The Challenges of Clinical Studies in Rare Diseases: Strategies for the Pharmaceutical Industry

Rare diseases collectively affect a considerable number of people: between 6,000 and 8,000 distinct conditions, affecting more than 300 million individuals worldwide, including around 30 million in Europe and nearly 3 million in France (Orphanet, 2025). In Europe, a disease is considered rare if it affects fewer than 1 in 2,000 people (Regulation (EC) No 141/2000). These conditions, mostly of genetic origin (about 72%), are often chronic, progressive, and disabling, and are life-threatening in nearly 50% of cases. Yet only 5 to 10% currently have a specific approved treatment.

Clinical trials for orphan drugs are the main route to fill this major therapeutic gap. However, they face structural, scientific, logistical, and regulatory challenges far more pronounced than for common conditions. This article details these obstacles and presents proven and emerging strategies, drawing on the EMA (European Medicines Agency) and FDA (U.S. Food and Drug Administration) frameworks, to guide pharmaceutical stakeholders toward more efficient development.

The main challenges of rare disease clinical studies

1. Patient recruitment and retention: the number one bottleneck

Extremely low prevalence (often <1/50,000 for ultra-rare diseases) leads to massive geographic dispersion of patients. A trial requiring 100 participants may need recruitment in 10 to 20 countries, multiplying investigator sites and costs. Conventional approaches (hospital advertising, local databases) often fail: recruitment timelines regularly exceed 2-3 years, and up to 30-40% of sites enroll no patients at all.

Retention is just as problematic. Pediatric patients, frequent in this field, face major constraints: repeated travel, school absences, and an impact on family quality of life. Severe comorbidities and the risk of adverse events increase dropout rates. In addition, late or incorrect diagnoses and socio-economic or cultural barriers further reduce the eligible population.

2. Protocol design: heterogeneity and unsuitable endpoints

Clinical and genetic heterogeneity (for example, different mutations within the same disease such as Duchenne muscular dystrophy) makes stratification and the definition of homogeneous endpoints difficult. The lack of robust natural history data complicates the interpretation of results and the construction of external or historical controls.

Randomized, double-blind, placebo-controlled trials (the gold standard) often become ethically and practically unfeasible: cohorts too small, impossibility of reaching conventional statistical power (80-90%), and a high risk for severely ill patients of being randomized to placebo. Traditional endpoints (overall survival, time to progression) are sometimes too distant or insensitive over reasonable timeframes.

3. Regulatory and ethical framework: high requirements vs. limited feasibility

The EMA and the FDA require "substantial evidence of effectiveness" (often at least two adequate and well-controlled pivotal trials, 21 CFR 314.126). In rare diseases, this is rarely achievable without compromising feasibility. The use of placebo raises major ethical questions (Declaration of Helsinki, art. 33), especially for lethal or rapidly disabling conditions.

Costs soar: a pivotal trial for a rare disease can reach €50 to 150 million, against a limited potential market, even at high prices. Despite incentives (orphan drug designation, US tax credits, EMA fee reductions), the return on investment remains uncertain.

4. Operational and cross-cutting challenges

These trials also face a shortage of investigators and centers of excellence, with only a few specialized university hospitals per condition. Added to this are the heterogeneous national regulatory requirements within the EU despite the Clinical Trials Regulation (CTR) 536/2014, and still-limited access to real-world evidence (RWE) to validate results in real-life conditions.

Innovative strategies to accelerate and succeed in trials

1. Patient-centric and digital recruitment

Partnerships with patient associations (EURORDIS, AFM-Téléthon, etc.) and national or international registries (Orphanet, RD-Connect, the French National Rare Disease Database) make it possible to quickly identify patients through targeted approaches. Digital campaigns (patient portals, social media, apps) and decentralized trials (telemedicine, home nursing, wearables) drastically reduce the burden and increase retention by 20 to 40% according to several post-COVID studies.

2. Innovative and flexible statistical designs

EMA guidelines (Reflection paper on methodological issues in confirmatory clinical trials planned with an adaptive design, 2007; Guideline on the use of surrogate endpoints, 2023) and FDA guidelines (Adaptive Designs for Clinical Trials of Drugs and Biologics, 2019) encourage several approaches: N-of-1 trials and crossover designs for ultra-rare conditions; basket and platform trials, such as COMBAT with several arms for neuromuscular diseases; single-arm trials with synthetic historical controls or natural history data, as in the approval of Zolgensma for SMA through historical comparison; and the integration of real-world data (RWD) and registries for post-approval confirmatory evidence.

ICH E9(R1) (Estimands and Sensitivity Analysis, 2019) and ICH E6(R3) (Good Clinical Practice, draft 2023-2025) modernize these approaches by promoting flexibility and digital technologies.

3. Accelerated regulatory pathways

Several mechanisms can speed up development: orphan designation, with protocol assistance, fee waivers, and market exclusivity (10 years in the EU, 7 years in the US); PRIME (EMA) and Breakthrough Therapy Designation (FDA), with enhanced interactions and rolling review; and conditional marketing authorisation (EMA) and Accelerated Approval (FDA), allowing approval on validated surrogate endpoints, such as dystrophin in DMD, with post-approval commitments. New hubs are also emerging, such as the Rare Disease Cures Accelerator (FDA) and the European Rare Disease Research Alliance (ERDERA). In France, the PNMR4 (2025-2030) strengthens the care-research-industry networks.

4. Technological innovation serving trials

Artificial intelligence and machine learning identify patients through EMR and claims databases. Digital biomarkers (apps, sensors) and omics (genomics, proteomics) accelerate the validation of surrogate endpoints.

Turning challenges into opportunities

Clinical trials in rare diseases require a complete overhaul: patient-centric, regulatorily agile, technologically advanced, and collaborative. By adopting these strategies, the industry can shorten timelines, control costs, and increase success rates.

At Keena Life Sciences, we put our expertise at the service of biotechs and pharmaceutical companies to design and execute high-performing orphan programs: development of innovative protocols, EMA/FDA regulatory strategy, recruitment optimization through patient networks and RWD, and support through to marketing authorisation.

Developing a drug candidate for a rare disease? Contact us today for a personalized strategic analysis and move your project toward the patients waiting for it.