On June 16 2014 EU Regulation 536/2014 on Clinical Trials on Medicinal Products for Human Use entered into force. Once it becomes applicable, the regulation will be the comprehensive legal framework for the authorisation of clinical trials in the European Economic Area (EEA) and will replace the EU Clinical Trials Directive (2001/20/EC). It will streamline the authorisation process and harmonise the requirements for clinical trials across Europe. A single authorisation procedure for clinical trials will be introduced that will be performed electronically via a new EU portal. However, actual approval will remain in the hands of member states. The regulation is not expected to apply before mid-2016, as the EU portal for the electronic procedure has to be established first.
Generally, a regulation requires no implementation into national law. This particular regulation is detailed and has left little room for national ruling. Nevertheless, accompanying national legislation is required to implement the new procedure. In Germany, it is expected that a complete revision of the clinical trials provisions in the Medicinal Products Act will be necessary. Germany will have to create a new mechanism to determine the competent ethics committee that enables immediate, automatised assignment. There are almost 50 ethics committees involved in the authorisation procedure for clinical trials, each with an important role. The regulation leaves significant discretion to national legislatures to determine the extent of inclusion of the ethics committees in the authorisation process.
In Germany, clinical trials are governed by Sections 40 to 42b of the Medicinal Products Act and the Ordinance on Good Clinical Practice. The performance of a clinical trial requires authorisation from a higher federal authority (eg, the Federal Institute for Drugs and Medical Devices (BfArM) or the Paul Ehrlich Institute (PEI)) and a positive statement from the competent ethics committee. Both approvals must be obtained separately. The approval is valid in Germany only.
Major implementation topics
Ethics committees' participation
The original draft of the regulation did not provide that an ethics committee must be included in the authorisation procedure for a clinical trial. This caused significant debate and a new provision was included in the final version of the regulation requiring that inclusion of an ethics committee in the authorisation process. However, Article 4(2) of the regulation gives member states the competence to determine the extent of the ethics committees' participation. In Germany, an ethics committee is likely to participate in the review of both parts of the application dossier. The review of Part 1 of the application dossier covers:
- the risk-benefit-ratio of the trial;
- manufacturing requirements;
- import of investigational medicinal products;
- labelling; and
- completeness and adequateness of the investigator's brochure.
Ethics committees will participate in the review of the expected benefit for public health and the risk-benefit ratio of the trial. If Germany is a reporting member state, the ethics committee and competent federal authority (BfArM or PEI) will issue a joint assessment report regarding Part 1 of the dossier, which also considers the comments of the other concerned member states. If Germany is simply a concerned member state, it is not yet clear whether the ethics committees and federal authorities will issue a joint statement or if they will work independently.
Part 2 of the application dossier is reviewed on a national basis by each concerned member state. It contains information with regard to areas that tend to be governed by national law – for example:
- recruiting participants;
- data protection; and
- quality management.
In Germany, the ethics committees will be involved in the review of all topics to be addressed in Part 2 of the dossier.
It is up to each concerned member state to determine the language of the application dossier and the language to be used on the product label. However, concerned member states are asked to consider accepting a language that is commonly understood in the medical field for documentation not addressed to clinical trial participants. For Germany, it has been suggested to apply a combination of German and English.
National contact points
According to Article 83 of the regulation, each member state must name a national contact point to facilitate the functioning of the procedures for authorisation of:
- a clinical trial; and
- a substantial modification of a clinical trial.
A list of the national contact points is issued by the European Commission. The national contact points will form a Clinical Trials Coordination and Advisory Group that has specific tasks set out in Article 85 of the regulation and is intended to support cooperation and exchange of information among member states and between the member states and the commission. The national contact points will also be responsible for monitoring ethics committee deadlines and the BfArM must comply in this regard.
Within one year of the trial's completion, a summary of its results must be submitted to the EU database. According to the BfArM, this disclosure obligation appears to cover Phase 1 studies if they are clinical trials and hence governed by the regulation. So far in Germany, only results of confirmatory clinical studies must be disclosed thus, Phase 1 studies are not subject to this obligation.
The disclosure obligation also requires that the results of the trial be summarised in a manner understandable for laypersons. This summary must be made available to all trial participants within one year. With regard to the one-year deadline, BfArM has expressed its opinion that it starts to run at the end of the trial (ie, last patient, last visit), and that no artificial delays in concluding the study will be accepted.
It is expected that the regulation will not become fully applicable before 2017, but when it does, there will be a transition period. If the request for trial authorisation is submitted before the start of date of the regulation's applicability, the trial will be governed by the old regime (ie, EU Directive 2001/20/EC) for three years. If the request for authorisation is filed between six and 18 months from the date of the publication (ie, within 12 months of the start date of applicability) the sponsor may choose whether to start the trial under the directive or under the regulation. If the directive is chosen, the directive will continue to apply to the trial for another 42 months. The amendment of the corresponding German law has not yet been initiated.
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