Clinical research and trials in rare diseases face evident obstacles: very or exceptionally low disease prevalence, small and heterogeneous patient populations, difficulty to recruit such patients, disease severity, lack of or limited knowledge of disease natural history and high attrition rates during R&D processes. The traditional randomized controlled study designs are difficult to conduct in small populations because it is very difficult to create homogeneous groups and to assess changes adequately between variable groups. Controlled rigorous designs that allow within-patient comparisons and treat all subjects would assess therapies more accurately, if feasible.
Response-adaptive methods modify treatment allocation ratios depending on which therapy demonstrates better results. Such methods are complex and rely on real-time data, which may in fact be easier in rare disease populations due to the slow recruitment process. Sequential designs are reasonably common in industry-sponsored trials, while Bayesian methods are still relatively novel. Some trials are first-in-human clinical studies proposed for proof-of-concept assessments, they must therefore be conducted in as homogeneous populations as possible. This further reduces the available population size.
The field needs to develop cost-effective, novel, rigorous controlled study designs and relevant analyses to assess treatment efficacy in heterogeneous small populations. Several international initiatives are selected to improve clinical trial methodologies, and industrial actors are also seeking innovative solutions to conduct clinical trials in small populations to boost research in rare diseases. The goal of this Task Force is to advance discussions on ways to optimize and improve commonly adopted approaches and to reach agreement between the different stakeholders on appropriate small population studies.
The Small-Patients Clinical Trial Task Force Steering members are:
- Simon Day, Clinical Trials Consulting & Training Limited, USA, Chair
- Ralf-Dieter Hilgers, RWTH Aachen, group leader IDEAL, Germany
- Nigel Stallard, University of Warwick, group leader INSPIRE, UK
- Ilan Irony, FDA/CBER/OCTGT, USA
- Kit Roes, UMC Utrecht, group leader ASTERIX, The Netherlands
- Kristina Larsson, EMA, UK
Together with the Scientific Secretariat, the Task Force is creating a draft document for debate on SPCT matters. This draft was open for the community at large for comments and suggestions. This draft is available for comments and consultation. The final Workshop Report and Recommendations are now also accessible.
Plans and timeline
- Late 2015 – Early 2016: Publication of a draft pre-workshop report, which will be open for comments
- March 3, 2016, London, UK: Workshop to be held at EMA to discuss actions to reach agreement between the different stakeholders on appropriate small population studies
- Early 2016 – Mid 2016: Publication of a draft post-workshop report, which will be open for comments
- Mid 2016: Publication of the final workshop report and Task Force recommendations
- End 2016: Publication of a scientific article in a peer-reviewed journal