EU Regulation on clinical trials on medicinal products for human use (the Regulation) was adopted by the EU Parliament on 2 April 2014. This Regulation will harmonize the rules applicable to clinical trials on medicinal products throughout the EU. Indeed, the provisions of the Regulation are directly applicable in the EU Member States and do not need any implementation in national law. The Regulation will come into force 20 days after its publication in the Official Journal of the EU. It will apply as from 6 months after the publication concerning the functionality of the EU database and the EU Portal but in any event no earlier than two years after its publication. A transitional period exists in Article 98.
The main provisions of the Regulation are the followings:
Definition of clinical trials
According to Article 1 of the Regulation, it applies to all clinical trials conducted in the EU on medicinal products only. The Regulation does not apply to non-interventional studies.
The Regulation clarifies the definition of clinical trial which contains two categories: clinical trials and low interventional clinical trials. Indeed, the recitals of the Regulation provide that many clinical trials pose only a minimal additional risk to subject safety compared to normal clinical practice and consider that these "low-intervention clinical trials" should be subject to less stringent rules, as regards monitoring, requirements for the contents of the master file and traceability of investigational medicinal products.
A clinical trial is defined as a clinical study in which:
- the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned;
- the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study;
- diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.
Low-intervention clinical trial is defined as a clinical trial in which:
- the investigational medicinal products, excluding placebos, are authorised;
- according to the protocol of the clinical trial,
- the investigational medicinal products are used in accordance with the terms of the marketing authorisation or
- the use of the investigational medicinal products is evidence-based and supported by published scientific evidence on safety and efficacy in any of the Member States concerned
- the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden to the safety of subjects compared to normal clinical practice in any Member State concerned.
Simplification of the procedure
The major change is the creation of a single web-portal (EU Portal) for the submission of one single application dossier by the sponsor. The harmonized application dossier is detailed in Annex I of the Regulation. The Regulation applies for mono as well as multicentric clinical trials involving one or several Member States. This EU Portal will be developed and hosted by the European Medicines Agency (EMA).
The assessing procedure is detailed in Articles 6 and 7. The Regulation provides for strict timelines. The assessment procedure shall be carried out within a maximum of 60 days.
The sponsor must propose a Reporting Member State, which role is to validate and to assess the application dossier. The Regulation provides the rules for the designation of the Reporting Member State. If at the end, there is no agreement among the Member States concerned, the Reporting Member State proposed by the sponsor shall be designated as Reporting Member State. It must notify the sponsor and the Member States concerned its designation through the EU Portal within 6 days after the submission of the application. The Reporting Member State shall validate that the application dossier is complete and compliant with the requirements of the Regulation and communicate the validation, or indicate that additional information is needed to accept the application to the concerned Member States and to the sponsor via the EU Portal. The Reporting Member State must further assess the application, draft an assessment report and submit it via the EU Portal to the sponsor and the other concerned Member States.
In parallel, the ethical review will still be performed by an independent Ethics Committee of the Member States concerned according to their national legislation. Each Member State shall ensure that the timelines for the ethical review are in compliance with the timelines of the Regulation. The Member States concerned have also to assess the compliance of the application dossier for their own territory regarding in particular informed consent, recruitment of patients, suitability of the sites and damages compensation.
Article 8 of the Regulation provides that each Member State concerned shall notify the sponsor through the EU Portal as to whether the clinical trial is authorized, is authorized subject to conditions or this refused. The notification shall be done by way of a single decision. Article 8 specifies that where the conclusion of the reporting Member State is that the conduct of the clinical trial is acceptable or acceptable under conditions, that conclusion shall be considered as the conclusion of the Member States concerned. Specific grounds of disagreement are provided in the Regulation for which a Member State can disagree to accept the assessment report of the Reporting Member State. Appeal procedure is provided in this case.
Recital 67 provides that in order to increase transparency, clinical trial data submitted in support of a clinical trial application should be based only on clinical trials recorded in a publicly accessible and free of charge database.
