Hostname: page-component-7b7567c8c-kwt9d Total loading time: 0 Render date: 2026-11-14T09:16:56.762Z Has data issue: false hasContentIssue false
  • English
  • Français

Competencies of Member States Concerned and of Ethics Committees to Assess Trial Applications Under the New EU Clinical Trials Regulation

Published online by Cambridge University Press:  26 April 2017

Markus K. LABUDE and
Tsung-Ling LEE
Rights & Permissions [Opens in a new window]

Abstract

An abstract is not available for this content. As you have access to this content, full HTML content is provided on this page. A PDF of this content is also available in through the ‘Save PDF’ action button.

I. Introduction

In 2018, the new EU Clinical Trials Regulation (CTR)Footnote 1 is expected to come into operation and replace the 2001 EU Clinical Trials Directive (CTD).Footnote 2 The scope of the CTR remains largely identical to that the of the CTD: both apply to the regulation of the testing of medicinal products on human subjects, with the “objective of ascertaining the safety and/or efficacy of those medicinal products”.Footnote 3 The difference between the two legislations is then in their form and content. In this regard, the European Commission has emphasized that the new Regulation “introduces some significant measures which will contribute to boost clinical research in Europe”,Footnote 4 particularly for multi-centre trials that take place in more than one Member State. Among these measures is a new and streamlined process for assessing clinical trial applications, which will be the point of concern of this report. Specifically, the report outlines how the Regulation achieves a streamlining of the assessment process and how this affects two actors in their assessment competencies. The first actor is the so-called “Member State concerned” (MSC). This position is assumed by any EU Member State that hosts at least one of the trial sites in a multi-country trial. The second actor is the Ethics Committee (EC). ECs are constituted in accordance with the national law of each MSC, but their uniform role under the CTR is to conduct an ethical review of trial applications.

II. The ambition to streamline the assessment of trial applications

The European Commission explained why it sought to replace the CTD with a new Regulation in a 2012 memorandum. The Commission opined that the CTD “had many direct effects on the cost and feasibility of conducting clinical trials which, in turn, have led to a decline in clinical trial activity in the EU”.Footnote 5 Specifically, the Commission acknowledged that the implementation of the Directive had led to a rise in administrative costs for trial sponsors alongside significant delays for launching multi-country clinical trials. Further, the Commission stated that with the introduction of the new Regulation it aims to reverse this undesirable development, streamline the rules and thereby “ensure that the EU remains an attractive location for clinical research”.Footnote 6

III. Streamlining through legal form

One way in which the introduction of the CTR streamlines the regulatory framework for clinical trials is through the establishment of a uniform framework across EU Member States. Indeed, the Regulation’s Recital states that “the legal form of a Regulation would present advantages for sponsors and investigators, for example in the context of clinical trials taking place in more than one Member State, since they will be able to rely on its provisions directly”.Footnote 7 This stands in contrast to the CTD, which called for regulatory harmonization but left Member States with discretion in crafting provisions specific to their regulatory needs. Under the CTD, sponsors that applied to conduct multi-country trials could, for instance, encounter the need to make multiple country-specific protocol amendments during the application process in order to meet the different provisions made by the various national competent authorities.Footnote 8

Further, the CTD left in place a fragmented application system. Sponsors had to submit individual application dossiers for each Member State in which a trial was to take place. This process becomes streamlined and simplified under the Regulation with the requirement to submit only “one application dossier to all the Member States concerned through a single submission portal”Footnote 9 , centrally maintained by the European Medicines Agency.

IV. Streamlining of the trial application process through appointment of RMS

Trial sponsors will welcome the fact that the Regulation streamlines the actual process of assessing trial dossiers by making provisions for the appointment of a “Reporting Member State” (RMS), which is to take a lead role in the assessment. In order to explain what the RMS’s lead role consists of and how it may help to lower the administrative burden on sponsors, one first needs to draw attention to the fact that the Regulation divides the assessment of dossiers into two parts.

Part I of the assessment is detailed in Article 6 and covers aspects of “safety measures”, “the risk to subject health”, “the reliability and robustness of the data generated”, as well as the general “relevance of the clinical trial”. Part II of the assessment is detailed in Article 7 and focuses on the national aspects of a research protocol, i.e. the recruitment process, the information leaflet and consent form, financial compensation to subjects, personal data protection, as well as the quality and suitability of the local investigator(s) and trial site(s).

