Ernst A. Singer, MD

	This article describes the experiences of the Medical University of Vienna (MUV) with the Directive 2001/20/EC (CTD) regarding academic clinical research and reflects on the changes introduced by the Regulation (EU) 536/2014 (CTR). See Dr. Singer’s previous article on the language in EU Regulation 536/2014 

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	The CTD establishes “specific provisions regarding the conduct of clinical trials, including multi-center trials, on human subjects involving medicinal products, in particular relating to the implementation of good clinical practice (GCP).” The scope of the CTD is extremely wide, embracing practically any research involving a medicinal product (this holds also true for the CTR). The only exception is the non-interventional trial, i.e. non-interventional research with registered drugs in registered use.
	
	When the CTD was introduced, it was not uniformly welcomed by academic researchers, as evidenced by a number of articles published in various journals, e.g. “EU Clinical Trials Directive: 0% inspiration, 100% perspiration?” in the Lancet or “Scientists beg EU to repeal new rules for CT” in the British Medical Journal. The authors were concerned that academic institutions would not be able to cope with the increased administrative and financial burden brought about by the CTD and, in consequence, academic research would suffer.
	
	In order to analyze the impact of the CTD at the MUV, we compared the number of applications to the EC involving medicinal products in 2000 (before the CTD) and 2006 (two years after the implementation of the CTD). The number of commercially sponsored trials was 183 and 184, respectively, whereas the number of academically sponsored trials dropped by 64%, from 110 in 2000 to 40 in 2006.
	
	In a next step, we searched for publications resulting from those investigator-initiated projects submitted in 1998 that would have fallen under the CTD. Only publications until 2004 and an impact factor of at least 3 were considered. Twenty-three such publications in 17 journals with a total of 115 impact points were identified. All trials involved registered drugs, were small (median number of participants = 19), carried only minimal risk and addressed basic research questions. This result gives an indication of the substantial loss in publication impact due to the decline in academic research caused by the CTD.
	
	In an attempt to facilitate investigator-initiated studies a new type of trial has now been introduced in the CTR: the “low intervention trial” constitutes a trial with registered drugs in standard use and minimal risk interventions. The text reads: “Those clinical trials should be subject to less stringent rules, as regards monitoring, requirements for the contents of the master file and traceability of investigational medicinal products. In order to ensure subject safety they should however be subject to the same application procedure as any other clinical trial.“
	
	Although it may be helpful for non-commercial clinical research to some respect (e.g. multicenter therapy optimization studies), the introduction of the low intervention trial will not help to promote the above-mentioned type of small scale trials: they will still fall under the scope of the CTR, and therefore GCP. As under the CTD, a substantial number of such trials will not be conducted simply because of administrative requirements.
	
	This perpetuates a formidable misconception of clinical research ethics regarding research with medicinal products. The CTD and the CTR (and GCP) are clearly based on industry requirements, where a commercial sponsor takes a compound through its development program. However, non-commercial research usually operates on a quite different basis.
	
	The ethical key issue of a clinical study is the risk to the participant and the scientific value, not the fact whether the intervention involves a medicinal product or not. There is no reason to put a low-risk study with a medicinal product under a different category of rules than any other low-risk study. If a study has high scientific value and minimal risk it need not fall under the scope of the CTR and therefore GCP.
	
	It should be kept in mind that in the area of preclinical research the vast majority of studies are not performed under Good Laboratory Practice (GLP), but the results are widely recognized, even in the regulatory environment of drug registration.
	
	In conclusion, a true promotion of academic research would be to choose a risk-proportionate approach that keeps small low-risk studies outside the scope of the CTR. The categorization whether a study should fall under the CTR or not could well be the task of Ethics Committees, who would make this decision based on a case-by-case analysis.
	
	

, is Professor of Pharmacology Ethics Committee, the Medical University of Vienna

Articles

This article describes the experiences of the Medical University of Vienna with the Directive 2001/20/EC (CTD) regarding academic clinical research and reflects on the changes introduced by the Regulation (EU) 536/2014 (CTR).

Academic Research Under the Clinical Trial Regulation – Partial Relief?

	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…“

 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

The language in Europe's Regulation (EU) 536/2014 regarding ethical review of protocols is concerning.

Ernst A. Singer, MD

Articles

Academic Research Under the Clinical Trial Regulation – Partial Relief?

Ethics Under the Clinical Trials Regulation