article / 17 May 2017

The New Clinical Trials Regulation

The way clinical trials are conducted in the EU will undergo a major change when the Clinical trials Regulation comes into force in 2018. This Regulation harmonises the assessment and supervision processes for clinical trials throughout the EU, via an EU portal and database. The new process, simplified in several aspects, is intended to enable the initiation of clinical trials in different Member States simultaneously.

Background

A major decline in the number of clinical trials in several European Union (EU) Member States is expected to be reversed with the implementation of a new EU Regulation on clinical trials(1). The purpose of the Regulation is to promote innovation by simplifying and speeding up the authorisation process as well as by increasing access to information about clinical trials and their results. A harmonised authorisation process is intended to ensure the rights, safety, dignity and well-being of the individuals who participate in a clinical trial, and to ensure that the data generated is reliable and robust.

Today, all clinical trials performed in the EU are governed by the Clinical Trials Directive(2). The purpose of the Directive was to simplify and harmonise the administrative regulations on clinical trials in the EU. However, the regulations were only partially harmonised, since the Directive was implemented differently in different Member States through national legislation. The Directive has been criticised for impeding the development of clinical trials in the EU. The costs, the number of employees needed for application proceedings, and the length of the proceedings have all increased following the implementation of the Directive in national legislation.

The new Clinical Trials Regulation was adopted on 16 April 2014 and entered into force on 16 June 2014. Since then, it has been uncertain when it would become applicable; application being dependent on the completion of an EU web portal and database developed by the European Medicines Agency (EMA). However, the EMA has recently confirmed that it is currently on schedule to introduce the new EU portal in October 2018. When the Regulation becomes applicable, it will replace the Directive and national legislation that was put in place to implement the Directive.

The Regulation foresees a transitional period of three years from the date of application of the Regulation. From October 2018 to October 2019, applicants may submit their clinical trial applications either under the new Regulation using the EU portal and database, or under the Directive using the EudraCT database. From October 2019 to October 2021, only clinical trials authorised under the Directive will continue to be governed by that Directive. Any trials authorised under the Directive and still on-going in October 2021 will, from then on, be governed by the Regulation.

The new Clinical trials Regulation

The new clinical trials legislation has taken the legal form of a Regulation. EU regulations are not incorporated into domestic law. Instead, they are binding and directly applicable in Sweden and other Member States, just like national legislation, which ensures that the rules are identical throughout the EU. The Clinical Trials Regulation will therefore further harmonise the manner in which Member States authorise and supervise the conduct of clinical trials.

The purpose of the Regulation is to create an environment that is favourable for conducting clinical trials, with the highest standards of patient safety, for all EU Member States. The Regulation governs all investigation in relation to humans with the objective of ascertaining the safety or efficacy of medicinal products. Both commercial and noncommercial clinical trials are covered, including academic research. However, the Regulation does not apply to non- interventional studies, where patients are treated with pharm- aceutical products in accordance with normal clinical practice.

EU web portal and database

The most important instrument that comes with the Regulation is an EU web portal and database to be used throughout the EU. All communication between the sponsor of the clinical trial and the concerned Member State will take place through the web portal. The database will serve as a source for information to the public, since all information entered into the portal will be stored there. The Regulation gives the EMA responsibility for setting up and maintaining the portal and database.

All information from clinical trials registered on the portal will, as a general rule, be public through the database. This includes the main features of the trial, e.g. the objectives, design, methodology, statistical considerations and organisation of the clinical trial, its title, the investigational medicinal product, the clinical trial population and number of subjects, and subject inclusion and exclusion criteria. Other public information includes the decision of the relevant authorities, substantial amendments, the end date of the trial, the summary of the results of the clinical trial, and, where the trial was used to obtain marketing authorisation, the clinical study report.

However, some information is excluded from publication. This includes personal data of subjects, commercially confidential information, confidential communication between Member States, and the supervision of the conduct of a clinical trial by Member States. Commercially confidential information is defined by the EMA as information whose publication might prejudice the commercial interests of individuals or companies to an unreasonable degree.

