natural history study more feasible, efficient, and patient-centered.

Jennifer: One example comes from an ongoing clinical trial in myasthenia gravis, where a sponsor was facing recruitment delays and needed a way to accelerate progress toward last patient in.

Within a short timeline, we co-created patient recruitment materials with our myasthenia gravis Patient Committee and launched an outreach campaign to participants in the AXIS Registry using both email and push notifications. Interested patients were directed to a landing page where they could learn more about the trial and answer a few brief questions about their interest and potential eligibility.

From there, a nurse contacted interested patients to conduct an initial prescreening against the trial’s eligibility criteria. This step was important for two reasons. First, it helped avoid overburdening sites with patients who were unlikely to qualify. Second, it helped protect patients and families from unnecessary site visits, particularly when long-distance travel was involved, and ineligibility could be identified remotely.
Patients who appeared to meet the prescreening criteria were referred to the site for the remaining screening and consent process. The site then confirmed eligibility and supported entry in the trial.

We were excited to see a high level of engagement from the registry community. Patients were not only responsive, but genuinely eager to learn about opportunities to participate in research. That kind of response reinforces the value of a registry not only as a recruitment tool, but as a trusted channel for connecting patients with research opportunities that may be meaningful to them.

Jennifer: The first piece of advice is to think of a registry as long-term infrastructure, not simply as a recruitment funnel. A registry can certainly support patient identification and trial recruitment, but its value is much broader when it is designed to generate evidence, deepen understanding of the patient journey, and create an ongoing relationship with the patient community.

Clinical operations leaders should also ensure the registry is built with scientific and regulatory utility in mind from the beginning. If a registry already exists, that may mean sharing input with the registry team on the data elements or evidence needs that would make the registry more useful for future research. If a sponsor is developing a new registry, it means selecting meaningful data elements, using standardized measures where possible, and ensuring strong consent and governance processes. It also means designing the registry with enough methodological rigor to support future research uses, including natural history analyses, external control arms, post-marketing evidence generation, or label-expansion strategies.

Giulia: I would like to underline that co-creation truly matters. Patients and advocacy partners should have a role in the registry’s design, including the questions being asked, the burden of participation, the communication approach, and how results will be shared back.

Wherever possible, sponsors should partner with trusted organizations that already have relationships with patients, such as advocacy groups, nonprofit organizations, research networks, or existing disease-specific registries and natural history studies. If a high-quality registry already exists in a rare disease, partnership with that registry should generally be the first path explored before creating something new.

Finally, I cannot underscore enough that sponsors need to build a deliberate value-return loop. Patients are more likely to remain engaged when they understand how their data are being used and what their participation is helping to advance.