Representative enrollment has been a core component of clinical research for years, but with the passage of the Food and Drug Omnibus Reform Act, it’s taken on greater significance, especially for rare disease researchers.

Sponsors are now expected to align enrollment goals with disease epidemiology, connecting study populations more directly to how conditions present in the real world. While this may seem like a small change, it has significant implications. After all, enrollment decisions influence how data is interpreted, how regulators evaluate submissions, and ultimately how confident clinicians feel applying the results.

At the same time, the operational hurdles haven’t gone away. Nearly 11% of research sites fail to enroll a single participant, and 37% of sites under-enroll, slowing timelines and draining industry resources.

For rare disease programs, these pressures tend to show up more quickly and with greater impact.

Why rare disease trials require a different approach

Rare disease research has always operated within tighter constraints. Patient populations are smaller, spread across wide geographic areas, and often receive care in community settings that don’t routinely participate in clinical trials.

But when enrollment falls short in this environment, the impact extends beyond timelines. Smaller sample sizes make it harder to interpret safety and efficacy data, especially when outcomes vary across different patient groups. It’s even more difficult in conditions where genetic or demographic factors influence response, since those gaps can shape how results are understood.

As expectations continue to evolve, rare disease research teams are taking a closer look at how they build their enrollment strategies from the ground up.

Rethinking enrollment as part of trial design

Enrollment has traditionally been treated as a downstream function, with teams focusing on site activation and outreach once protocols are finalized. But that approach can create friction when enrollment goals don’t align with how a disease presents in the real world. 

Many organizations are shifting their focus earlier in the process, connecting enrollment strategy with data, site selection, and patient experience from the start. As a result, a few key adjustments are becoming more common:

1) Start with a clear view of the patient population

Enrollment targets tend to be more effective when they reflect real-world disease patterns rather than internal assumptions. Data sources, such as electronic health records and patient registries, offer a clearer picture of where patients are located and how conditions present across different populations.

Using this information to guide recruitment helps teams set targets that are grounded in reality and easier to justify in regulatory discussions. In rare disease programs, it also provides a way to document when certain enrollment goals may not be feasible due to the nature of the population itself.

2) Build site networks that extend beyond major centers

Many advanced therapies are still administered at specialized academic centers or large hospitals, which makes sense from a safety and oversight perspective. But limiting participation to those locations can leave eligible patients out of reach.

In response, site networks are expanding to address this gap. Structured referral pathways between community providers and specialized centers make it easier to identify patients who might otherwise be missed. When those pathways are supported with clear processes and dedicated coordination, participation becomes more accessible. It also avoids adding unnecessary complexity for providers.

3) Make long-term participation more manageable

Rare disease trials often require routine follow-up, sometimes over the course of several years. For patients and families, that commitment can be difficult to sustain, especially when it involves frequent travel or time away from work and daily responsibilities.

The good news is that technology is helping reduce some of that burden. Remote monitoring, telehealth visits, and home-based services allow certain aspects of follow-up to happen outside the clinical site. When these options are incorporated thoughtfully, they can support more consistent participation and lead to more complete data over time.

4) Incorporate patient perspectives earlier

Patient advocacy groups and care communities have long been involved in supporting awareness and recruitment efforts, but in many cases, that input came in after core design decisions were already made. That’s starting to change as teams bring those perspectives into recruitment and protocol planning earlier in the process. 

Early engagement helps teams identify barriers that might not be obvious from an operational standpoint. Visit schedules, eligibility criteria, and logistical requirements all influence who can realistically participate. Bringing that feedback into protocol development creates a stronger alignment between study design and patient experience.

A more integrated path forward

The expectations tied to FDORA are influencing how clinical teams think about enrollment across the entire trial development process. Decisions that were once made independently are becoming more connected, from how targets are set to how patients are identified and supported throughout the study.

For rare disease research, where each participant contributes meaningful weight to the data, that level of coordination matters. Thoughtful planning, broader access, and sustained engagement all contribute to studies that reflect real-world conditions and hold up under regulatory review.

At Harbor Clinical, we regularly support biopharmaceutical organizations navigating these regulatory changes through flexible functional service provision. Whether you need targeted support or broader operational coverage, our subject matter experts work alongside sponsor teams to help align trial execution with evolving expectations.

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