Practical tips for designing and conducting an effective rare disease clinical trial

In the case of rare diseases, where treatment pathways are often undefined and patient populations are small, early and strategic engagement with regulatory authorities is critical. Due to the limited precedent for clinical trials in these conditions, early communication with agencies, such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA), can significantly streamline drug development efforts.

Mechanisms like pre-investigational new drug (pre-IND) meetings with the FDA or scientific advice procedures with the EMA offer valuable opportunities to gain insight into regulatory expectations. These engagements can help you clarify key elements, such as appropriate endpoints, acceptable clinical protocol designs, biomarker usage and criteria for selecting patient populations.

By proactively aligning with regulators, you can mitigate the risk of costly delays or rework later in the drug development process and improve the likelihood of successful product approval. Early engagement also allows for discussion of accelerated pathways, such as orphan designation, fast track or PRIME eligibility, which are particularly relevant in the context of life-threatening rare diseases.

When patient populations are limited, traditional randomised controlled clinical trials can be difficult to conduct. In such cases, real-world data and natural history studies play an essential role in supporting clinical development. These data sources provide valuable insights drawn from clinical practice, patient registries, electronic health records and observational studies of disease progression over time.

Using this information can enhance clinical trial design and support regulatory submissions in several ways:

• Serve as external control arms. In the absence of a feasible control group, real-world data and natural history data can offer a comparator for assessing treatment efficacy, especially when placebo use is ethically or logistically challenging.
• Inform inclusion/exclusion criteria. These datasets help identify relevant clinical characteristics and disease subtypes, improving patient selection criteria and ensuring the study population accurately reflects the target population.
• Help define clinically meaningful endpoints. Understanding how a disease progresses naturally enables you to select endpoints that capture meaningful changes in patient health, function or quality of life — criteria that resonate with both regulators and patients.

Recruitment and retention in rare disease clinical trials can be particularly difficult due to the small, geographically dispersed patient populations and the high physical and emotional demands often placed on both patients and their caregivers.

Many participants face complex health conditions, mobility limitations and the need for ongoing medical care, making it critical to minimise trial-related burden wherever possible. To enhance participation and reduce drop-out rates, patient convenience, accessibility and comfort must be considered for clinical protocol designs.

Key approaches include:

• Minimising travel and site visits. Frequent travel to trial sites can be taxing, particularly for patients with chronic or debilitating conditions. Reducing the number of in-person visits or allowing assessments at local clinics can significantly lower the participation barrier.
• Using decentralised trial elements. Incorporating decentralised clinical trial (DCT) strategies — such as telemedicine visits, remote monitoring and electronic consent (eConsent) — can allow participants to complete many study activities from home, improving accessibility and engagement.
• Including patient advocacy groups in protocol development. Engaging with patient advocacy organisations early in trial planning helps ensure the protocol reflects the lived experiences and needs of patients. These groups can provide valuable insights into acceptable procedures, appropriate endpoints and optimal ways to communicate with the community.

Because rare disease patient populations are often small and geographically dispersed, global trials are frequently necessary to meet enrolment targets and gather meaningful data.

However, operating across multiple countries introduces several challenges: differing regulatory requirements, variable site infrastructure, language barriers and logistical complexities related to drug supply, data collection and patient monitoring. Choosing the right sites is critical to overcoming these hurdles and ensuring your clinical trial runs efficiently.

A successful global site strategy requires careful consideration of:

• Regulatory timelines and processes. Each country has unique regulatory and ethics committee procedures, which can impact clinical study start-up timelines.
• Site experience and infrastructure. Sites must not only have prior experience with rare disease trials but also the appropriate facilities, staffing and patient referral pathways.
• Access to eligible patients. Some sites may have excellent infrastructure but lack access to the specific patient population required, making early feasibility assessment essential.
• Cultural and language considerations. Patient recruitment materials, consent forms and communication strategies must be adapted to local contexts.

