Major Changes to Clinical Trials Regulation in the EU

On April 2, 2014, the European Parliament approved the new European Union Clinical Trials Regulation and on May 27, 2014, the EU Clinical Trials regulation (No 536/2014) was published in the Official Journal of the EU (OJEU).  The European Commission estimates that all the changes could save researchers €800 million (over $1 billion) a year.

The new regulation will replace the existing EU Clinical Trials Directive (2001/20/EC), which has often been criticized as having excessive bureaucracy. Although the directive was intended to simplify and harmonize the administrative provisions for clinical trials of investigational medicinal products across the EU, it did not achieve this, because, as it is a Directive, it has been implemented differently in Member States. It is also blamed for increasing the administrative and regulatory burden in the EU making the EU a less attractive location for running clinical trials. However, it cannot be solely attributed to the Clinical Trials Directive that the number of clinical trials in Europe has declined, and the costs of trials have increased since it was implemented but it does appear to have contributed significantly to this.

The new Clinical Trials Regulation introduces an overhaul of the existing regulation of clinical trials for medicinal products in the EU. As a regulation, it will be directly binding in all EU Member States without the need for any national implementing legislation.

The aim of the regulation is to streamline the clinical trial authorization and harmonize requirements for clinical trials in Europe.

The Clinical Trials Regulation is expected to come into force in May 2016 following the full functionality being in place of a new EU Database infrastructure and single online EU Portal created under the new Regulation.  

An outline of some of the major changes concerning the conduct of clinical trials in the EU includes:

A simplified and streamlined regulatory and ethical application process. Applicants will now submit a single electronic application for a clinical trial by the EU portal, regardless of the number of participating member states, and there will be one application per Member State. This will also result in a single decision on a clinical trial, which will replace the current separate approvals given by the Regulatory Agency and the Ethics Committee in each Member State.

More efficient in extending the clinical trial to another EU Country. The new regulation allows the extension of a clinical trial to an additional Member State by a more efficient procedure than the current process of having to submit a new authorization procedure in the additional Member State.

When a sponsor submits an application for authorization of a clinical trial to the additional EU country, this country will assess only Part II of the assessment report.  The original Part I of the assessment report will remain valid unless the additional EU country disagrees on the basis of one of the specific circumstances permitted by the Regulation.

Co-sponsorship.The Regulation introduces the concept of co-sponsorship for clinical trials. Co-sponsorship is widely used in England by the National Health Service where clinical trials are often carried out in partnership with universities.  Each co-sponsor will assume full regulatory responsibility for the entire clinical trial unless the co-sponsors agree otherwise.

Increasedtransparency requirements.  All clinical trials in the EU will need to be registered. Summaries of the results of authorized clinical trials, including a summary drafted by the Sponsor in plain language, 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 30 days of the authorization, rejection, or withdrawal of the marketing authorization of the medicinal product. Sponsors may be subject to penalties if they fail to adhere to these transparency obligations

Risk based approach - A category of “Low-intervention trials” has been introduced 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.

Low-interventional studies are subject to less stringent requirements for monitoring and documentation.

Indemnity and Insurance for low-interventional studies will be covered by insurance covering the investigator, the institution, or product liability insurance rather than being required to provide a specific insurance or indemnity for a trial.

Protection of subjects and informed consent. Changes to protection of subjects in clinical trials are intended to harmonize requirements and also allow for national rules in some aspects, such as who may act as a legal representative of a subject or the legal age of consent. Additionally provisions have been added including allowing clinical research for emergency situations and where clusters of subjects enter a clinical trial.

Data privacy changes. Sponsors 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 for scientific reasons. 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.

Simplified Safety reporting requirements. The Regulation provides that suspected unexpected serious adverse reactions (“SUSARs”) can be reported by the sponsor directly to the online EU pharmacovigilance database, EudraVigilance, instead of being submitted to each EU Country as well.

Additional notification to regulatory authorities regarding specific events in the trial. 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.

Clearer duration of archiving Trial Master Files. These are to be archived for 25 years, which is a more specific time period than with internationally accepted practice of ICH GCP.

The Health Commissioner Tonio Borg April 2, 2014: “I am convinced that the new rules will ensure a big boost for research & development in the EU for the benefit of patients, and contribute to the Europe 2020 objectives of smart, sustainable growth.” 

It now remains to be seen whether the new legislation will help to make the EU a more attractive location for clinical research.

Laura Brown, PhD, Course Director, MSc Clinical Research, Cardiff University laura.brown.training@googlemail.com