On 14 April 2014, a new Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC (hereafter “Clinical Trials Regulation”) was adopted following a vote by the Council of the European Union (hereafter “Council”). The Council voted in favour of the text adopted by the European Parliament on 2 April 2014.
The new Clinical Trials Regulation, which will replace the existing Clinical Trials Directive, introduces a complete overhaul of the existing regulation of clinical trials for medicinal products in the European Union (hereafter “EU”). As a regulation, it will be directly binding in all EU Member States without the need for any national implementing legislation. Moreover, for harmonisation purposes this New Clinical Trials Regulation is expected to serve as a model for the on-going work by the European Parliament and the Council regarding the revisions of the EU medical devices regulatory framework.
The Clinical Trials Regulation is expected to enter into force six months following the full functionality of a new EU Database and single online EU Portal (hereafter “EU Portal”) created under the new Regulation. However, the Regulation states that, in any event, it will enter into force no later than two years following its publication in the Official Journal of the European Union.
An outline of some of the most noteworthy changes concerning the conduct of clinical trials in the EU is provided below.
Coordinated authorization procedure
Under the existing Clinical Trials Directive, a clinical trial is approved by a competent national authority and an Ethics Committee in each EU Member State where the sponsor intended to conduct the clinical trial. This authorization procedure is conducted in parallel in all relevant EU Member States.
The new Clinical Trials Regulation replaces these parallel national procedures with a coordinated procedure initiated through an EU Portal managed by the European Medicines Agency (hereafter “EMA”) in cooperation with the European Commission and the EU Member States. All the competent authorities of the EU Member States involved in the assessment of the application for the authorisation of a clinical trial will be subject to strict deadlines for review. This will include a provision for automatic authorisation of the clinical trial if the concerned EU Member States do not notify the Sponsor of their decision within the specific deadlines.
Under the new coordinated procedure, the sponsor of a clinical trial will be required to submit a single application for authorisation of a clinical trial to a reporting EU Member State (“RMS”) through the EU Portal. The submission procedure, which is reminiscent of the mutual recognition procedure for marketing authorisation of medicinal products, will be the same irrespective of whether the clinical trial is to be conducted in a single EU Member State or in more than one EU Member State. Once the RMS has validated that the application is complete and contains all the required information, the assessment of the application for authorisation will be conducted in two parts:
Part I is the RMS’s initial assessment of the scientific, therapeutic and safety aspects of the proposed clinical trial. The RMS will prepare a draft assessment report which will be submitted for consideration and review to all of the concerned EU Member States. Based on this review, the RMS will consolidate and finalise Part I of the assessment report for the application for authorisation of the clinical trial. The assessment report will conclude whether the conduct of the clinical trial is either; i) acceptable, ii) acceptable subject to specific conditions, or iii) not acceptable. The conclusions of the RMS’s assessment report will be applicable in all concerned EU Member States. Part II of the assessment report will involve the assessment of the application by the individual EU Member States on the basis of their national and ethical requirements concerning the conduct of clinical trials. As an example, the concerned EU Member States will assess the national requirements governing biological samples, clinical trial agreements, informed consent and recruitment of subjects. The responsibilities and composition of Ethics Committees will continue to be determined independently by each EU Member State.
Notification to the sponsor of the EU Member States’ conclusions concerning the application for approval of a clinical trial shall occur through the EU Portal in a single decision. This will include whether the clinical trial i) is authorized, ii) is authorized subject to conditions, or iii) if authorization has been refused in each of the concerned EU Member States.
The EU Member States may, in limited circumstances, disagree with the conclusion of the RMS concerning Part I of the assessment report. These circumstances include disagreements based on safety, data reliability and robustness considerations.
Extending the clinical trial to another EU Member State
The Clinical Trials Regulation permits the extension of a clinical trial to a new EU Member State in a more efficient procedure than the current process of having to initiate a completely new authorization procedure.
When a sponsor submits an application for authorisation of a clinical trial to the new EU Member State this State will assess only Part II of the assessment report. The RMS’s conclusions in Part I of the assessment report remain valid unless the new EU Member State disagrees on the basis of one of the specific circumstances permitted by the Regulation.
The new Clinical Trials Regulation also aims to increase the transparency of data generated from authorised clinical trials conducted within the EU. The EMA, in cooperation with the European Commission and the EU Member States, must establish and maintain a publicly accessible and searchable EU database of all approved clinical trial data relating to medicinal products. Confidentiality may be claimed for an exhaustive list of data including personal data processed on the basis of Regulation 45/2001, commercially confidential information, and actions to ensure effective supervision of the conduct of a clinical trial by an EU Member State.
This database must include:
Detailed summaries of the results of authorised clinical trials, including a summary drafted by the Sponsor in plain language which must be submitted within one year of the termination of the clinical trial; Final clinical study reports that were submitted to support a marketing authorization should be uploaded onto the EU database within thirty days of the authorization, rejection, or withdrawal of the marketing authorisation of the medicinal product.
Sponsors may be subject to penalties if they fail to adhere to these transparency obligations.
New reporting requirements
The Clinical Trials Regulation aims to streamline and simplify the rules on safety reporting for clinical trials. The Regulation provides that suspected unexpected serious adverse reactions (hereafter “SUSARs”) can be reported by the sponsor directly to the online EU pharmacovigilance database, EudraVigilance, instead of being submitted to each EU Member State.
Sponsors must notify each EU Member State of certain events during the conduct of a clinical trial within fifteen days of their occurrence. These events include the start of the trial, the end of the recruitment, the end of trial, any temporary halt of trial and the early termination of trial.
Data privacy issues
Sponsors of clinical trials will be permitted to seek the consent of the trial subject to use his or her data for purposes which are outside the scope of the trial Protocol. Such purposes must be exclusively scientific. Consent for use of personal data for these purposes may be sought at the same time as consent for participation in the clinical trial. This consent may, however, be withdrawn by the trial subject at any time.
Irrespective of whether consent to further scientific use of subjects’ personal data is granted, Sponsors will still be required to comply with the provisions of the Data Protection Directive.
Indemnity and Insurance
The Clinical Trials Regulation provides that insurance covering the investigator, the institution, or product liability insurance will be sufficient for low-intervention clinical trials. As a result, Sponsors of low-intervention clinical trials will not be obliged to provide a specific insurance or indemnity compensation.
Low-intervention clinical trials are defined in the Clinical Trials Regulation as clinical trials in which:
- the investigational product is already authorized;
- its use in the trial is in accordance with the terms of the marketing authorization or its use is based on published scientific evidence of safety and efficacy; and
- the additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden compared to normal clinical practice in a Member State.
The Regulation permits the co-sponsorship of clinical trials. Each co-sponsor will assume full regulatory responsibility for the entire clinical trial unless the co-sponsors agree otherwise.