Getting Ready for Godot: Rehearsals for Europe's New Clinical Trials Rules

In broad political debates about medicines, the term "clinical trials" is often thrown about rather lightly, as if it were a clear and simple process well understood and widely accepted. The fallacy of any such assumption is powerfully demonstrated by a 98-page compendium that has just emerged from the European Commission: an updated guide to the EU's 2014 clinical trials regulation.

This extensive questions-and-answers goes into the most intricate level of detail about some of the choices, dilemmas, and decisions that have to be made every day by anyone involved in trials - or in supervising them. The guidance is a "live" document that has been in constant development by the EU's group of clinical trials experts drawn from the member states, and is periodically updated as procedures become better defined. This latest version includes an extensive new section on safety, along with updates to the previous guidance.

The new section on safety reporting occupies 30 pages and consists of 47 separate questions such as how the definition of an adverse event should be applied in clinical trials to when ‘suspected’ serious adverse reactions are considered unexpected because of specificity, severity, or frequency. It covers the format that should be chosen for the reference safety information, and what safety information should not be included in it but may be presented elsewhere in the investigator’s brochure.

Here are discussions of whether unblinding is necessary in case of serious adverse reactions being unexpected for either the investigational product or its comparator, and of who should unblind and be unblinded. Some definition is brought to when requirements start and end for the investigator and the sponsor in relation to recording and reporting safety issues, and to which development international birth date should be used for an investigational product with marketing authorization in Europe when used in a trial initiated by an investigator and not by the marketing authorization holder.

The updated answers range from when a study can be considered as a clinical trial within the scope of the 2014 regulation if it starts after administration of/or exposure to the investigational product has finished, to how "substantial modification" is defined. New clarity is brought to how responsibilities are shared in case of co-sponsorship, and to the obligations on the legal representative of a non-European sponsor in view. And extended guidance is provided on how "early termination" is defined.

To add to the complications, the 2014 regulation has yet to enter into force, and meanwhile clinical trials in Europe remain subject to the provisions of the 2001 directive.

The European Medicines Agency has both warned and promised that, "the way clinical trials are conducted in the European Union will undergo a major change when the clinical trial regulation comes into application." Central to the regulation is a so-called clinical trials information system, which will be a portal acting as a single entry point for submitting clinical trial information in the EU, and a database to store the information. But "due to technical difficulties with the development of the IT systems, the system's go-live date was postponed”, EMA admits, and the application of the regulation "depends on confirmation of full functionality" of the new system. The latest update on that assessment is that in June the system entered, "a phase of agile, iterative delivery, to prepare the system for audit. It will then be further enhanced for go-live and beyond, in close cooperation with the user community." No firm date is yet fixed for the regulation to come into effect.

So, during this interregnum between the 2001 directive and the 2014 regulation, triallists are not only obliged to comply with the current rules, but at the same time to prepare themselves for the future rules. This is why the final question in the just-published guidance on safety reporting is: "How to report suspected unexpected serious adverse reactions during transition time from Directive 2001/20/EC to EU Clinical Trials Regulation (EU) 536/2014?"

Nothing is simple in clinical trials - and that is even more true in Europe.