Over 30 million European citizens suffer from rare diseases with an incidence of fewer than five in 10,000 people. The European project IDeAl for “Integrated Design and Analysis on small population group trials”, involving LIH as a partner, addresses the limitations of conventional statistical methodology in evaluating new therapies in clinical trials.
IDeAl is a multiparty research project coordinated by the University Hospital Aachen, Germany, and funded by the 7th Framework Programme for Research and Technological Development of the European Commission. It was successfully completed after having run for 3.5 years until mid 2017. The project aimed at establishing new statistical methods specifically adapted to clinical trials on treatments for rare diseases typically involving small sample population groups. At LIH, members of the Competence Centre for Methodology and Statistics headed by Prof Stephen Senn have been leading one of the work packages of the project.
Clinical trials with limited sample sizes
From 2000 to 2010 in Europe alone, over 60 orphan drugs have been approved with the majority based on studies with sample sizes below 50. Ethical limitations and age variability in paediatric clinical trials also limit sample size, as do studies on personalised medicine where efforts to tailor therapies to individual patients’ needs significantly lower the participant number.
Statistical methodology is well-accepted for validating the results of clinical trials and proving the efficacy and safety of new therapies. However, most statistical methods are suited for large population studies where assumptions on the validity of the methods are usually handled by increasing the sample size. This cannot be implemented in small group trials where the rarity of the disease or the sparse geographic distribution of patients hampers clinical trial recruitment numbers.
There is an imminent need for adapting innovative methodologies in the setting of small sample population group trials. To address this, the scientists of the IDeAl project proposed to refine statistical methodology for application in small population group trials such as those testing novel therapies for rare diseases.
Addressing the shortcomings of existing methods
According to the guidelines of the European Medicine Agency, clinical trials should be designed based on benefit risk assessment and avoided if knowledge can be transferred from similar large population studies. ‘If information about the dose response relation is known in larger populations, such as adults, extrapolation would allow smaller clinical trials in the paediatric population,’ explains project coordinator Prof Ralf-Dieter Hilgers from the University Hospital Aachen.
When applied to small population size trials, conventional statistical methodology leads to reduced confidence. Furthermore, it cannot adequately address heterogeneity in patient outcome or the limited repeatability of clinical trials. To circumvent these issues, IDeAl researchers developed statistical methods to adapt the significance level and allow confirmatory decision-making in clinical trials with small populations.
In addition, they developed methodology for the selection of the best practice randomisation procedure, a key technique used in clinical trials to avoid bias. Further achievements included modelling approaches for trial outcome analysis, methods accounting for individual responses as well as identifying biomarkers and prognostic scores in small sample studies.
Clinical benefits
Undoubtedly, the methodological progress achieved by the IDeAl project will aid the design and analysis of clinical trials, leading to more cost-effective and reliable studies. ‘Importantly, the tools, software packages and the 33 recommendations generated during the IDeAl project will support clinical research of rare diseases and pave the way for medical and pharmaceutical advances,’ predicts Prof Hilgers.
It is no surprise that the project attracted worldwide interest from patient advocacies and rare disease consortia as well as regulatory agencies that have over 1,000 new therapies in the pipeline for approval.
News adapted from CORDIS – Community Research and Development Information Service, European Commission: http://cordis.europa.eu/result/rcn/203830_en.html