Warwick Medical School is to lead one of three prestigious EU projects on developing methodology for clinical trials within small populations, aiming to create further opportunities for new treatments of rare diseases. Professor Nigel Stallard will lead the InSPiRe (Innovation in Small Populations Research) project, with an EU grant of €2.3m to bring together international experts in innovative clinical trial design methodology from across the globe. The focus will be on the development of novel methods for the design and analysis of clinical trials in rare diseases or small populations defined, for example, by a rare genetic marker.

A rare disease is defined to be one that effects less than one in 2,000 of the general population, though many are much less common than this, perhaps affecting only a handful of people in any country. Around 30 million people in Europe suffer from a rare disease.

In such settings where numbers are scarce, the large clinical trials that are generally used to evaluate new drugs and other healthcare interventions are infeasible or often impossible. As a result, new approaches to the design of such studies, or improved methods of data analysis and subsequent decision-making, are needed.

Speaking about the InSPiRe project, Professor Stallard said, “The conduct of clinical trials in small populations is exceedingly challenging and this acts as a brake on the development of new treatments. This project will develop methods that will enable more reliable results to be obtained from clinical trials more quickly, ultimately leading to improved healthcare for these small population groups.”

“It’s important that these new, improved methods enable rapid evaluation of treatments whilst maintaining scientific and statistical rigour. New methods will include the combination of trial data with information from other studies, adaptive trial designs that allow most efficient use of the data and optimal decision-making processes that allow a conclusion to be made as quickly as possible.”

HEALTH.2013.4.2-3 identifies a need for new or improved statistical methodology for clinical trials for the efficient assessment of safety and/or efficacy of treatment for small population groups.

Clinical trials in small populations present a number of novel statistical challenges associated with the need to draw inference from the necessarily small sample sizes. The EMEA CHMP Guideline on Clinical Trials in Small Populations and the report of the US Institute of Medicine Committee on Strategies for Small-Number-Participant Clinical Research Trials propose a number of potential statistical approaches. These include efficient trial designs, such as sequential and adaptive methods, and innovative methods that enable data from outside the trial to be used both at the design stage and assimilated with trial data in the final inferential process. Based on the recommendations of these guidelines and building on recent relevant methodological advances in this area, the aim of this project is to develop novel statistical methodology for clinical trials in small populations.

We have identified four specific areas where we believe novel methodology for clinical trial design is needed and achievable. These are (i) early phase dose-finding studies in small populations, (ii) decision-theoretic methods for clinical trials in small populations, (iii) confirmatory trials in small populations and personalised medicines, (iv) use of evidence synthesis in the planning and interpretation of clinical trials in small populations and rare diseases. These four areas will form the four main Work Packages, WP1, WP2, WP3 and WP4, of the project

The project team brings together a team of international experts in innovative clinical trial design methodology along with key stakeholders including regulatory authorities, clinicians, industry and representatives of patient groups. Team members have been carefully chosen for their knowledge and experience in the four key areas listed above. Strong working relationships already exist between many members of the team, with a track record of published work and grant funding as evidence of successful previous collaborations. This makes us confident that we can work effectively on this project to meet the objectives described below and to address the need stated in HEALTH.2013.4.2-3.