Application

The current system in Sweden requires separate applications to be submitted to the Regional Ethics Committee (Regionala etikprövningsnämnden) and the Medical Products Agency (Läkemedelsverket). For proceedings conducted under the Regulation’s provisions, however, the application is submitted only once, and coordinated through the web portal. In contrast to the current procedure, the EU portal will also enable applicants who wish to conduct a multi-jurisdictional study in the EU to submit one single application dossier to the EU portal for trials in all Member States.

An application for authorisation to conduct a clinical trial can concern authorisation for a new trial as well as authorisation to extend an authorised clinical trial to another Member State or to make substantial amendments to an already authorised trial.

Assessment

The Member States in which the applicant wishes to conduct the clinical trial concerned coordinate their procedures regarding the application in accordance with the Regulation, after receiving the application dossier through the portal. Participation of ethical committees in the assessment is governed by the national legislation in the Member State concerned, and the ethical review is performed in accordance with the time frame of the Regulation. The Member States assess whether the application is valid and put together two different assessment reports.

The first report contains documentation which in a multijurisdictional study is the same for all Member States. One Member State is the reporting Member State responsible for the assessment and for drawing up the assessment report, taking into consideration any communication from other Member States concerned. The report includes the assessment of whether the study is a low-intervention clinical trial, the anticipated therapeutic and public health benefits of the trial, and the risks to the subject.

The second report is based on assessment of the clinical trial of each Member State for its own territory. This report includes, for example, assessment of compliance with requirements for informed consent, compensation and recruitment of subjects.

Decision

When each Member State concerned has made a decision on the clinical trial based on the assessment reports, the decision is communicated in a single decision for each Member State through the EU portal. The decision can be either that the clinical trial is authorised, that it is authorised subject to conditions, or that authorisation is refused.

All steps in the application process are governed by time limits. This means that a clinical trial could, at least in theory, commence in all 28 Member States at the same time, no later than 90 days after the application was submitted and approved.

Special provisions

The Regulation includes simplified rules for trials where the medicinal products have marketing authorisation and are either used in accordance with the terms of such authorisation or their use is evidence-based and supported by published scientific evidence.

The Regulation also sets forth conditions that need to be met in order to protect subjects and provisions on informed consent to participate in the clinical trial. Special provisions concern clinical trials on minors, incapacitated subjects, pregnant or breastfeeding women, and clinical trials in emergency situations.

Furthermore, the Regulation includes provisions on the conduct of a clinical trial and how safety reports concerning serious adverse events and reactions should be submitted.

There are provisions on the manufacture, import and labelling of investigational medicinal products and auxiliary medicinal products. The sponsor’s and investigator’s obligations are regulated, and it is stated that the Member States must make sure there are systems for compensation in place for any injury suffered by a subject.

What’s to come

Several Swedish legislative instruments and other regulations that describe the work of the Medical Products Agency and the Regional Ethics Committee need to be adapted to the new Regulation. The Swedish Government has submitted a proposal(3) for the changes needed, including amendments to the Medical Products Act(4) and the Public Access to Information and Secrecy Act(5). The changes have not yet been decided, however. We will monitor developments closely.

For companies interested in sponsoring clinical trials, the EMA has announced that sponsors of trials of medicinal products may participate in training in how to use the EU portal and EU database. Training sessions will be made available by the EMA during the second half of 2017 for the version of the system that has been built at that point. Further training will be made gradually available as additional functionalities are developed and added to the EU portal and the EU database. We encourage sponsors to take the opportunity to try out the EU portal and database, in order to be prepared for the extensive changes which it is anticipated will become applicable as from next year.

(1) REGULATION (EU) No 536/2014 OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 16 April 2014 on clinical trials on medicinal
products for human use, and repealing Directive 2001/20/EC

(2) DIRECTIVE 2001/20/EC OF THE EUROPEAN PARLIAMENT AND OF THE COUNCIL of 4 April 2001 on the approximation of the laws,
regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on
medicinal products for human use