The Best-Laid Plans...

Those readers who remember John Dalli—the European Union's health commissioner forced to resign last autumn over questions about his relations with lobbyists—may also remember what he said when he proposed the new clinical trial rules, less than a year ago. "Today's proposal significantly facilitates the management of clinical trials", he said on July 17, 2012. And his officials added: "The measures proposed today will speed up and simplify the authorization and reporting procedures."

Dalli is gone, replaced by a fellow citizen of Malta, Tonio Borg. And with him, the optimism over the prospects for new rules on clinical trials has largely evaporated too, leaving serious doubts about whether there will be any real improvement on July 17 this year, next year, or the year after.

The scale of the problem is currently being graphically illustrated in the European Parliament—which has a key role in agreeing new EU legislation. Attempts at "speeding up" and "simplifying" have been buried in a storm of debate—some of it tackling the central elements of the proposal, but much of it, indeed most of it, swirling around secondary issues. The consequence is that four committees in the parliament are battling their way through more than a thousand amendments proposed by their members, and the momentum needed to get any new laws onto the EU statute book is being eroded by the week.

Central elements

The breakthrough in the Dalli proposals—or so it was seen at the time—was to streamline the discussion of clinical trial authorizations at the EU level through a single portal for applications, obliging the national authorities to focus on a limited range of issues in deciding on whether to permit a multi-country trial. But one of the devices employed by the commission was to restrict discussion of ethical aspects uniquely to national level. This has run into all sorts of trouble.

A demand for explicit mention of ethics committees and of their role is a frequent feature of the amendments. "The responsible ethics committee should assess the direct benefit of the clinical trial to the patient," says a wide cross-party coalition of MEPs, led by center-right German Peter Liese.

Similarly, a group of center-right MEPs also urge more specific guidance on ethics committee involvement: "The role of ethics committees does not seem to be very clearly defined in the commission's proposal. It is necessary to clarify that the assessment necessary for the authorization of a clinical trial also involves ethical aspects," they observe.

In order to allow for independent control as to whether the Helsinki principles are adhered to, a clinical trial should be subject not only to prior authorization, but also "approval by an ethics committee prior to commencement," they insist.

Not only is the need felt for explicit acknowledgement of the importance of ethical assessment. The constitution of the ethics committee should also be spelled out, according to Romanian liberal Cristian Silviu Busoi: Member states "should ensure the involvement of lay persons and patients. They should also ensure that the necessary expertise is available. In any case, however, and in accordance with international guidelines, the assessment should be done jointly by a reasonable number of persons who collectively have the necessary qualifications and experience. The persons assessing the application should be independent from the sponsor, the institution of the trial site, and the investigators involved, as well as free of any other undue influence."

Low intervention trials

Another of the principal innovations in the 2012 approach was the aim to ease the regulatory constraints on academic or investigator-led trials by introducing the concept of "low-intervention trials." Again, this has met with wide opposition in the parliament.

"The principle of 'no medicine without side-effects' applies to all medicines, whether approved or being tested," according to Greek liberal Theodoros Skylakakis in an amendment he is urging. "A distinction between high-risk and low-risk trials does not hold water, given the absence of objective assessment criteria," he claims in his written justification.

A similar point is made by Danish Green MEP Margrete Auken: "Low-intervention does not necessarily mean risk free. Unexpected adverse effects can happen and subjects must be compensated in these cases. Therefore the sponsor shall ensure that compensation is provided for all clinical trials", she insists in one of her proposed amendments.

Timelines

The commission also targeted decision timelines. "The authorization procedure for clinical trials will allow for a fast and thorough assessment," it boasted. Not everyone agrees with the concept—the new and tighter timelines proposed for national authorities to reach decisions are considered excessively short by several MEPs. Similarly, the commission intention of winning general agreement on tacit approval—a trial may start if an application for authorization is not rejected within a set period—is widely contested. "Such a tacit authorization procedure would impair the safety and rights of subjects," argued French Green group MEP Michèle Rivasi in her opinion on the proposal.

Wider information

Intense debate is also underway on the amount and type of information that should be released on trial results. In line with the prevailing tendency in Europe—and elsewhere—to greater disclosure, the commission's proposal offered numerous concessions to wide availability of data, including through the creation of a specific database. But this has not been enough to satisfy the transparency hawks in the Parliament.

Auken urges that "for effective transparency and to ensure access for independent researchers to do randomized trials and meta-analysis, the database should be publicly accessible." And in another amendment, she argues for the removal of any constraints on information provision on the grounds of commercial confidentiality.

"According to the European Ombudsman, there is nothing in a clinical study report that can be considered commercially confidential," she says. "Furthermore, the interests of public health and the citizens' right to know should override any invocation of commercial confidentiality. Subjects volunteer for research to benefit society and future patients, not to benefit a particular drug company."

Divisions within the parliament are evident in the counter-amendments put down by MEPs with greater sympathy for commercial confidence. French center-right member Philippe Juvin is seeking additional protection for data, including a proposal for "protecting confidential scientific information which has not yet been published in a scientific journal."

He is arguing that the new rules should "preserve the added value and the expertise of European researchers as well as their legitimate interests to benefit from the results of investments used to develop a clinical trial."

A jungle of detail

It is in the peripheral areas of the proposal that the draft amendments are conspicuously numerous. A telling example is in the discussion of labelling of investigational medical products. Juvin argues that if these have a marketing authorization, "additional labelling is superfluous and a waste of resources." At the same time, he argues that "it would be of real practical use to advise clinical trial subjects that they should always carry a card or leaflet indicating that they are taking part in a trial and providing some information about it and, possibly, safety recommendations."

Busoi is urging a refined nuance to the rules relating to the language of labels on investigational medical products. The text proposed by the commission is that "the language of the information on the label shall be determined by the member state concerned. The medicinal product may be labelled in several languages." This is not enough for Busoi. He wants to insist not only that the language of the information on the label shall be determined by the member state concerned, but that it also "shall be one of the official languages of the European Union." His justification is that "in order not to impose unnecessary burdens, the information on the label should appear in EU official languages only". As a further complexity, he adds: "This should not prevent member states concerned from imposing the use of a language which is not an official language of that member state, but which is relevant to the localization of the clinical trials site. The latter should be taken into account also by member states having more than one official language of the European Union."

Distrust, resentment, even hostility are detectable in many of these detailed amendments. Auken wants to boost the proposed requirements on inspection reports. Not content with the commission proposal: "Following an inspection, the member state under whose responsibility the inspection has been conducted shall draw up an inspection report. That member state shall make the inspection report available to the sponsor of the relevant clinical trial and shall submit the inspection report through the EU portal to the EU database." She wants to add that the report "shall be publicly available." Her justification is that "subjects taking part in the clinical trial have the right to know whether the trial has been conducted in accordance with the regulation for them to be able to withdraw their consent should they wish to do so. Moreover these inspections are carried out in the public interest and the inspections are often paid with public money which is why the report should be made publicly accessible."

The list of changes demanded is almost endless, from provisions on insurance and indemnification through to consent and data protection. It is an indication of the importance of clinical trials that the proposed changes to the rules have attracted so much attention. It is an indication of the challenges of getting anything done in the European Union that the debate in the Parliament seems, at present, at least, to be bogged down in a chaos of rival schools of thought.

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