Revisions to the Clinical Trials Directive

This column does not normally devote itself to just one document coming from the European authorities. But this is a special occasion, and in recognition of the importance of the subject, this month is a snapshot of the just-published European Commission concept paper on the revision of the Clinical Trials Directive, on which proposals are due next year. It is out for public consultation, so this is a heads-up to look at the document in detail (http://ec.europa.eu/health/files/clinicaltrials/concept_paper_02-2011.pdf).

The paper presents a "preliminary appraisal" of the most suitable way to address some of the key concerns already identified in the Clinical Trials Directive. It also looks at the figures being used to evaluate the impacts of the different policy options.

Peter O'Donnell

Regulatory cooperation

One of the main issues addressed in the concept paper is cooperation in assessing and following up applications for clinical trials. As the document concedes, because the current legislation does not provide any mechanism for a single submission jointly to several member states where a trial is to be conducted, nor for any cooperation among them in assessing the trial, largely identical information has to be sent to several different member states, with unnecessary administrative costs. In addition, the requirements in the directive are applied differently across Europe, with conflicting points of view on details of the authorization.

The options under consideration comprise a single submission via the European Medicines Agency (EMA), but with separate national assessments; a single submission with central assessment by a scientific committee with representatives of all 27 EU member states; or—most favored at present—a single submission with a coordinated assessment procedure involving just the member states concerned.

Analyzing the options

The concept paper examines the pros and cons of the options it presents. For instance, while a single submission is seen as unquestionably reducing the administrative work of sponsors for submission of documentation to the member states concerned, the assessment process is subject to many more factors. An independent assessment by each member state, as at present, would insufficiently address the diverse interpretations that mar the current procedures, the paper suggests.

Similarly, it argues, a central assessment by a scientific committee of representatives of all the member states is not appropriate for clinical trials approval: it would "insufficiently take account of ethical, national, and local perspectives" (so "a parallel, national procedure would have to be established in any case"); the volume of multinational trial applications per year (estimated at around 1,200, even without counting all the substantial amendments) "would make centralized assessment very difficult;" and the involvement of all member states is not needed, as very few clinical trials are rolled out in more than five or six countries in the EU. In addition, it goes on, a centralized committee would require frequent meetings with a robust supporting infrastructure, and the costs (and, consequently, fees) involved would make this mechanism unattractive for academic researchers.

So the paper comes down in favor of the coordinated assessment procedure, because it would allow all member states concerned input to the assessment of the application, with one member state designated to lead the assessment, and address only certain aspects of the assessment of an application. It would have the merits of leading to a "single decision" per member state on the aspects assessed, as well as on the ethical/local aspects of an assessment.

This coordinated assessment option could be tweaked to allow an individual member state to opt out if it disagreed with the result of an assessment, as long as it justified the opt-out on grounds of a "serious risk to public health or safety of the participant." It might be made mandatory for all clinical trials, or for all multinational trials, or it could remain optional—in which case sponsors could continue to rely on the national procedures in the Clinical Trials Directive.

Risk-adapted approaches

Another major issue dealt with is how to adapt the practical requirements and achieve a more harmonized, risk-adapted approach to the procedural aspects of trials. At present, the legislation does not address some of these procedural aspects in much detail, with the result that member states have created their own national provisions—which diverge from one country to another. "The harmonizing effects of the clinical trials directive get lost," says the EMA document, making multinational trials, "more burdensome and expensive," and hurting clinical research, particularly in rare diseases.

The options here include limiting the scope of the current directive (for instance by enlarging the definition of "non-interventional" trials so as to exclude more studies from the scope of the directive); excluding trials by "academic/non-commercial sponsors" from the scope of the directive; or—clearly the EMA's favorite among these options—making the rules more precise and risk-adapted for the content of the application dossier and for safety reporting.

Narrowing the definition of "investigational medicinal product" and establishing rules for a new concept of "auxiliary medicinal products" with less demanding requirements is another option examined to simplify and streamline the rules. So too is a change in the rules on insurance, to take into account the very different risk profiles of different trials: either removing insurance requirements for low-risk trials or making member states liable for damages incurred during clinical trials performed in their territory. Similarly, because the concept of a "single sponsor" per trial—central to the current rules—makes multinational trials unduly onerous, other forms of sponsorship should be envisaged: multiple, joint, shared, or co-sponsorship.

GCP beyond the EU

A third major area of concern relates to ensuring compliance with good clinical practices in clinical trials performed in non-EU countries. Here the commission's paper makes clear that any weakening of the standards would be "in contradiction to the fundamental principles of human rights and dignity and their universal guarantee and protection, to which the EU is fully committed." The ideas that the commission puts on the table here include helping non-EU countries build up their capacity for regulating clinical trials.

Figures and data

In addition, the paper seeks verification, confirmation, or clarification of the figures it has compiled and on which it bases its planning.

These figures include an estimate of the number of trials performed each year in the EU (between 4,000 and 6,000, based on some 8,000-10,000 clinical trial applications). The commission calculates that some 64% of clinical trials are sponsored by the pharmaceutical industry and 36% by academics or other non-industry sources. But commercial sponsors account for 80% of applications, since one clinical trial can imply up to 27 applications—depending on the number of member states concerned.

The commission calculates that approximately 25% of EU clinical trials are performed in more than one EU member state—accounting for 60% of all clinical trial applications, and covering about 70% of all trial subjects. It indicates that the biggest share of clinical trials take place in Phase I: 1,383 in 2010, followed by 1,185 in Phase II, 918 in Phase III, and 707 in Phase IV. In 2010, there were plans for 396,784 participants to take part in EU clinical trials, and the total number of clinical trial participants planned worldwide for clinical trials with at least one site in the EU was 866,155.

Staff available across the EU as a whole, in national authorities, totaled 142 for scientific evaluation of clinical trial applications and amendments, and 90 for related administrative tasks (the figures are for 2007). Only 10 full-time equivalent staff are available across the EU for assessing suspected unexpected serious adverse reactions and annual safety reports, the commission estimates.

The estimates presented by the commission of how much time is needed for sponsors to comply with administrative requirements (collecting information regarding the application procedures, putting papers and documents together, filling in forms and sending them—but not the substantial work, such as developing the design of a clinical trial) is five man-days for the initial submission, and a further two days to supply the follow-up information invariably requested. Each of the 154,000 SUSARs filed each year takes 90 minutes to compile, and it takes an average of 10 man-hours to put together each of the 27,000 substantial amendments submitted each year. Costs per man-hour in regulatory affairs in clinical trials is estimated at €45 ($61.50).

A further two man-hours per application is needed to cover the administrative costs of complying with national insurance/indemnification requirements, and the cost of the insurance itself (per patient, per annum), ranges from a low of €14.50 ($19.82) in Belgium to a high of €75 ($102.50)in France or Germany.

Participating

Now you know, don't just read the document (which provides a lot of detail on the pros and cons of the options raised), but get your input ready, and send it in to the EU while there is still time for you to influence the process.

Author's Note: The deadline for commenting is May 13, 2011. Responses should be sent preferably by e-mail to sanco-pharmaceuticals@ec.europa.eu, or by post to Unit SANCO/C/8, BREY 10/114, BE-1049 Brussels.

Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium