Clinical Trials in Rare Diseases: Challenges and Opportunities

In addition to disease-specific barriers, therapeutic developments in rare diseases face many challenges, such as incomplete understanding of natural histories to inform trial designs, need for alternatives to randomized controlled clinical trials, requirement for more sensitive outcome measures to quantify diseases, limited access to resources – including funding – required to set up clinical trials, and difficulties of recruiting small patient samples to participate in trials. 
Among the above barriers, patient recruitment and enrollment is probably the most challenging, as enrolling enough patients in order to generate statistically meaningful results from a trial can turn to be highly time, energy and money consuming. Such a challenge may be overcome by good trial planning and design from the outset. Involving patient groups at as an early stage as study design could be rewarding as this can help suit patient needs and ensure those that join a study do not withdraw prematurely. 
Planning, design and delivery of clinical trials is rare diseases may also be very challenging in small, dispersed populations, from both logistical and statistical perspectives. Here are some insights that could help on conducting a clinical trial in a rare disease:

• Engage with regulatory authorities early so that an appropriate strategy to achieve approval can be agreed.
• Investigate retrospective studies that can be used to better understand the disease’s natural history, define study endpoints and identify patient groups who are likely to show treatment effects while tolerating the treatment. 
• Maximize the information from the fewest patients – it is desirable that all patients receive the active drug. When patient numbers are very small, a single-arm design may be unavoidable. However, where larger patient numbers are feasible, the use of two-stage parallel designs can gather more information whilst still having all patients receive active drug. 
• It is important to perform a formal sample size calculation – Wherein the expectations of treatment effect size and variability of the primary endpoint are incorporated with adequate control of type 1 error and suitable statistical power given the expected efficacy.
  
• Plan your data collection processes carefully – The small number of patients makes it even more important to ensure that the data collected in rare disease studies is of the highest quality so that you can maximize usage of all data available.