Translating an early clinical development plan into an effective site and patient selection strategy for rare disease clinical trials

The global rare disease clinical trials market is projected to grow at a compound annual growth rate (CAGR) of 6.8% from 2025 to 2030, with the increasing prevalence of these diseases heightening

demand for clinical research and specialised, innovative treatments — especially in complex oncology and advanced therapeutic modalities like gene and cell therapies.

Equally, greater regulatory support, the growth of patient advocacy groups, and the implementation of hybrid approaches are all making clinical studies significantly more accessible to patients with rare diseases.

Yet one of the first major operational hurdles small to mid-sized biotech and pharma companies face is turning an early clinical development plan into a practical site and patient selection strategy.

Getting this right not only accelerates drug development timelines but is often the difference between a trial that succeeds and one that stalls before it really gets going.

Understanding the unique challenges in rare disease clinical trials

Rare disease research presents several unique hurdles that must be addressed early in strategy — especially for small to mid-sized biotech and pharma companies, where budgets, headcount and operational resources are constrained.

Inherent challenges include:

1. Extremely small and dispersed patient populations. By definition, rare diseases affect very few patients spread across large geographies. This makes traditional site selection less effective and requires innovative approaches, often forcing you to work ‘backwards’ from where patients actually are.
2. Recruitment and retention difficulties. Identifying eligible patients is one of the top challenges biotech and pharma companies face — especially those with limited internal clinical operations infrastructure. Competition from other clinical studies further exacerbates this issue.
3. Complex clinical study protocols and high trial burden. Conventional clinical study protocols don’t always apply to rare disease clinical trials. These trials often involve complex endpoints, intensive monitoring or decentralised components that can deter patient participation.

These challenges are real pain points, but when anticipated early, they can be mitigated through strategy and smart execution, such as patient-first clinical study protocol design, early site/patient ecosystem mapping, natural history integration, and a clinical development plan built specifically for rare disease recruitment/retention.

From clinical development plan to actionable study strategy

Turning a clinical development plan into a site and patient strategy is mostly about making assumptions explicit, pressure-testing them with data, and then building an operating model that can deliver — especially when you have limited internal resources.

Here are five key consideration points to help you turn your plan into a successful trial.

1. Use data-driven site feasibility

Traditional feasibility (site surveys and historical enrolment claims) is often too optimistic in rare disease clinical trials. The goal is to move from ‘site interest’ to a defensible view of where patients actually are, how they flow through care and what fraction is trial-ready.

As such, you should use multiple sources — registries, natural history cohorts, real-world data where available and advocacy group insights — to triangulate patient concentrations. Then, convert prevalence into a practical forecast by applying real filters (diagnosis rate, genotype availability, stage, travel tolerance, exclusions and competing trials).

This approach reduces the risk of opening non-performing sites and protects timelines tied to funding and milestones.

2. Broaden the site network without losing control

Academic medical centres (AMCs) are essential for rare disease expertise, but an AMC-only network can bottleneck enrolment and limit diversity.

A hub-and-spoke approach is often more effective: use expert centres for diagnosis confirmation and complex procedures, complementing them with community sites or specialist clinics for routine visits and follow-up. This method expands reach, improves diversity and reduces travel burden — while keeping the science anchored in experienced hubs.

The key is standardisation with training, clear workflows and consistent endpoint administration so that added sites don’t introduce variability that undermines small sample sizes.

3. Lean into decentralised clinical trial elements

Decentralised clinical trial components help rare disease studies more than most because geography and burden drive dropout risk, but only if they’re implemented with operational simplicity and data integrity in mind.

Start by identifying which assessments truly require a site and which can be done remotely or locally. Prioritise high-impact, low-friction components — such as tele-visits, home nursing for routine labs and travel support — before adding more complex technology.

For small to mid-sized sponsors, the operational risk is vendor sprawl and data fragmentation, so success depends on simple ownership, clear workflows and proactive monitoring to prevent missing data.

4. Engage patient advocacy groups early to de-risk protocol and enrolment

Advocacy groups can accelerate awareness, improve trust and, most importantly, surface practical barriers that determine participation — helping you design a clinical study protocol people will actually join and stay. However, engagement with these groups must be done in a way that is ethical, compliant and mutually valuable.

You should engage advocacy groups before protocol lock to stress-test visit schedules, procedures and what outcomes matter to patients before co-developing patient-facing materials that are understandable and credible.

For small and mid-sized sponsors, early engagement also helps overcome limited brand recognition and clarifies how patients move through the diagnostic and referral ecosystem.

5.  Adopt industry trends selectively and tie them to operational outcomes

AI, advanced analytics and hybrid trial models can be powerful, but they only matter if they change execution. As such, it’s essential to know when to adopt and how to adopt without overbuilding.

Use AI and digital tools to support cohort estimation, site targeting and pre-screening — not as a replacement for clinical validation. Data-driven recruitment works when models translate into actionable leads through registries, referral pathways and diagnostic ecosystems. Hybrid participation is becoming commonplace, but technology should be chosen based on endpoint relevance and operational simplicity, especially when internal teams are small.

Strategise early and execute clinical studies confidently

For rare disease clinical trials and complex therapeutic programmes, success hinges on understanding where patients are, how they live and what tools and partnerships will bring them into your trial.

Translating an early clinical development plan into a pragmatic site and patient selection strategy, therefore, requires foresight, creativity and cross‑disciplinary alignment.

If you want to improve participant access while maintaining data quality and regulatory compliance, you need local expertise and integrated, dynamic teams with extensive experience and a deep understanding of the inherent challenges of complex indications Top of Form

TMC Clinical specialises in early-phase clinical trials for rare disease, complex oncology and advanced therapeutic modalities — combining the responsiveness of a specialist pharma services company with the expertise of a clinical research organisation.

Our clinical development services provide complete support — from site feasibility, key opinion leader identification and submitting your clinical trial application for first-in-human pivotal studies to ongoing site management, medical monitoring and reporting to relevant regulatory agency gateways.

TMC Clinical enables you to move efficiently from first-in-human to global pivotal trials. Contact our team today at connect@tmcpharma.com to see how we can support you, as a single partner from development through market entry, to conduct seamless clinical studies for your novel treatment.