The EMA will, in collaboration with the Member States and the European Commission, set up and maintain a database at EU level (EU Database). This EU Database will identify each clinical trial by a unique EU trial number. The EU database will contain the data and information submitted in accordance with the Regulation. It will be publicly accessible unless, for all or parts of the data and information contained therein, confidentiality is justified on any of the following grounds:
- protecting personal data in accordance with Regulation (EC) No 45/2001;
- protecting commercially confidential information, in particular through taking into account the status of the marketing authorisation for the medicinal product unless there is an overriding public interest in disclosure;
- protecting confidential communication between Member States in relation to the preparation of the assessment report;
- ensuring effective supervision of the conduct of a clinical trial by Member States.
However, data in the application dossier will not be publicly accessible until the decision on the clinical trial has been made.
Recital 68 specifies that “for the purposes of this Regulation in general the data included into clinical study reports should not be considered commercially confidential once a marketing authorisation has been granted, the decision-making process on the application for a marketing authorisation has been completed, or an application for marketing authorisation has been withdrawn”. Moreover, the main characteristics of the clinical trial, the conclusion of the assessment report of the Reporting Member State and the decision on the authorisation of the clinical trial should not be considered confidential. Consequently, the concept of commercially confidential information is defined narrowly. This could be an issue for pharmaceutical companies.
Furthermore article 37 states that “irrespective of the outcome of the clinical trial, within one year from the end of a clinical trial in all Member States concerned, the sponsor shall submit to the EU database a summary of the results of the clinical trial”, which is accompanied by a summary written in a manner that is understandable to lay persons. However, where, for scientific reasons detailed in the protocol, it is not possible to submit a summary of the results within one year, the summary of results shall be submitted as soon as it is available. In this case, the protocol shall specify when the results are going to be submitted, together with a justification.
In addition to the summary of the results, where the clinical trial is intended to be used for obtaining a marketing authorisation for the investigational medicinal product, the applicant for marketing authorisation will have to submit to the EU database the clinical study report 30 days after the marketing authorisation has been granted, the decision-making process on an application for a marketing authorisation has been completed, or the applicant for marketing authorisation has withdrawn the application.
For cases where the sponsor decides to share raw data on a voluntary basis, the European Commission will produce guidelines for the formatting and sharing of those data.
These rules of transparency will apply independently of the outcome of the cases AbbVie vs. EMA and InterMune vs. EMA brought in front of the General Court of the European Union, which relates to the right of a pharmaceutical company to request the EMA to grant access to clinical trials data that are part of a marketing authorisation file.
In this context, the EMA released in June 2013 a draft policy on publication and access to clinical-trial data for a three-month public consultation. According to the EMA, the draft policy “balances the commitment to give the widest possible access to data with the need to protect personal data and commercially confidential information”. According to the press release of the EMA dated 24 March 2014, during the 19-20 March 2014 Management Board meeting, “the Board was updated on the progress made on the draft policy on proactive publication of clinical trial data. Based on the set of key principles endorsed by the Management Board at its December 2013 meeting, efforts were made to identify redaction criteria for those parts of clinical-trial data that exceptionally contain commercially confidential information, on a consultation process with the concerned data owners and on user-friendly technical measures to make the data accessible under the new policy, whilst addressing the need to reasonably protect against unfair commercial use of the data”. The final policy and an implementation plan will be presented to the Management Board for endorsement at its June 2014 meeting.
The key principles agreed by the Management Board in December 2013 include:
- a stepwise approach for implementation with, as a first step, preparation for the publication of clinical study reports redacted as appropriate;
- development of a methodology for de-identification (“anonymisation” in French) of patients;
- definition of a standard format for the submission of data.
The disclosure of clinical trial data is a concern for pharmaceutical companies since it may have significant commercial consequences. Pharmaceutical companies are looking for more legal certainty and protection of their commercially confidential information.
The Regulation may not be applicable before the middle or end of 2016. The Regulation provides for transitional rules which allow a clinical trial to be started in accordance with the rules of Directive 2001/20/EC even though the Regulation is applicable. The clinical trial started according to the transitional provisions will continue to be governed by the Directive for a limited period of time (maximum of 5 years from the publication of the Regulation).
It should be reminded that the Regulation only covers clinical trials on medicinal products. The harmonization does not extend to other regulated products. Consequently, the national laws of the EU Member States will still apply for clinical trials on other products like medical devices or cosmetics.