Reorganizing research ethics committees and the new regulation for clinical trials

Although all EU member states have established a procedure for ethics review of clinical drug trials, the new Clinical Trials Regulation (EU) No 536/2014[1] will bring significant changes within the infrastructure of this kind of review. Concerns have been raised that the Regulation (EU) No 536/2014 will require a radical reorganizing of the work of research ethics committees, which might eventually weaken the existing research ethics infrastructure. Therefore, reflections on implementation challenges of the new Regulation (EU) No 536/2014 are important not only for the countries with rather recently established research ethics committees (RECs) but even for those member states that have a rather well functioning ethics review infrastructure.

Legal context

Clinical trials on medicinal products for human use (clinical drug trials, CDTs) represent the most strictly regulated type of biomedical research. For example, CDTs are reviewed by RECs and state medicines control agencies (“competent authorities”, CA), while other types of clinical research are reviewed by RECs only (with some exception e.g. for clinical trials on medicinal devices). In addition, RECs must be notified about any amendment of the CDT and all serious adverse events. They also must receive annual study reports. For almost all other non-drug clinical research, these safeguards are missing[2]. This regulatory framework of the CDTs in Europe was provided by the Clinical Trials Directive 2001/20/EC[3], which set up a uniform standard for CDT assessment. However, its adoption into the national laws also led to significant national differences that caused delays in decision making and increased administrative costs of those conducting multinational CDTs. Therefore, the Directive 2001/20/EC has been sharply criticized for hindering the conduct of clinical trials in the EU[4].

It is expected that the new Regulation (EU) No 536/2014 will not lead to the mentioned drawbacks. The Regulation is directly applicable in all Member states and therefore will harmonize the approval process for clinical trials in the EU. It introduces a single electronic application for all interventional studies to be submitted via a single EU Portal and database system managed by the European Commission. Its evaluation procedure involves all the Member States where the sponsor intends to conduct the trial and provides for strict time limits for decision making[5]. In addition, the Regulation (EU) 536/2014 provides a more structured approach for the assessment procedure, as it divides the assessment procedure into two parts. Part I of the assessment is often presented as a technical‖ and scientific one. It includes some technical issues like manufacturing and labeling of medicinal products as well as scientific and methodological aspects of the CDT. However, its main overall objective is the assessment of therapeutic and public health benefits as well as risks and inconveniences to research subjects. Part II of the assessment includes locally relevant ethical issues such as informed consent and recruitment of research subjects, rewarding or compensating research subjects, data protection, suitability of investigators and trial sites, and damage compensation. The Regulation does not explicitly assign what issues are to be assessed by ECs. It only states that the review by the ethics committee may encompass aspects addressed in Part I of the assessment report for the authorization of a clinical trial and in Part II of that assessment report as appropriate for each Member State concerned. This division of the assessment report is in itself a useful tool to better structure the complex procedure of the review. However, its simplistic interpretation may lead some MSs to limit the scope of ECs review to only the Part II issues[6].

Changes of the established national systems of reviewing CDTs

Implementation of the Regulation (EU) No 536/2014 will require to develop a close multinational cooperation between national competent authorities making a joint assessment as well as reaching one single decision per member state concerned. In their attempt to comply with the Regulation (EU) No 536/2014 requirements, the member states may face certain challenges in complying with the strict time frames for assessments, reaching the internal consistency for the opinions, identifying experts in specific areas, and assuring adequate internal resources to ensure ongoing timely evaluation process.

Thus, the implementation of the Regulation (EU) No 536/2014 makes it necessary to reorganize national processes, especially coordination and cooperation between the national competent authorities and the ethics committees[7]. It also raises the need to coordinate and clearly define the activities of local research ethics committees. In some countries the Regulation (EU) No 536/2014 may lead to substantial changes of the established system of reviewing clinical trial applications by RECs. The positive outcome has been that in many countries the preparation for the implementation of the Regulation (EU) No 536/2014 for the first time forced the legislator to specify in detail the composition, functioning, tasks and responsibilities of RECs. On the other hand, it is foreseen that a number of RECs involved in the approval of clinical trials on medicinal products within the member states will be reduced. For example, in Germany, ECs must be registered with the federal drug authority BfArM and if a REC does not perform properly the registration can be withdrawn. There are also some doubts whether the RECs will not lose their financial autonomy as the fees will be fixed by the government[8] as well as how will the RECS independence, including from the CA be ensured.

Impact of the Regulation (EU) No 536/2014 on the future work of RECs

There are two features of the Regulation (EU) No 536/2014 that can have an influence on the future work of RECs. Namely, the scope of ethical review, which is left up to the member states to be defined and multiple restrictive deadlines for the decision to be made regarding different phases of the assessment procedure. The most challenging consequences might be the following ones: narrowing of the scope of ethical review performed by RECs (marginalization of RECs), procedural changes in REC decision making as well as professionalization of RECs.

“Marginalization” of RECs in the review process of CDT. There is a structural difference between the scope of REC review as defined in current CT Directive which clearly incorporates methodology and risk/benefit analysis and the Regulation (EU) No 536/2014. This leaves it to the member states to choose the scope of ethics review. Thus, it is possible that some member states will choose a narrow model of review - only the Part II assessment of “local” aspects, such as informed consent documents, suitability of investigators and trial sites, etc. This model would exclude methodology and risk/benefit ratio from the scope of REC review. If this happens, such issues as the choice of control and placebo use; protection of vulnerable research participants (decision on a minimal risk standard) would not fall within the scope of RECs review.