The Regulation stipulates a different assessment process for the two parts. For Part II, each MSC is to conduct its own individual assessment, while for Part I the assessment is led by the RMS. As an initial step, the RMS, through its health or pharmaceutical authority, must validate the application, which requires determining whether the proposed trial falls within the scope of the Regulation and ascertaining that the application dossier is complete. In terms of the actual Part I assessment of the dossier, the RMS is to, first, generate an initial draft assessment report; second, it is to disseminate this draft to the remaining MSCs for their feedback; and, third, the RMS is to issue a consolidated final report which must “take due account of the considerations of the other Member States concerned [...] and shall record how all such considerations have been dealt with.”Footnote 10 In the final report, the RMS shall provide its conclusion as to whether the conduct of the trial is acceptable, acceptable subject to certain conditions, or whether it is not acceptable. Crucially, while the final assessment report and its conclusion are issued by the RMS, they are to be considered valid for all MSCs.

The appointment of a single RMS for the Part I assessment contributes to streamlining in several ways. Primarily, it enables a sponsor to liaise with a single entity for all matters pertaining to Part I. Should, for instance, specific additional documentation be requested to proceed with an assessment of this part, sponsors would receive such a request only once.

The introduction of the role of RMS offers further potential for streamlining the assessment process because trial sponsors are to propose which Member State is to assume the role of RMS. Here, selective nomination might take place if sponsors propose only or primarily those Member States to become an RMS, which they expect to lead the assessment in manner that is efficient and consistent with the Regulation’s stipulated timelines. Conversely, trial sponsors might refrain from nominating Member States with supposedly less efficient assessment authorities.

In addition to efficiency, sponsors might also take into consideration the existing level of scientific expertise, when they nominate a Member State to act as, RMS. This is particularly relevant if a trial involves advanced therapy investigational medicinal products; medicinal products involving recombinant DNA technology; gene therapy; or hybridoma and monoclonal antibody methods.Footnote 11

V. Effect of streamlining on the assessment competence of MSCs

The Regulation provides that at the end of the assessment process each MSC “shall notify the sponsor through the EU portal as to whether the clinical trial is authorised, whether it is authorised subject to conditions, or whether authorisation is refused.”Footnote 12 Further, the Regulation stipulates the grounds on which an MSC may refuse to issue such authorization. One ground is that the assessment report for Part II is negative, i.e. if the MSC finds, on duly justified grounds, that certain country-specific elements of the dossier do not meet the provisions set out in the Regulation. Another ground for refusing to authorize a trial would be that the RMS’s assessment report for Part I is negative.

An interesting scenario occurs, however, if the MSC and the RMS disagree about the Part I assessment. Specifically, if an RMS’s report for the Part I assessment is positive but an MSC finds itself in disagreement with this conclusion, the Regulation appears to curtail the assessment competence of an MSC.

1. Restricted grounds on which MSC may disagree with RMS

While an MSC may, in principle, disagree with the RMS’s positive assessment of Part I and may issue its own negative decision, the MSC may base this disagreement only on three grounds, which are: that a trial would “lead to a subject receiving an inferior treatment than in normal clinical practice in the Member State concerned”; that a trial would lead to “infringement of [the MSC’s] national law”; and that the MSC has concerns about “considerations as regards subject safety and data reliability and robustness”.Footnote 13

On a strict reading, the listing of these three grounds suggests that other grounds may not be invoked by an MSC when it seeks to reject an RMS’s positive Part I assessment. In other words, while an MSC may, in principle, reject an RMS’s positive assessment, it is prevented from basing this rejection on factors concerning the “general relevance” of the trial or the trial’s “expected therapeutic and public health benefits”, even though both factors explicitly are to be considered under the Part I assessment.

Furthermore, the listing of some factors as acceptable grounds for disagreement and the omission of others fails to appreciate that they may be inexorably linked. To illustrate, in order for an MSC to adequately assess whether certain risks to trial participants’ safety are indeed acceptable, it might need to weigh these risks against the anticipated benefits of a trial. The link between risk and benefit assessment makes it difficult to see how the Regulation can uphold the provision that an MSC’s may appeal to concerns about subject safety in the trial, while it may not appeal to the related grounds that a trial offers insufficient expected (therapeutic or public health) benefits.

