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The language in Europe's Regulation (EU) 536/2014 regarding ethical review of protocols is concerning.
To get a feeling of how much emphasis is put on ethical review in the Regulation (EU) 536/2014 (CTR), a simple comparison was performed with the current legal document regulating clinical trials, known as the Directive 2001/20/EC (CTD). Searching for the character string “e t h i c” results in 62 hits on 19 pages of the CTD, whereas in the CTR the result is 18 hits on 76 pages (a drop from 3.26 hits per page to 0.24). This finding may indicate that ethics committees (ECs) were not among the most prominent concerns when the Regulation was written.
However, another, and much more serious, indication that this may be so is the wording of Article 4 of the Regulation, addressing the authorization procedure. Here it reads: “The review by the ethics committee may encompass aspects addressed in Part I of the assessment report…“
This means that the EC may look at the study protocol but is not obliged to do so, which is in sharp contrast to what can be found on this topic in several internationally accepted documents, including Good Clinical Practice (ICH-E6(R2); article 1.31) and the Declaration of Helsinki (current version Fortaleza 2013, article 23). Both documents state quite explicitly that it is the obligation of an EC to review the protocol and its amendments.
A further aspect to be considered is the impact of the CTR on the workflow of ECs. The following analysis applies to Austria, but is most likely applicable to other European Union member states. From all projects handled by the EC of the Medical University of Vienna (MUV), only 17% represent trials on medicinal products. Ten percent represent trials on medical devices and the remaining 73% are clinical studies addressing issues such as new methods, basic science questions and retrospective and other non-interventional research. All these projects have a monthly application deadline, followed by a monthly session (12 sessions per year). The four weeks before the session are dedicated to intense-and in great part written-review, thus allowing the time in the session to be used for discussion of open issues. All necessary members for voting on a particular study are present at one time in one place. The applicant receives a reasoned opinion from the EC within 35 days of receipt of a valid application. This timeline is CTD-driven and kept for all types of studies.
The described procedure is no longer feasible under the terms of the CTR, because there is no application deadline. As a consequence, the EC will continue to assess 83% of the applications following its current procedure, but will have to implement a new one for the 17% of studies falling under the
scope of the CTR. It is obvious that such a situation will not facilitate competent ethical review. The feeling remains that the CTR has been written neglecting the fact that there exists clinical research outside of what’s conducted on medicinal products.
The issue of timelines of the CTR deserves special consideration. The CTR allows for the assessment of a clinical study a period of 45 days (after a 10-day validation period). The reporting member state can request additional information (RFI) from the sponsor, who must respond within 12 days, otherwise the application will lapse. The member states, in turn, have 12 days for review of the additional information and seven days for consolidation. Thus, the entire procedure of issuing and handling a RFI is 31 days.
In 2011, under the Directive, the EC of MUV had performed an analysis of all RFIs handled in that year. The median times found to resolve an RFI were 59, 73 and 45 days for trials on medicinal products, medical devices and other studies, respectively. Based on these results, it is conceivable to assume that under CTR a substantial number of applications will lapse.
The CTR represents an important step toward facilitating clinical research on medicines in the EU. However, there are some issues regarding ethical review. The wording of Article 4 is not acceptable; ethical review of the study protocol must be mandatory. And the imposed timelines represent a formidable challenge for maintaining the current standard of ethical review.
Ernst A. Singer, MD, is Professor of Pharmacology Ethics Committee, the Medical University of Vienna