Will ethics committees buy into the radical new approach of latest draft regulation?
Not for the first time, the European Forum for Good Clinical Practice (EFGCP) has demonstrated its ability to keep its finger accurately on the pulse of what really matters in European discussions on clinical trials. That sensitivity for the hotspots was doubtless behind its decision to hold a workshop in Brussels in November on "options and challenges for ethical assessment in the clinical trial regulation proposal." Now that wise heads around Europe have had time to reflect on the European Commission's July proposal for new rules, one of the principal areas of potential difficulty that has been identified is whether ethics committees will buy into the radical approach of the draft regulation.
Few readers of this publication will need reminding that among the changes proposed, all the existing EU requirements on ethics committee involvement in assessing applications for clinical trials authorization would be scrapped. This doesn't mean that ethics has gone out of the window. But it does mean that the European Union is planning to leave ethics considerations to national authorities—where, in strictly legal terms, they necessarily belong anyway, since the European Union has no writ on questions of ethics. Like taxation or social security, or indeed like most health matters, including drug pricing and reimbursement, ethics is one of those areas that has never been a subject on which the European Union has any authority.
Accordingly, the proposed new clinical trials rules aim to achieve their intended streamlining by splitting the procedures into European and national component parts. The European level would consist of a harmonized list of documents to be submitted, an electronic portal for a single submission of an application (irrespective of the number of member states concerned), a coordinated scientific-technical assessment procedure, and tight timelines for member states to decide on applications. At national level, each member state will have to organize itself as it sees fit to integrate an ethics committee review within the timelines.
The commission remarked in its proposal that "a crucial element of the rules for authorization of a clinical trial is the clear distinction between aspects where member states shall cooperate in the assessment of the application for authorization of a clinical trial and those aspects where member states conduct their assessment individually, [which] includes aspects which are of an intrinsically national (for example, liability), ethical (for example, informed consent), or local (for example, suitability of the clinical trial site) nature."
If this description leaves open a lot of questions, that is because the planned procedure itself leaves open a lot of questions. The EFGCP workshop aims to start a dialogue that could help to answer some of them. The mechanism of this integration may require different solutions from one country to another. The workshop is looking at the practical implications of the proposal for ethics committees, and particularly at how to integrate all the aspects of the assessment into one decision per member state within the proposed timelines, without compromising scientific or ethical review standards, or levels of patient protection.
Just how acute the challenge may prove to be is demonstrated by hostile reactions from ethics committees. One aspect of the difficulties was spelled out eloquently in a recent letter to the European Commission from the Chairman of the Ethics Committee of the Medical University of Vienna, Ernst Singer. Singer wrote to Stefano Soro, the Head of the Medicinal Products Unit in the European Commission, pointing out that merely in terms of the envisaged timelines, the commission's proposal was unworkable. "In its present form the regulation is not compatible with the current mode of operation of ethics committees, in particular in terms of scheduling," he stated.
The scheduling envisaged by the commission is indeed tight. An application might lead to effective authorization in all member states concerned in as little as 20 days. "In order to meet the deadlines proposed in the new regulation the ethics committees meetings would have to be replaced, or supplemented by an ethics committees making decisions on a day-to-day basis," according to Singer. He pointed out that under their current schedule, committees such as his operate through regular monthly meetings of experts from a range of medical specialties, along with lawyers, patient representatives, and statisticians. "These meetings also provide the opportunity to discuss open points in the protocol with the principal investigator and the sponsor," he wrote—adding that in Austria "this is currently done within 35 days (including obtaining an external review)." He added that the meetings are not held on a monthly basis because the ethics committees do not want to meet more often, "but purely for inherent practical constraints: it is just not possible to have all the necessary highly specialized people available at all times."
To meet the deadlines in the proposed new rules, "all involved experts would have to be constantly available"—which Singer points out is "highly unrealistic"—and it would become impossible to invite the principal investigator or a representative of the sponsor for discussion, or at any rate not in the presence of everyone concerned. "All this would unquestionably lead to a decline in the quality of the decisions made by the ethics committee, which cannot be in the interests of anyone."
Singer provides some revealing statistics to support his arguments, highlighting the fact that clinical trials of medicines form only a part of the studies an ethics committee typically has to deal with. In 2011, he says, his ethics committee dealt with 233 clinical trials of medicines—comprising 19% of studies assessed. In addition, his committee dealt with 93 clinical trials of medical devices, and 901 other studies. "It would be wrong to assume that these 'other studies' are generally less challenging scientifically or pose a lesser risk to participants than medicinal product studies," he underlines.
The consequences, Singer calculates, are that the proposed regulation would lead to the introduction of a dual standard: the majority of studies (in his committee's case about 75%) would be treated in the established way through monthly meetings, while for medicines, decision-making would have to occur on a day-to-day basis. "For the ethics committee (and the member state) this will definitely not facilitate procedures but introduce additional workload and two standards of review," he concludes. High-quality reviews would continue for everything but for medicines, which would suffer from a lower-quality review.
The potential problems extend wider than just the timing of ethics committee review. Even those with long experience of clinical trials in Europe admit to finding it difficult to grasp exactly how the national approval process will function.
"The proposal does not interfere with the member state's internal organization of the bodies involved in authorizing (or not) a clinical trial," the commission said in its proposal. "It is left to member states to define the organizational set-up to comply with the authorization procedure." Explicitly, the commission does not attempt to establish which national body or bodies approves (or not) a clinical trial, nor does it "regulate or harmonize the precise functioning of ethics committees, impose a systematic cooperation at an operational level between ethics committees in the EU, or limit the ethics committee's scope of the assessment to genuinely-ethical issue (science and ethics cannot be separated)." Instead, the proposal "leaves it up to member states to organize, internally, the attribution of tasks to different bodies."
It is almost with a dismissive wave of the hand that the commission says "what matters is that member states ensure an independent, high-quality assessment within the timelines as set out in the legislation." In effect, the commission is saying that the European Union is prepared to do only so much to speed clinical trial authorizations: a single portal, and a single assessment procedure led by one member state, leading to a single decision, on which other member states are supposed to sign off within a few days.
This is, as senior figures in the European clinical trials community have pointed out, a high-risk scenario. By leaving everything up to each member state to sort out its own approach to reaching a decision, the commission is exposing itself—and, more to the point, clinical trial sponsors—to the risk that not every member state will feel it is in a position to sign off. Constrained by time, and obliged to create new national systems for integrating all aspects of the assessment into one opinion, some members states may feel unable—or unwilling—to participate. If the streamlined system works, it could work well. But if member states are not prepared to play ball, it could prove disastrous. The subject merits plenty of exploration over the coming weeks and months.
Peter O'Donnell is a freelance journalist who specializes in European health affairs and is based in Brussels, Belgium.