June 01, 2016 – Are first-in-man (FIM) clinical trials unsafe? This question can certainly be answered with no, first-in-man (FIM) clinical trials (clinical Phase I studies) are generally not unsafe. In spite of this notion, and in the wake of the tragic incident which took place during a Phase I first-in-man (FIM) clinical trial in Rennes, France, in January 2016, which led to the death of one participant and hospitalisation of five others, the European Medicines Agency (EMA) sees room for improvements in guidelines and procedures and has started a EU-wide reflection on necessary changes to best practices in order to further improve the safety of FIM clinical trials.
Thus, EMA has started a review of the guidelines currently applicable that describe first-in-man (FIM) clinical trials and the data needed to enable their appropriate design and allow initiation. This is being done in cooperation with the European Commission and the Member States of the European Union (EU). The review particularly will identify areas which may need to be revised in the light of the incident in Rennes in the course of the FIM clinical trial with BIA 10-2474, a fatty acid amide hydrolase (FAAH) inhibitor.
EMA’s review will take into account the findings from two in-depth investigations into what went wrong during this trial, one carried out by the Temporary Specialist Scientific Committee (TSSC) set up by the French Medicines Agency (ANSM) and the other by the Inspection générale des affaires sociales (IGAS), the inspectorate for social affairs in France (see here the complete documentation by the ANSM for this trial and the ensuing investigations). Both reports include a series of recommendations regarding the requirements for authorisation and conduct of first-in-human clinical trials for further examination by the international regulatory and public health community. EMA’s work will focus on best practices and guidance. The aim is to agree a concept paper by July identifying areas for change and proposals to further minimise the risk of similar accidents. The concept paper will form the basis for an EU-wide review of the guidelines. This process will include targeted discussions with stakeholders and a public consultation on proposed changes later in 2016.
The EMA review has started with two groups of experts who are carrying out preparatory work.One group is looking at pre-clinical aspects and the data needed from laboratory tests or animal studies to safely initiate first tests in humans. The other group is looking at clinical aspects of the design of first-in-human trials and how these could be improved to better ensure the safety of human volunteers taking part in these trials. This will lead into one EU-wide expert group discussion on revision of guidelines.
Clinical trials are essential for the development of medicines and without them patients cannot gain access to new potentially life-saving medicines. In the EU, the approval and conduct of clinical trials is within the remit of the relevant authorities of the European Member States. EU guidelines are in place to ensure that these clinical trials are conducted as safely as possible. These guidelines include the requirement for extensive studies, including in animals, to gather information about a medicine before it is given to humans.
Back to the question if first-in-man (FIM) clinical trials were unsafe. Severe adverse reactions in healthy volunteers such as those observed in the trial in Rennes are extremely rare during clinical trials. Thus, since 2005, approximately 14,700 phase I clinical trials (with participation of 305,000 subjects) have been conducted in the EU, including 3,100 first-in-human (FIM) studies. Only one other severe incident has been previously reported concerning a trial with TGN1412 in London in that time in the EU.