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Advances in Small Trials dEsign for Regulatory Innovation and eXcellence

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Advances in clinical trial design for rare diseases

In Europe alone, an estimated 30 million people suffer from a rare disease, a disorder that affects less than 5 out of a population of 10 000. The ASTERIX project addressed the limitations of clinical trials for such diseases, aiming to speed up the implementation of novel therapies.


Currently there are more than 6 000 rare diseases known for their chronic and debilitating effects. From the multitude of new drugs in development with an orphan designation, only a small fraction has reached the market. This highlights the need to revisit methodology for the design of clinical trials for rare diseases, in light of the inevitable sample size restrictions. Randomised controlled trials are the gold standard for testing the efficacy, safety and benefit-to-risk ratio of new treatments. Existing statistical methodology is mostly tailored to large population studies. In the case of rare diseases, increasing trial recruitment numbers is not possible and further hampered by the sparse geographic distribution of patients. Furthermore, the small number of patients limits the treatments that can be studied for the same disease. Since classical statistical methodology can overlook treatment effects in small groups, there is an imminent need for adapting innovative methodologies to suit clinical trials of rare diseases. To improve clinical trial design in small populations, the EU-funded ASTERIX project proposed a comprehensive set of directions for improvement. These included methods to combine observational and clinical data, adapt efficient statistical methods to small groups, design innovative endpoints and address the level of evidence needed. The ultimate goal was to provide innovative statistical design methodologies to achieve more reliable clinical development of treatments for rare diseases. A unique approach in clinical trial design The consortium aimed to produce a consistent framework for reliable and efficient trials in rare diseases. Filling the gap between theoretical development and real-life implementation was a key objective of ASTERIX. As such, partners focused on end-users by testing the acceptability of methods with both regulators and patients. This was the only way to facilitate the uptake of recommendations in routine practice. ‘Unique in our project was that patients were directly involved in the process and their input was taken into account in directions of the projects, such as developing novel endpoints,’ project co-ordinator Professor Kit Roes explains. The idea was further to illustrate the impact of making treatment available sooner and propose improvements for regulatory purposes. Towards this goal, researchers evaluated methods against actual drug development programmes implemented for new medicines for rare diseases. The methodological advances were achieved by looking afresh at traditional concepts such as randomisation, as well as by developing new methodology. This included the integration of evidence from multiple endpoints, efficient multi-armed trials to investigate multiple treatments simultaneously and the use of prior information to increase the level of evidence. The next era in rare disease trials Undoubtedly, methodological progress will aid the design and analysis of clinical trials, leading to more reliable studies. ASTERIX followed an integrated approach of existing and novel methodology that will improve statistical power of clinical trial design in small populations. Implementation will undoubtedly increase the reliability of clinical trial results, and thus speed up availability of truly valuable treatments to the patients in need. ‘Validation of methods from a regulatory perspective will ease the uptake of new methodologies by decision makers and thus the degree of uncertainty on the outcome of licensing,’ continues Prof. Roes. More predictive licensing decisions means that companies may invest and commercialise novel therapies faster, offering access to high quality treatment at affordable prices to patients that suffer from rare diseases. Prof. Roes’ view of the future is ‘to stimulate a search and implementation for treatments for these devastating and largely ignored diseases.’ The ASTERIX deliverables undoubtedly bring us a step closer to more effective clinical research studies.


ASTERIX, clinical trial, rare disease, statistical methodology

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