Recruiting participants for your clinical trial is uniquely challenging due to the small, dispersed and often hard-to-identify patient populations. Traditional recruitment methods, such as outreach through clinical sites or physician referrals, are often insufficient on their own.

To overcome these barriers, you must adopt innovative, patient-centric strategies that broaden outreach and build trust within the rare disease community. Collaborating with patient advocacy organisations, leveraging rare disease registries and employing targeted digital recruitment techniques can dramatically improve both awareness and enrolment outcomes.

Patient advocacy groups play a particularly powerful role — not only in helping identify potential participants but also in serving as trusted voices that can educate communities about trial opportunities, reduce misconceptions and encourage participation. Simultaneously, digital platforms offer tools to reach patients in real time, even in geographically remote areas, and tailor messaging to resonate with specific patient demographics.

Best practices include:

• Building partnerships with advocacy organisations. Engage with patient groups early in the trial planning process — not just for recruitment, but to gain insights into disease burden, trial expectations and how best to communicate with the community. Co-develop outreach materials to ensure messaging aligns with patient values and priorities.
• Using social media and geotargeting to reach patient populations. Platforms like Facebook, Instagram and patient forums allow for highly targeted outreach based on geography, disease keywords, age or caregiver status. Paid campaigns with geotargeting can be particularly effective in regions with known patient clusters or registry hubs.
• Offering multilingual, culturally sensitive recruitment materials. Ensure all study materials are translated accurately and adapted to reflect local culture, healthcare norms and communication preferences. This enhances inclusivity and builds trust, especially in multinational clinical studies.
• Collaborating with rare disease registries. Work with global or regional registries to identify pre-consented patients who may be eligible for trials. Registries also offer valuable epidemiological insights that can inform recruitment strategies.
• Creating patient-friendly digital platforms. A dedicated trial website with lay-friendly language, FAQs, eligibility criteria and contact forms can streamline engagement. Include videos or testimonials from patients, investigators or advocates to humanise the trial experience.
• Providing clear pathways to trial enrolment. Make it easy for patients or caregivers to take the next step — whether it’s contacting a study coordinator, joining a pre-screening database or signing up for updates on future clinical studies.

Traditional fixed clinical trial designs often lack the flexibility needed to optimise outcomes. Adaptive trial designs offer an alternative that allows you to pre-specify modifications to your clinical trial based on interim data, without compromising the integrity or validity of the study.

These designs can include features such as seamless Phase I/II or II/III transitions, response-adaptive randomisation, Bayesian statistical models and dose-finding algorithms, all of which enable more efficient use of limited patient data.

Adaptive designs also help you learn more from fewer patients, accelerate clinical development timelines and reduce exposure to ineffective treatments. Additionally, adaptive designs can enhance patient safety by enabling early stopping for futility, efficacy or safety concerns — an especially important consideration in vulnerable populations.

Therapies for rare diseases may offer transformative benefits, but they also carry potential long-term risks and unknowns that may only emerge years after treatment. As a result, regulatory agencies such as the FDA and EMA often mandate extended post-treatment observation periods — sometimes up to 15 years for certain gene therapies.

Beyond regulatory compliance, long-term data is essential to building payer confidence, informing real-world effectiveness and supporting future label expansions. You must, therefore, plan proactively for post-marketing commitments and post-authorisation safety studies, which often include patient registries, observational cohorts or long-term extensions of the original trial.

Establishing infrastructure early — such as data capture systems, patient re-contact mechanisms and partnerships with patient advocacy groups — can help ensure seamless continuation of patient follow-up after trial completion and product approval.

TMC is a global pharma services group that partners with innovative biotech and pharmaceutical companies to bring new medicines to market. We support clinical development and delivery — across all phases of clinical studies globally — for rare conditions and diseases. Contact us today to find out how we can help you successfully bring potentially life-saving treatments to patients as quickly as possible through our clinical services.