2. Positive MSC decision is not required

A second way in which the streamlined assessment process affects an MSC’s decision-making competence rests with the fact that the Regulation incorporates an automatic decision-making mechanism: should an MSC fail to notify the sponsor of its overall decision on the authorization of a clinical trial within a stipulated timeline, then the decision of the RMS’s Part I assessment automatically will be considered as the MSC’s decision on the application. Specifically, “[w]here the Member State concerned has not notified the sponsor of its decision within the relevant periods [...], the conclusion on Part I of the assessment report shall be deemed to be the decision of the Member State concerned on the application for authorisation of the clinical trial.” The default time period for completion of the Part II assessment is 45 days from the time of the initial validation of the application.

A potential benefit of this mechanism is that it provides an incentive for MSCs to communicate their decisions to sponsors within stipulated timelines. Further, the mechanism gives trial sponsors the assurance that a decision on their application will be issued within the timelines set by the Regulation – either because the MSC issues a decision on authorization or because the automatic decision-making mechanism is triggered.

However, there are various grounds for concern with the automatic decision-making mechanism. First, there is a danger that the mechanism threatens what might be regarded as a prerogative of any Member State: namely, that a clinical trial receives authorization to commence within its territory only after the competent national authority has reached and communicated its decision on the matter.

An additional concern is that the mechanism would affect resource-poor Member States disproportionately. It might be more difficult for resource-poor Member States to establish or sustain a health or pharmaceutical authority that consistently meets the Regulation’s ambitious timelines and, thus, they might be at an increased risk of failing to issue timely decisions on the authorization of clinical trials.

The most important concern, however, is that the automatic decision-making mechanism appears to compromise the protection of trial subjects’ rights, safety, dignity and well-being. This is the case because the automatic decision-making mechanism opens up the possibility that a trial may receive authorization to commence in an MSC even though there has been no proper Part II assessment. The automatic decision-making mechanism relies on the Part I assessment of the RMS only. Hence, the mechanism allows for the possibility that a sponsor receives a notification about authorization for the trial even though there has been no review of the documents covered in the Part II assessment, including the participant information sheet, the informed consent form, provisions for protection of personal data and the local investigator(s) and trial site(s).

The alternative to the automatic decision-making mechanism would have been for the Regulation to stipulate that an MSC’s positive assessment of Part II is required before the arm of a multi-country trial may commence in that MSC. It might be objected that such a requirement would run counter to the interest of sponsors work with stipulated fixed timelines. However, it should be stressed that the Regulation states in its Recital that “[t]he interests of the subjects should always take priority over all other interests.”Footnote 14 This stated priority cannot be overridden by appeal to the interests of sponsors to work with predictable timelines.

VI. Ethics committees

In addition to the two-part scientific assessment of the trial application, the Regulation requires that “[a] clinical trial shall be subject to [...] ethical review”Footnote 15 and it explicitly obligates a Member State to “refuse to authorise a clinical trial” in case of a negative EC opinion.Footnote 16

1. Provisions on composition and remit of EC

The Regulation holds that the ethical review is to be conducted by an EC “in accordance with the law of the Member State concerned”Footnote 17 and that ECs’ specific composition and their involvement “are a matter of internal organisation for each Member State.”Footnote 18 Further, the Regulation states in broad terms that when ECs are to give an opinion for the purpose of the Regulation, this should be done by “taking into account the views of laypersons, in particular patients or patients’ organisations.”Footnote 19

The embodiment of EC involvement in the Regulation is consistent with the EU’s governing principle of subsidiarity where the political decision is taken by the competent national authority instead by a central authority, ensuring that the political decision is made at a level closest to those affected by it, unless EU is able to act more effectively than its Member States.Footnote 20

In addition to the principle of subsidiarity, the broad provisions of the CTR might also be seen as affirming, on the level of EU law, the independence of ECs themselves. The provisions give ECs ample discretion to determine what substantive factors they deem relevant for an ethical review of trial dossiers. Indeed, the Regulation further affirms this independence when it explicitly states that “[t]he review by the ethics committee may encompass aspects addressed in Part I of the assessment report […] and in Part II of that assessment report.”Footnote 21

One concern is, however, whether the CTR makes room for ECs to appeal to considerations that fall neither under Part I nor under Part II assessment. To illustrate, an EC might want to object on general ethical grounds to a clinical trial that involve xenotransplantation of chimeric organs and these grounds would not fall under the Part I or Part II assessment.Footnote 22

2. EC review and timelines

The way the CTR conceptualizes the involvement of ECs suggests, again, that the streamlining of the application process and the desire to adhere to predictable timelines play a dominant role. The CTR explicitly instructs Member States to “ensure that the timelines and procedures for the review by the ethics committees are compatible with the timelines and procedures set out in this Regulation”Footnote 23 and “to organise the involvement of ethics committees within the timelines for the authorisation of that clinical trial as set out in this Regulation.”Footnote 24

Moreover, while the Regulation does not explicitly stipulate a time frame for the completion of ethics review, the relevant benchmark is set at 45 days, which is the default time frame given for the completion of the Part I and II assessment of the application dossier. This is notably shorter than the maximum of 60 days under the repealed CTD. Given the emphasis on the timeline, the Regulation can be seen as prioritizing the interests of sponsors (specifically the interest to receive a timely response) above patient safety.

