On June 16, 2014, Reg. (EU) No. 536/2014 on Clinical Trials on Medicinal Products for Human Use (Regulation) has entered into force. Once it becomes applicable, the Regulation will provide a comprehensive legal framework for the authorization of clinical trials in the European Economic Area (EEA) and will replace the Clinical Trials Directive (Dir. 2001/20/EC) (Directive). It will streamline the authorization process and harmonize the requirements for clinical trials in Europe. A single authorization procedure for clinical trials will be introduced that will be performed electronically via a new European Union (EU) portal. However, the actual approval of individual clinical trials will remain in the Member States’ hands. Applicability of the Regulation is not to be expected before mid-2016, as the EU portal for the electronic procedure has to be established first.
Clinical trials are presently subject to Directive 2001/20/EC, which is repealed by the new regulation but will remain in force until the new regulation is fully applicable. As directives do not apply directly but have to be implemented by the Member States, leaving each Member State with a significant amount of freedom, the field of clinical trials is not yet fully harmonized in the European Union. Particularly, the procedures concerning the consultation of ethics committees are not harmonized and are still very different in the Member States.
Under the current regime, an approval is only valid in one Member State—to the extent clinical trials are conducted in multiple EEA Member States, a separate approval is required in each EEA Member State. As many clinical trials are conducted on an international basis, further harmonization is beneficial for both patients and the pharmaceutical industry.
Major aspects of the New Regulation
Terms and Definitions
While the current Directive only contains a definition of the term “clinical trial,” the new Regulation also contains definitions for “clinical studies” and “low intervention clinical trials,” as well as “non-interventional studies”. However, the latter are explicitly excluded from the Regulation, as it only covers clinical trials, and non-interventional studies are defined as clinical studies that are not clinical trials.
The term “sponsor” is defined differently in the Regulation than the Directive. Under the Regulation, a company is only to be regarded as the sponsor of a trial if it is in charge of its initiation and management and is financing it. Hence, sponsorship is not triggered by mere funding of a trial. Co-sponsoring is possible, but each sponsor bears all responsibilities set out in the Regulation, unless the co-sponsors decide otherwise in a written contract. Such contract has to set out the responsibilities of each sponsor; any responsibilities not clearly allocated will be borne by all sponsors.
The application procedure under the new Regulation is performed via an EU portal, which is still to be established. It is initiated by the submission of the application dossier.
The application dossier will be divided in two parts. The first part, containing mostly scientific information, is assessed by all concerned Member States (cMS) (i.e., the Member States in which the clinical trial will take place), under the leadership of the reporting Member State (rMS). The rMS is determined on the basis of the sponsor’s recommendation; however, if more than one cMS is willing to act as the rMS, the rMS is selected by agreement among all cMSs. The review of Part I of the application dossier covers the risk-benefit ratio of the trial; requirements concerning the manufacturing and import of the investigational medicinal products, as well as its labelling; and the completeness and adequateness of the investigator’s brochure. Part II of the application dossier is reviewed on a national basis by each cMS. It contains information regarding areas that tend to be governed by national law, such as recruiting participants, data protection and quality management.
The applicant can either submit both parts of the dossier at once or first submit Part I and then submit Part II up to two years later (Art. 11 of the Regulation). The review procedure starts with the validation phase, when, among other things, the rMS is determined and the application is checked for completeness. The validation phase is followed by a 45-day assessment phase, in which the rMS reviews and comments on the application. If necessary, the sponsor receives a list of requested additional information that has to be provided within 12 days. As this deadline is very short, it is advisable to submit only well-prepared, complete applications from the outset. The sponsor reply is also reviewed and commented on by all cMSs. After consolidation of all comments, the rMS sends the final assessment report to the cMS and the sponsor via the EU portal. The final report includes the decision whether the trial is acceptable, acceptable subject to specific conditions or not acceptable.
Part II of the application dossier is usually simultaneously reviewed by each cMS. The steps of the procedure are similar to the review of part I. In Germany, the ethics commission will most probably participate in the review of both parts of the application dossier. After the completion of the assessment, every cMS notifies the sponsor within 5 days as to whether the trial is authorized, authorized subject to conditions or refused. In general, the cMS has to follow the rMS assessment, but there are some exceptions to this rule. If the cMS fails to report within the deadline, tacit approval is assumed.
Within one year after trial completion, a summary of its results must be submitted to the EU database. According to the German Federal Institute for Drugs and Medical Devices (BfArM), this disclosure obligation appears to cover Phase I studies, too, if they are clinical trials and, hence, are governed by the Regulation. So far, in Germany, only results of confirmatory clinical studies must be disclosed; hence, Phase I studies are not presently covered. In the United States, Phase I studies are also exempt from disclosure obligations. Thus, the new EU Regulation appears stricter, in this respect.
The disclosure obligation also contains the requirement to summarize the results of the trial in a manner that is understandable for laypersons. This summary must be made available to all participants of the trial within one year. With regard to the one-year-deadline, BfArM has already expressed the opinion that it begins with the actual end of the trial (i.e., “last patient, last visit”) and that no “artificial delays” of the study’s conclusion will be accepted.
The Regulation entered into effect on June 16, 2014, but it is not yet applicable. It is expected that the Regulation won’t become fully applicable before 2017, due to the fact that the EU portal and database have to first be up and running. When the Regulation becomes applicable, there will be a transition period: If the request for authorization of a trial had been submitted before the date of Regulation applicability, the trial will be governed by the old regime (i.e., Dir. 2001/20/EC) for three years. If the request for authorization is filed within 6 and 18 months from the date of the publication (i.e., between the date of applicability and 12 months after), the sponsor may choose whether to start the trial under the Directive or the Regulation. If the Directive is chosen, the Directive will continue to apply to the trial for another 42 months.