It is anticipated that the new European Union Clinical Trials Directive, will be a major improvement over the previous Directive 2001/20/EC. It redefines the basic regulatory framework covering clinical trials performed anywhere within the European Union (EU).

One can expect the new clinical trials legislation, which was adopted on April 16, 2014, comes into full force in October 2018, following the development and launch of the EU Clinical Trial Portal and Database.

There will be a transition period of at least three years from when the regulation becomes effective to when the existing EudraCT is decommissioned. During the first year, clinical trial studies can be entered in both new and old systems. Companies will be allowed the full three years to make significant modifications and assessments, either before the regulation became effective or in the first year after it became effective if the sponsor opted for the old system (EudraCT). [1]

Before we fully understand what improvements the new EU regulation will bring into play, first we need to understand what the challenges of the EU Directive were.

The Problems Posed by the Current EU Directive

EU Directive 2001/20/EC worked to simplify and harmonize the administrative provisions governing clinical trials. It became, and remains, an amazing attempt but many hold the opinion that the full benefits of the directive haven’t been realized, primarily due to the “enormous” variations in local implementation. 

The necessity for a review of the regulatory framework for clinical trials was extensively recognized in view of the problems raised by Directive 2001/20/EC, predominantly in regard to:

• Differences in implementation levels across member states
• The excessive levels of bureaucracy involved in meeting the administrative requirements of the Directive, some of which were not effectively justified
• The need for multiple applications for trials involving more than one state
• Difficulties in handling divergent decisions, especially in relation to the opinions expressed by ethics committees
• The lengthy and uncertain time intervals required for authorizations
• The shortcomings of the Directive with regard to the increasingly global scale of clinical trials [1,2]

Due to the challenges presented by the Directive 2001/20/EU CE to perform a clinical trial in several member states simultaneously, the European Parliament and the Council of the European Union enacted new EU Clinical Trial Regulation No. 536/2014 to encourage sponsors to conduct trials across all the member states.

New Directive Demands Greater Transparency

With the creation of this new regulation, the government bodies’ intention is to create an environment favorable to conducting clinical trials within the EU, with the highest standards of safety for participants. It also establishes new rules on how to perform and conduct clinical trials that should be consistent throughout the EU.

The European Union Clinical Trials Directive will totally transform the level of information openly available for each clinical trial by demanding transparency on the authorization, conduct, and results of any trial. This will increase the efficiency of all trials in Europe, with the greatest benefit for those conducted in several member states (making the EU more attractive for clinical trial research, reversing the decrease in the number of clinical trials conducted across the continent).

It aims to encourage innovation and research, avoiding unnecessary duplication of clinical trials or repetition of unsuccessful trials. This will guarantee that the rules for conducting clinical trials throughout the EU are identical, ensuring that all the member states, base themselves on identical rules, when authorizing and supervising the conduct of a clinical trial.

However, we must remember that before the new regulation becomes effective, the EMA must have established an operational database for clinical trials and a portal for submissions. Six months after these two components are functional, the Regulation comes into full effect. [3]

Key Considerations for the New EU Regulation

The scope of the new regulation is extensive, with several primary components covered in the core text and multiple appendices. These include:

• Authorization procedures
• Start of trial
• Suspension or temporary holds
• Early termination
• Protection of subjects
• Informed consent
• Conduct of trials
• Safety reporting
• IMP manufacturing
• Labeling and import
• Insurance

By harmonizing these requirements, submissions have been simplified from what might have been a total of 28 submissions to just one!

However, certain aspects will not be covered by the regulation and will remain country specific, such as ethical considerations, legal representation, site requirements and some administrative procedures.

Here are important things you need to know:

• The EMA requires only one clinical trial submission to the Regulatory Authority and the Ethics Committee for all involved EU countries together [4]
• An online portal is being built for a release in 2018 where applications will be submitted, authorized and supervised through a single entry point (link is external). All recruitment and study termination information will be managed in this single portal [4]
• EMA authorities and committees now require responses within 12 days from sponsors. Failure to provide satisfactory answers within the new 12-day timeframe will result in a rejected application [4]
• The clinical trial application is now divided into two parts:

1) Part I – Study specific documents – The concerned member states cooperate in the assessment of scientific, therapeutic and safety aspects

2) Part II – Country/site specific documents – The assessment is made by each concerned member state individually, applied to items, such as biological samples, clinical trial agreements, informed consent, recruitment of subjects

• By law, all information entered in the clinical trial database is publicly accessible, except personally identifiable information, commercially confidential information, and confidential communication between and among member states [4]

What it means for sponsors:

• Detailed summaries of the study results, including a summary in plain language, are to be submitted within one year of termination of the clinical trial
• Final study reports that were submitted to support a marketing authorization are to be uploaded onto the EU database within 30 days of authorization, rejection, or withdrawal of the marketing application
• Monitoring can be flexible based on the intervention level, objectives and methodology of the trial, and the degree of deviation of intervention from normal clinical practice
• SUSARs (Suspected Unexpected Serious Adverse Reactions) are required to be electronically reported by the sponsor directly into EudraVigilance*, instead of being submitted to each member state
• Under the new regulation, co-sponsorship is now permitted, with each co-sponsor assuming full regulatory responsibility unless co-sponsors agree otherwise
• If trial data from the U.S. is to be considered for the EU marketing application, then it must be registered prior to start, rather than within 21 days after recruitment start as typically required in the U.S.
• Clinical trial data submitted in an application dossier must be based on clinical trials that have been registered, prior to their start, in a public registry that is a primary or partnered registry of the international clinical trials registry platform of the World Health Organization

*EudraVigilance (European Union Drug Regulating Authorities Pharmacovigilance) is the European data processing network and management system for reporting and evaluation of suspected adverse reactions during the development of new drugs and for following the marketing authorization of medicinal products in the European Economic Area (EEA). (https://en.wikipedia.org/wiki/EudraVigilance)

Conclusion

The original objectives of revising this legislation included the reduction of unnecessary administrative burden without compromising standards and improving the attractiveness of Europe as a location for clinical research.

The new 536/2014 Regulation “symbolizes” changes that are being welcomed by pharmaceutical companies in the EU, and seems to have been elaborated with special consideration towards them. It eases the expenses related to carrying out a clinical trial, particularly in multiple member states. As such, the regulation reduces the required paperwork, staff, and fees, and concurrently, simplifies the authorization process.

All things considered, simpler guidelines, increased cost-effectiveness, and easier access to the European population will probably make the EU more attractive for companies seeking to perform large studies.

This change could possibly reverse the recent tendency of pharmaceutical companies to turn to developing countries with large populations.

The adjustments in EU life sciences regulations are being made to:

• Improve knowledge
• Standardize, simplify, and align regulations and procedures
• Increase efficiency and reliability for manufacturers, distributors, service providers, notified bodies, and member states

This is with the ultimate goal of protecting and improving patient safety. Finally, one can expect a benefit not only for sponsors in general, but also for the scientific community and the general population, thanks to the increased transparency provided by the new Regulation.