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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).
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 here.
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.
Ernst A. Singer, MD, is Professor of Pharmacology Ethics Committee, the Medical University of Vienna