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Compared to the Directive 2001/20/EC, which will be repealed on January 31, 2022, the Regulation (EU) No 536/2014 changes and systematizes the law at the European Union level regarding obtaining the authorization to commence and conduct clinical trials. Due to the functionality of the Clinical Trial Information System – CTIS (the EU portal and database), it is possible to harmonise electronic submission for authorization, synchronize the evaluation process and supervise simultaneously of a given clinical trial by all Member States concerned (MSCs) involved in this clinical trial. Single entry point submission replaces national clinical trial application processes for approval by both national health authorities and national ethics committees. There will be only one application to all MSCs, and each Member State will already internally, without the participation of the applicant, distribute the dossiers for evaluation between national health authorities and national ethics committees. Such a functioning of the system means that there will be only one payment per activity per Member State.

After the submission of the application dossier the 10-day validation is carried out regarding the completeness of the application and its compliance with the Regulation. The validation may be extended by additional 15 days for the sponsor to fill in the deficiencies at the request of the RMS. The submission of an application for clinical trial authorization under the regulatory framework of the Regulation is a two-part evaluation process. After the validation, the evaluation of Part I and Part II of the submitted application begins at the same time (Table 1).

The evaluation of Part I is a 45-day substantive assessment period carried out under the direction of the RMS. This period can be extended for 50 days for the purpose of consulting with experts in the case of clinical trials involving an advanced therapy investigational medicinal products or a medicinal product as defined in point 1 of the Annex to Regulation (EC) No 726/2004. In Part I are assessed the key clinical trial documents e.g. a protocol, an investigator’s brochure, an investigational medicinal product dossier (IMPD) and labelling, certificates of compliance with Good Manufacture Practice (GMP) for IMP. The RMS evaluates among others: type of trial (if it is low-interventional), future therapeutic and public health benefits, risks and inconveniences for the subject, manufacturing and labelling of IMP, and the content of the investigator’s brochure. In case of doubt, prior to posting on the CTIS assessment report, the RMS may request information from the sponsor and extend the process by a maximum 31 days, with the sponsor having 12 days to respond. Other MSCs also participate in Part I assessment, but it is the RMS that is responsible for the final assessment conclusions and for contacting the sponsor with a request for additional information. The conclusion from Part I may be authorization for a clinical trial, or authorization acceptable subject to compliance with specific conditions or no authorization to conduct the clinical trial. With the exception of the decision not to allow the clinical trial to be conducted, the MSCs may disagree with the final RMS decision and issue their own for Part I.

Part II assessment is a national evaluation carried out individually by each MSC. The assessed documentation is prepared in accordance with the requirements of a given MSC and includes documents such as e.g.: recruitment arrangements, subject information, informed consent form and informed consent procedure, information about investigators and study sites, proof of insurance cover or indemnification, financial and other arrangements, compliance with data protection requirements. The evaluation of Part II takes 45 days, but due to MSC questions to the sponsor, it may be extended for another 31 days, including 12 days for the sponsor to respond. Each MSC informs sponsor about decision by the CTIS (one single decision within 5 days from the reporting date Part I or from the last day of the assessment referred to Part II, whichever is later). The MSC may give consent to conduct a clinical trial, consent under certain conditions, or disagree. Where the MSC has not posted on the CTIS the decision within the relevant periods, the conclusion of the MSC on the application for authorisation of the clinical trial will be the conclusion from  assessment on Part I.

The Regulation provides sponsors with new possibilities for submitting applications for authorization to conduct a clinical trial. Sponsors do not have to always submit together Part I and Part II of a new application for the clinical trial authorization, for example a sponsor may submit Part I and II to some MSCs, and Part I only to other MSCs. Moreover, a sponsor may submit only Part I, and in the event of a positive decision, should submit Part II within 2 years, otherwise the aspects covered by Part I of the assessment report will lapse.

Following authorisation, a sponsor can add a new MCS to the clinical trial. A request to add a new MSC may be submitted after approval of an initial submission and when there is no ongoing assessment of any Part I, or Part I and Part II substantial modification in any MSC. From the date of submission of application, the additional MSC has 52 days to evaluate application and inform sponsor about decision, however the procedure can be extended for maximum 31 days when additional information is requested from the sponsor (Table 1).

Sponsor may submit an application for a substantial modification, which may concern aspects covered by Part I, Part I and Part II, or only Part I of application dossier. The procedure for authorization of substantial modification concerning of Part I, or Part I and Part II can be started only if the procedures of initial submission, substantial modification or adding new MSC are finished. In the case of substantial modification concerning only Part II, the procedure can be started after the full authorization of the trial in the MSC and if there is no ongoing assessment of a Part I, or Part I and II or Part II in other substantial modification in that MSC. The whole process starts from validation of provided documentation (6 days + additional 15 days), then evaluation of applications follows (38 days + additional 31 days), and after the evaluation is finished the final decision is announced in the CTIS within 5 days (Table 1).

Table 1. Comparison of the maximum time frames for the processes carried out in accordance with the Directive and the Regulation

The Regulation unifies the regulatory framework of clinical trials at the EU level, but also causes requirement of appropriate planning in line with the regulatory framework of the Regulation in management of clinical trials. Introducing changes to clinical trial design (e.g. adding a new MSC to the clinical trial) or changes to documentation will be more ‑time-consuming than in the case of the Directive and will require forward-thinking to avoid overlapping of the processes.

Clinmark has been participating in the development of the clinical trials market in Poland and around the world for over 20 years, its extensive experience allows Clinmark team to quickly adapt to the changing requirements of clinical trials. Our experts provide support in planning, regulatory issues and agile management of clinical trials. Do not hesitate to contact us for professional advice and support.