This may lead to the so-called marginalization of RECs. This issue was emphasized in the EGE Statement of 2012[9] as the RECs were not referred to in the early draft of the Regulation at all. The Regulation (EU) No 536/2014 leaves MSs a free choice on the involvement of the REC in the evaluation process (within the established times). If a member state intends to involve the REC for ethical and scientific evaluations, the REC will also have to interact with the EU portal[10].

Procedural changes in REC decision making. Hopefully, the tasks and responsibilities of the RECs will remain unchanged and the RECs will be involved in the assessment of both parts of the application dossier (part I assessed together with the competent authorities (CA) and part II that would remain the sole responsibility of the REC). However, as the envisaged deadlines for the assessment are rather short, in particular for multinational trials, and the communication with the sponsor will be in writing only, the established procedures of RECs will have to be modified.

It should be noted that multiple and short deadlines and the need for an exchange with the CA on the decisions will require much more intensive workflow not limited to the traditional monthly meetings. Some authors say that the involved ethics committees should have at least weekly meetings while the others say that time lines will not allow to continue with the “traditional” model of face-to –face ethics review.

In addition, up to now it was common to verbally discuss problematic issues with the sponsor. The Regulation (EU) No 536/2014 is focused on a written communication with the sponsor via the EU portal[11]. The RECs, their office staff and chairpersons will need considerable professionalism and respective training. The future workflow will also require a substantial IT support. Some member states expect that in addition to the new EU Portal/database system a national IT system for national cooperation and interaction will be necessary[12].

Professionalization of RECs. Short processing deadlines and the complex assessment procedure will require a high level of human resources and technical competence. It is expected that institutional model of “self-regulation” based on honorary participation will have to be replaced by “professional” committee.

The call to “professionalize” RECs was already flagged in 2009 by Ch. Druml and colleagues who claimed that “The future of ethics committees can only be the small but professionalized committee of highly qualified and trained experts who are adequately paid for their contribution as an integral part of clinical research.”[13]

According to some authors, the most likely institutional model for CDTs is a single coordinating ethics committee or a few recognized RECs for both Part I and Part II assessment composed of full-time members with a secretariat including persons with experience in CDTs[14] and experts from different therapeutic fields rather than representing geographical and regional specificities. However, such an approach may clash with the “lay” representation required by the Regulation (EU) No 536/2014, as well as with the multidisciplinary deliberation as a key feature of what has so far been perceived as an “appropriate” ethics review.

Impact on non-CDT after the implementation of the Regulation (EU) No 536/2014

It seems that one of the possible scenarios of the future development of ethics review system under the new Regulation (EU) No 536/2014 may lead to diversification of ethics review for biomedical research. Different modalities of ethics review for CDT and other types of biomedical research might be established. As it was already mentioned, for the CDTs, it is most likely that a “central” REC or a few recognized RECs will make an assessment with some input from local/regional REC, at least for the small countries. It is also likely that most of the work will be carried out on-line by “professional” members with a strong commitment to strictly follow complex timeframe (e.g. employment contract) with a limited lay member perspective.

Regarding other types of biomedical research, a more “traditional” multidisciplinary face to face meetings can still be retained. In this respect, there might be no short-term changes in those countries that have already established a comprehensive system of ethics review for human research. However, in the long-term perspective requirements for ethics review of non-CDTs can loose a “legal support” enforced by the current Clinical Trials Directive[15].

It is difficult to predict what will happen in the countries, which have not yet developed a comprehensive research ethics infrastructure. However, it is likely that the mentioned negative long term consequences of “splitting” ethics review into different modalities might be more visible in these countries as compared with those having a longer history of ethics review. On the other hand, it should also be noted, that the need to introduce elements of “professional” management of RECs as well as an opportunity to exchange information during the assessment process could also have a positive impact on the quality of ethics review of other types of human research.

For the further information on the impact of the Regulation of clinical trials please refer to the section 2.3.6 of the E-manual available at  http://eneri.eu/reri-manual/.

References

Druml C, Wolzt M, Pleiner J, Singer EA. Research Ethics Committees in Europe: Trials and Tribulations. Intensive Care Med. 2009;35(9):1636–1640

Gefenas E., Cekanauskaite A., Lekstutiene J., Lukaseviciene V. Application challenges of the new EU Clinical Trials Regulation. Eur J Clin Pharmacol. 2017 Jul;73(7):795-798.

Gefenas E, Dranseika V, Cekanauskaite A, Hug K, et al. Non-equivalent stringency of ethical review in the Baltic States: A sign of a systematic problem in Europe? Journal of Medical Ethics. 2010; 36:435–439. doi: 10.1136/jme.2009.035030

Hasford, J. The impact of the EU Regulation 536/2014 on the tasks and functioning of ethics committees in Germany. Bundesgesundheitsbl (2017) 60: 830. https://doi.org/10.1007/s00103-017-2580-3

Petrini, C. & Garattini, S. Trials, Regulation and tribulations. Eur J Clin Pharmacol (2016) 72: 503. https://doi.org/10.1007/s00228-016-2009-1

Stahl, E. Implementation status of Regulation EU 536/2014 in the member states. Bundesgesundheitsbl (2017) 60: 836. https://doi.org/10.1007/s00103-017-2579-9

Tenti E, Simonetti G, Bochicchio MT, Martinelli G. Main changes in European Clinical Trials Regulation (No 536/2014). Contemp Clin Trials Commun. 2018;11:99-101. Published 2018 May 17. doi:10.1016/j.conctc.2018.05.014