FDA & EMA´s collaborative Clinical Trials Approach for rare Diseases

The European Medicines Agency (EMA) published a joint proposal together with the U.S. Food and Drug Administration (FDA) on July 3, 2017, entitled "Paediatric Gaucher disease - A strategic collaborative approch from EMA and FDA". The FDA is going to publish this strategy paper in a different format during the next few months.

The document, which seeks to facilitate the development of medicines for rare diseases, focuses on drug development for Gaucher disease. However, its underlying principles may be extended to other areas of drug development in rare diseases, the agencies say. This is an area where there is typically only a limited number of patients available to take part in trials. Therefore, the proposal deals with general considerations for study population, and practicalities in the design and execution of pediatric trials of drugs for rare diseases, and the use of extrapolation of efficacy data for these diseases.

This is also in line with the recently revised International Council for Harmonization (ICH) E11 guideline CLINICAL INVESTIGATION OF MEDICINAL PRODUCTS IN THE PEDIATRIC POPULATION which, in its addendum of August 2016, promotes the use of innovative study design. This Design can be supported by agencies provided it is justified, appropriately conducted, and agreed beforehand with those agencies.

A multi-arm, multi-company trial is proposed in the joint document. EMA and FDA say that "this approach may allow for a reduction in the total number of children to be enrolled as compared to separate controlled trials, because a single control arm can be used to assess the effects of more than one drug product." It covers topics such as the following:

• study design features;
• study population and subset definition;
• number of study participants by pediatric subset (e.g., age, sex, severity or stage);
• main inclusion and exclusion criteria;
• study duration for participants;
• dosage, treatment regimen, and route of administration;
• controls and endpoints with times of assessment;
• statistical plan (SAP) including study conduct and analysis;
• measures to minimize pain and distress and external independent data safety monitoring boards.

With this approach, medicine developers should be encouraged to make better use of:

• extrapolating available clinical data. This might include the use of appropriate modelling and simulation techniques, to predict how the product might work in children and adolescents based on studies conducted in adults or other pediatric populations;
• testing the safety and efficacy of medicines developed by different companies in one single trial (so-called multi-arm, multi-company clinical trials).

Product developers who wish to use this new approach in their development plan are advised to seek scientific advice either from EMA or FDA separately, or request parallel scientific advice from the two regulatory authorities. The agencies emphasize that the document is not a formal guidance and the principles presented should be viewed as suggestions only. “Specifics should be determined following discussions with the individual regulatory agencies as deemed appropriate and feasible by both drug manufacturers and regulatory agency(ies).” “Due to differences in the regulatory requirements of both Europe and the United States, particularly regarding extrapolation of efficacy from adults to children, additional trials may be required to support an application for approval,” they add.

Furthermore, the EMA is finalizing a reflection paper which outlines a systematic approach to scientifically sound and reliable extrapolation of data to support medicine authorization. The paper, which is expected to be published the fourth quarter of 2017, will complement the joint approach already published.

For more information please visit EMAs News and press releases website.