Community Research and Development Information Service - CORDIS


ASTERIX Report Summary

Project ID: 603160
Funded under: FP7-HEALTH
Country: Netherlands

Periodic Report Summary 2 - ASTERIX (Advances in Small Trials dEsign for Regulatory Innovation and eXcellence)

Project Context and Objectives:
An estimated 30 million European patients suffer from a rare disease. More than 6000 rare diseases are known, many of them chronic, potentially very disabling and typically affecting children. There is a substantial unmet need for drug treatment for rare diseases and if this is to be met, many clinical trials will need to be performed in small populations. ASTERIX is specifically designed to optimize methodology for clinical trials in small populations to achieve more reliable and cost efficient clinical development of treatments for rare diseases. The main objectives are:
• Develop and evaluate design and analysis methods for single trials and series of trials in small populations;
• Include patient level information and perspectives in design and decision making throughout the clinical trial process;
• Validate new methods and propose improvements to enhance regulatory decision making for treatments for rare diseases.
By choosing an integrated approach leveraging statistical methods, combining observational and clinical data as well as improved sequential and adaptive approaches, ASTERIX aims to improve statistical power of clinical trial design in small populations. ASTERIX is systematically including patients and the patient perspective into its research, and is developing an approach to involve patients in clinical trial design in a methodologically sound manner. Key methodological innovations include:
the proposal and evaluation of new standards of evidence that take into account the rare prevalence of disease, leveraging prior information and the availability of multiple endpoints, enabling adaptive designs and sequential meta-analysis using multiple endpoints. Patient perspectives are included by providing a model on how to involve their perspective in crucial parts of trial design and developing more patient centered outcomes, that also deal with the large heterogeneity between patients with the same rare disease.
Relevance and clinical value of the newly designed methodological approaches are validated twofold. Firstly, by cross testing with available clinical trial data of a broad range of highly relevant rare diseases and secondly, by assessing the methods against current and improved regulatory approval strategies.
Importantly, in total three projects were funded: besides ASTERIX, also INSPIRE and IDEAL. Collaboration was established, further strengthening the research in this highly relevant area.

Project Results:
Framework for rare diseases. The optimal trial design depends on characteristics of the disease and the research question. We provided a clustering into 6 clusters of rare disease characteristics, connected to the optimal design choices. Over 100 European Assessment Reports (EPARs) were clustered based on this framework, and form the basis for the regulatory validation of new methodologies.
Patient involvement. The POWER model for inclusion of patient’s preferences in trial design was established: Patient participation in Outcome measure WEighing for Rare diseases. Prospective validation in a clinical trial has started. Goal Attainment Scaling (GAS) as truly patient centered outcome was investigated. A comprehensive review was published, and theoretical properties are evaluated. Simultaneously, experience is building through prospective inclusion of GAS in trial for a new treatment for mitochondrial disease. The practice of registries was reviewed and comprehensive recommendations on content and management of registries to contribute optimally to clinical research have been drafted.
New methodology. The challenge is one of statistical power: small populations of patients with a rare disease can only provide small samples for a clinical trial. In addition, only a limited number of clinical trials can be set up within a small population. Highlights of the progress made are:
Individual trials. Sequential monitoring in clinical trials leads to smaller expected sample sizes. Current sequential methods rely on large sample properties, which are not applicable to rare diseases. We addressed the situation where the number of patients to be recruited has an a priori maximum, which must be utilized in the most efficient way. We assessed the operational characteristics of sequential designs in the setting of very small to moderate sample sizes and demonstrate the necessity of simple corrections of the critical boundaries. We introduce a method for deciding on an optimal sequential design given a maximum sample size and a - data driven or based on expert opinion – prior belief on the treatment effect.
In multi-arm trials several treatments may be evaluated simultaneously, which contributes to efficiency. Multi-arm group sequential trials are even more efficient. They stop randomization to a treatment arm in an interim analysis if a significant treatment effect in that arm is observed. A variant of such designs with a simultaneous stopping rule was developed for the evaluation of two experimental treatments against a control. The improved stopping boundaries minimize the expected sample size. It is possible to generalize to more treatment arms. The procedure is illustrated with a clinical trial in systemic sclerosis for two treatment arms and a clinical trial in the rare disease narcolepsy for three treatment arms.
Series of trials. Effective synthesis of results from trials in a (sequential) meta-analysis may be difficult in the presence of heterogeneity. This problem is amplified when there is a small number of small trials available. Our research highlights crucial situations in which conclusions on efficacy are not reliable. Solutions that robustly control the type I error virtually have no power to detect a treatment effect. To tackle the problem, solutions were pursued using more robust estimators for heterogeneity, exact likelihood methods and Bayesian approaches. The latter prove the most promising.
An approach to sequential evidence synthesis is to integrate prior information in the analysis of a present clinical trial. A relatively simple method using so-called power priors was explored, suitable for the case when one historical dataset is available. The method is based on predictive distributions and weighs the historical data by the degree of similarity between the new and historical data. The weights can be parameterized such that type I error (or other frequentist characteristics) can be controlled.

Potential Impact:
Ultimately ASTERIX aims to influence the standard of regulatory assessment in rare diseases. Intermediate results and ongoing research were shared at multiple scientific meetings and conferences, particularly aimed at meeting and discussing with scientist as well as representatives of regulatory bodies and patient organizations. Amongst which the IRDiRC workshop at the EMA on Recommendations for Small Population Clinical Trials.

ASTERIX will deliver validated innovative statistical design methodologies for cost efficient clinical trials, especially focusing on rare diseases. ASTERIX delivered an approach to involve patients in clinical trial design in a methodological sound manner. The potential impact of making treatment available sooner by reducing the time to market is directly evaluated by assessing the methods against current and improved regulatory approval strategies. Integrating the perspectives of different stakeholder groups such as industry, patients, clinicians and regulators in the course of the project is helping to smooth uptake of these guidelines. This approach has the potential that the licensing decisions will become more predictive, enabling drug development companies to commercialize novel therapies giving patients suffering from rare diseases faster access to new treatments. Implementation will result in a reduction of time and effort to assess the safety and efficacy of clinical trials in small patient groups, maximizing the added value of trials in rare diseases and potentially reducing the time to market of new products. 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 and reimbursement decisions may be reduced. This may enable drug development companies to invest in developments aimed to commercialize novel therapies giving patients suffering from rare diseases access to high quality treatment.

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Life Sciences
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