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Clinical trials community reacts favorably to tentative set of new rules, yet questions remain.
The new clinical trials rules for Europe made their tentative appearance in mid-July. Tentative, because at present they are merely in the form of a proposal from the European Commission: the legislation as such will come into effect only once the European Parliament and the 27 member states have given their views and, probably, imposed some of their own modifications. But the shape of the likely outcome is discernible even at this stage.
So what does European Health Commissioner John Dalli propose as the escape route from the current rules—which virtually everyone, including Dalli himself, agrees are deeply unsatisfactory? On the surface, his ideas look like an imaginative and even courageous attempt to tackle the inconsistencies and divergences that plague clinical trials—and particularly multi-country trials—in Europe. At the heart of the proposal is a bid for some greater uniformity, through creating a mechanism for a single application for trial authorization, a coordinated European assessment procedure, a single opinion from each of the 27 member states, and—it is hoped—a single decision valid for all the countries concerned by a trial.
The immediate response from the clinical trials community has been largely favorable—even enthusiastic. But at the same time, questions remain over some aspects of the proposal that will require longer study and greater clarity.
First, let's take a quick look at what the proposal contains.
The scope is largely unchanged—covering virtually all pre-authorization clinical research on medicines. The only exception is for non-interventional studies, such as surveys amongst doctors without additional data mining. (Post-authorization safety studies remain governed by the European Union's basic 2001 directive on medicines).
The major innovation is a new authorization procedure for clinical trials, based on a harmonized authorization dossier, a single submission point (a "portal") for applications, and a faster assessment procedure with a key role for a "reporting member state," and the possibility to extend a trial to additional member states. The portal would be managed by the European Commission and be free of charge for sponsors.
Clearer—and much shorter timelines—would be established, and the concept of tacit approval would be generally applied. Modifications would require authorization only if they implied "a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated." And a coordination forum would address conflicting views that might arise among member states in the authorization procedure—although a dissenting member state would be able to opt out of the conclusions reached at EU level on an application. Member states should be allowed to levy fees for processing trial authorization applications, but they should not require multiple payments to different bodies engaged in the assessment.
The start of the clinical trial, the end of recruitment for the clinical trial, and the end of the clinical trial should be notified. The results should be reported to the competent authorities within one year of the end of the trial. Clinical trial data submitted in support of a clinical trial application should be based only on clinical trials recorded in a publicly accessible database.
Risk assessment would play a much greater role than under the current rules. How much a trial needs monitoring would vary according to the degree of intervention, the objective and methodology, and how far it deviates from normal clinical practice. The rules on safety reporting would be streamlined. The rules will be made less onerous for medicines used in a clinical trial that are not investigational medicinal products— "auxiliary medicinal products" (or, until now, "non-investigational medicinal products"). "The applicable rules should allow for some flexibility," the proposal recommends. Similarly, "the rules for labelling should be adapted to the risks to subject safety and the reliability and robustness of data generated in a clinical trial." In particular, no additional labelling should be required in open-label trials for investigational or auxiliary products that have already been placed on the market.
Similarly, insurance obligations would be eased. The commission accepts that the obligatory insurance/indemnity in the current rules has driven up costs and administration without perceptible benefit. So the new rules "acknowledge that clinical trials do not in all cases pose an additional risk to subjects compared to treatment in normal clinical practice." Consequently, where there is no—or negligible—additional risk, it would no longer be necessary to provide specific damage compensation.
To cover trials that do pose additional risk, the regulation would oblige the sponsor to ensure compensation —through insurance, or through an indemnification mechanism that the new rules would require member states to set up to help non-commercial sponsors overcome difficulties in obtaining coverage for possible compensations.
Other innovations include the introduction of provisions for clinical trials in emergency situations where urgency makes it impossible to obtain free and informed consent, wider powers for European Commission staff to perform controls and inspections in member states and beyond, and allowance for the concept of co-sponsorship, "since clinical trials are increasingly initiated by loose networks of scientists or scientific institutions" (although "it is clearly preferable to have only one sponsor per clinical trial"). New provisions would make clear that the responsibility of the sponsor is distinct from issues of liability for harm of a patient. "The rules on liability depend on the applicable national liability laws and are independent from the responsibility of a sponsor," says the commission.
But certain fundamental principles remain unchanged and are clearly reiterated. "The rights, safety, and well-being of the subjects shall prevail over the interests of science and society," says the proposal.
One of the areas that has provoked questions is how the split will be made between matters dealt with at European level and what will remain under national control. The commission says its aim is to make "a clear distinction between aspects where member states cooperate in the assessment, and aspects of an intrinsic ethical or national/local nature where the assessment is made by each member state individually" (notably, liability, ethical considerations such as informed consent, or local factors such as the suitability of the trial site). The answer proposed is to leave to each member state the definition of "the organizational setup and internal competencies for assessing clinical trial authorizations," subject only to the provision that "international guidelines on the independence of the assessors are observed."
The permission to conduct a clinical trial should "be contained in one single administrative decision by the member state concerned." The distinction "does not have implications for the body that performs the assessment, nor does it interfere with the member state's internal organization of the bodies involved in decision-making," the proposal says. The new rule would not lay down which body or bodies should make the decision, nor would it regulate or harmonize the precise functioning of ethics committees, nor impose a systematic cooperation at an operational level between ethics committees in the EU. What the commission insists on is only that applications "will have to be assessed jointly by a reasonable number of persons who are independent, who have collectively the necessary qualifications and experience in all relevant fields, including the view of lay persons."
This formalizes an overlap—not to say a blurring—of responsibilities. As the commission says, "since science and ethics cannot be separated, it does not limit the ethics committee's scope of the assessment to issues which are purely ethical."
Language use has also prompted some questions. The text says it should be left to each member state to decide what languages it will accept applications in—merely adding that "member states should consider accepting a commonly understood language in the medical field as the language for the documentation not destined to the subject." Although this implies that English should be widely accepted, it would not prevent some countries from imposing other requirements.
The legal form of the proposal would be a regulation (rather than the rather form of a directive—which is the basis for the current rules). This, the commission points out, ensures that the member states work from an identical text, rather than on diverging national transposition measures, when they make their assessment of a trial authorization application, monitor safety reporting during clinical trials, or labelling of products used in a trial. It also prevents member states from introducing additional procedural requirements. "Clinical trials, including multi-national clinical trials, can be planned and conducted on the basis of one regulatory framework, rather than on the basis of a 'patchwork' of 27 national frameworks." To allow for a smooth transition from the current directive to the new regulation, both sets of rules would apply in parallel for three years.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.