All those engaged in trials within Europe should be familiar – at least to some degree if not intimately – with the ‘Clinical Trials Directive’ (or to give it its full, and understandably seldom used, full document title: ‘Directive 2001/20/EC of 4 April 2001, of the European Parliament and of the Council on the approximation of the laws, regulations and administrative provisions of the Member States relating to implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use’).

This Directive and clinical trials regime that it embodies is being replaced by a new EU Clinical Trials Regulation, a draft of which was published in the Official Journal of the European Union (EU) on 27 May this year ^[1].  It has now been reviewed and put before the European Parliament, which has given their full approval. Although the Regulation entered into force on 16 June this year, it will not be able to be applied before 28 May 2016.

The seemingly long gestation period to practical usage is because a new complex unified IT infrastructure, which underpins the Regulation and enables the system to work effectively, must be put in place and functioning properly. Six months must have passed from the point at which this new EU portal and database becomes fully operational and this is believed to be no earlier that May 28^th 2016.

One might ask why the current Directive is being repealed, as happens once the Regulation comes into force.  Well, it is quite widely acknowledged that since its introduction in 2004 the attractiveness of the EU for conducting clinical trials has, unfortunately, been reduced. As pointed out on the UK’s MHRA’s (Medicines and Healthcare products Regulatory Agency) website, this is because the directive:

• Introduced unnecessary administration
• increased regulatory burdens
• lacked clarity in some aspects
• allowed Member States to introduce additional requirements when implementing the Directive which limited harmonisation, resulting in:
  • creation of delays
  • increased costs for researchers.

The Regulation aims to restore the EU’s competitiveness in clinical research and the development of new and innovative treatments and medicines by cutting red-tape to streamline the process and to bring patient-oriented research back to Europe. As we’ve seen in an earlier Clinical Accelerator Blog, ‘Patient-centricity’ in research is an all important facet of success.

Brief highlights of the Regulation and main changes are as follows:

Firstly, and as previously, the scope of application, covers all interventional Clinical Trials, but now adopts less onerous requirements for those considered ‘low-intervention’; a new concept of ‘co-sponsors’ (already acknowledged in current UK applications) and new categories of medicinal products (e.g. a concept of “auxiliary medicinal products”).

Secondly, the most innovative and notable introduction in the new Regulation, is the planned ‘harmonised’ authorisation procedure’ incorporating a single application through a single EU portal as well as centralised assessment by a nominated ‘reporting member state’ and shorter time frames (including 45 days for the assessment report rather than 60 and, interestingly, includes an explicit system of tacit approval if it is not assessed within required timeframes) for the two-part application. Part I of the dossier, dealing with general aspects (e.g. type of clinical trial, risk-benefit analysis, and compliance with technical requirements etc.) being assessed by the single so-called ‘reporting Member State’ with an opinion valid for all EU state participants and Part II, addressing aspects of a national nature (e.g. informed consent and compensation of subjects etc.) being assessed individually by the other relevant Member States concerned. Within this system of harmonised approvals, there are also rules governing the type and integrity of data in the application when providing reference to results of other clinical trials.

Thirdly, the Regulation aims to streamline sponsors’ obligations to report adverse reactions and other events to the authorities of the relevant Member States with simplified adverse reaction reporting using a new module of the Eudravigilance database to be set up within the central IT portal. However, more detailed reporting of events is required and so although there is some simplification in reporting, there appears to be an increase the pharmaceutical companies’ reporting obligations. Notification of milestone trial events (e.g. start of the trial, first visit for first subject, end of recruitment etc.) will be more systematic and common for all Member States involved through the central IT portal.

Fourthly, rules for the public disclosure of all (non-confidential) clinical trial information are extended and clarified with more information available in the public arena through the EU portal.

In addition to the main changes above, the Regulation also covers other aspects and revises the rules concerning, among other things, subjects’ informed consent; indemnity and insurance obligations; manufacturing, import and labelling of investigational medicinal products; trials conducted outside the EU; and the supervision, inspection and control of trials by the Member States and the European Commission.

It is significant that the new set of rules is being introduced as a ‘Regulation’ rather than a ‘Directive’.  A “Regulation” is a binding legislative act, which must be applied in its entirety across the EU whereas a “Directive” (i.e. the old set of rules) is a legislative act that merely sets out a goal that all EU countries must achieve. However, it is up to the individual countries to decide how and so this has, arguably, led to some of the disparity between Member States with the current 2004 CT Directive.

Nevertheless, the Regulation itself often resorts to rather vague concepts such as “normal clinical practice” or “duly justified grounds”, which still leaves a little room for interpretation by individual Member States.  This would seem to afford a small degree of independent control in practice, which may well be to the detriment of full and effective regulatory harmonisation for some aspects of the new clinical trial regime.

One should note that the scope of the new Regulation still does not include specific rules for non-commercial trials (amounting to more than 20% of all EU trials) but recommends creation of national measures to encourage these types of trials.  Furthermore, even for commercial clinical trials covered by the new regime, the Member States still remain the central players for all local ‘non-ethical’ matters (a few relevant to Part 1, for which in certain circumstances, the central opinion can be challenged, as well as Part 2 of an application).  These elements may also jeopardise the practical ability of the Regulation to establish a fully harmonised trial regime throughout the EU.

Whilst the Regulation represents a significant step forward with regard to the harmonisation of clinical trial regulations in the EU, it certainly remains to be seen how these changes will apply in practice and whether they will be effective in leading to a harmonised and faster assessment of EU clinical trials and thus enhance the competitive position of the EU. No doubt, additional guidance will be published to support this nearer the time.  Meanwhile, the EU states will have to fare as best they can against other non-EU territories, like Russia, Ukraine, Serbia, Croatia and CIS countries such as Belarus, Moldova or Georgia who have captured significant trials business during the last decade.

[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