Rare Disease Day 2020

In honour of Rare Disease Day 2020, we look at the main challenges of undertaking clinical trials in rare diseases.

Good planning and trial design are vital from the outset

The biggest challenge of any clinical trial in a rare disease is the recruitment of enough patients, in order to generate statistically meaningful results from your trial.

At CROS NT, we strongly believe that this challenge can be overcome by good trial planning and design from the outset and involving patient groups. There are many active and informed patient groups, committed to securing treatments for their patients. By bringing patient groups onboard early, trials can be designed to suit patient needs, helping to ensure those that join a trial stay to the end.

Rare Disease Day 2020Developing new and effective treatments

This is a huge challenge in rare diseases, due not only to their low prevalence and often heterogeneous nature, but also due to the lack of medical and scientific knowledge, and the absence of natural history data and drug development expertise. The chronic, degenerative, and often life-threatening nature of rare diseases means that they are fast becoming a public health priority.

Conducting efficient and successful drug development programme

In 2000, the European Medicines Agency launched the orphan designation programme that gave companies specific incentives to encourage development of new medicines for rare diseases. There are currently more than 140 orphan medicines marketed in the EU and over 1,900 medicines have been granted orphan status. Agencies collaborate internationally to aid the designation and assessment of orphan status of medicines for rare diseases.

In January 2019 the FDA published draft guidance entitled Rare Diseases: Common Issues in Drug Development. The purpose of this guidance was to help sponsors conduct more efficient and successful drug development programmes for products intended for the treatment and prevention of rare diseases.

Top 5 tips to improve your clinical trial

The planning, design and delivery of clinical trials for rare diseases is very challenging in small, dispersed populations, from both logistical and statistical perspectives. We have been working with sponsors for over 28 years and have gained some valuable insights that we would like to share.

  1. Engage with regulatory authorities early – Regulatory authorities understand the problems associated with drug development in rare diseases and are supportive of innovative approaches to study design. Discussion with regulatory authorities at an early stage of development is essential so that an appropriate strategy to achieve approval can be agreed.
  2. Investigate retrospective studies – In rare diseases, a small number of patients are affected, and an even smaller number are available to participate in clinical trials. Retrospective studies can be used better understand the disease’s natural history, define study endpoints and identify patient groups who are likely to show treatment effects and tolerate the treatment. This information will be essential for designing a prospective study in terms of the selection of patients, whether liberalizing eligibility criteria would increase patient numbers, choosing disease-relevant endpoints with feasible treatment effect sizes and variabilities, and duration of therapy.
  3. Maximise the information from the fewest patients – It is desirable that all patients receive 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. For example, patient enrichment for responders or those who can tolerate the active treatment in the Randomized Withdrawal Design and differentiating disease-modifying effects from short-term beneficial effects on symptoms in the Delayed Start Design.
  4. 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.
  5. 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 maximise usage of all the data available. This data will help you support the decision-making process at every stage, from concept to commercialisation.

Working together to advance rare disease research

CROS NT has been supporting sponsors to design and implement clinical trials to support rare disease development programmes and is looking forward to further advances in medicine.