It should also be noted that the Regulation makes no explicit provisions for ECs to extend the time frame for ethical review. In contrast, the Regulation permits extension for both Part I and Part II assessment: an RMS may extent the Part I assessment period by 31 days, if it needs to review additional document from the sponsor.Footnote 25 Likewise, a Member State may extend the period for its individual Part II assessment by 31 days.

The above inconsistency is problematic. The Recital of the Regulation emphasizes that “[i]n a clinical trial the rights, safety, dignity and well-being of subjects should be protected”,Footnote 26 where such consideration of patient safety is typically within the purview of ECs. Then as a procedural matter, since the ethical review is conducted in accordance with the law of the MSC, individual Member States should also enjoy discretion as to whether, and how, extensions of ethical review timeframes may be granted. Yet, the Regulation is currently silent on whether ECs enjoy such power of extending timeframes for review.

VII. Conclusion

There is reason to believe that the introduction of the CTR will reduce administrative burdens on trial sponsors because it establishes a uniform framework across EU Member States and, along with this, a streamlined process for assessing trial applications.

Concerns, however, remain about the way in which the Regulation appears to prioritize the establishment of short and predictable timelines. The desire to establish predictable timelines is particularly evident, it was argued, through the introduction of an automatic-decision making mechanism, which is triggered when an MSC fails to deliver its Part II assessment. Equally problematic is the fact that the Regulation does not make explicit provisions for ECs to extend review timelines, which, again, appears to keep timelines predictable at the expense of ensuring adequate ethical review of trial dossiers.

Footnotes

*

Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Corresponding author: medmkel@nus.edu.sg.

1 Council Regulation (EC) 536/2014 of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, OJ L158/1 (the “Clinical Trials Regulation” or the “Regulation”). It should be noted that the date of full implementation of the Regulation will depend on the operational readiness of the EU portal and database, maintained by the European Medicines Agency.

2 Council Directive 2001/20/EC of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use, OJ L121/34, as amended (the “Clinical Trials Directive” or the “Directive”).

3 Regulation, Art 2.2(1).

4 Commission, “Health Commissioner, Tonio Borg, welcomes agreement on the revision of EU rules on Clinical Trials” (Memo) (2013) MEMO/13/1190.

5 Commission, “Proposal for a Regulation of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC” COM (2012) 369 final, at p. 3. It should be pointed out that the development of the number of clinical trial applications was not uniformly negative across EU Member States. While there has been an overall decrease in both trial applications and conducted trials in the EU, some countries, notably Italy, have actually seen an increase in both numbers since the introduction of the Directive. See Markus Hartman, “Impact assessment of the European Clinical Trials Directive: a longitudinal, prospective, observational study analyzing patterns and trends in clinical drug trial applications submitted since 2001 to regulatory agencies in six EU countries” (2012) 13 Trials 53.

6 MEMO/13/1190, supra note 4.

7 Regulation, Recital 5 (emphasis added).

8 For illustration, see e.g. Eva van Doorn et. al., “National Differences in Requirements for Ethical and Competent Authority Approval for a Multinational Vaccine Trial under the EU Directive 2001/20/EC” (2015) 3(2) Vaccines 263.

9 Regulation, Recital 4 (emphasis added).

10 Regulation, Art. 6.5.

11 The Clinical Trials Regulation recognizes that the assessment of trials involving medicinal products from these categories may require additional expertise. To this effect, the Regulation provides for the RMS to extend the part I assessment process by an additional 50 days. See Regulation, Art. 6.7.

12 Regulation, Art. 5.1.

13 Regulation, Art. 8.2.

14 Regulation, Recital 1.

15 Regulation, Art. 4.

16 Regulation, Art. 8.4.

17 Regulation, Art. 4.

18 Regulation, Recital 18.

19 Regulation, Art. 2.2(11).

20 Consolidated version of the Treaty on the Functioning of the European Union [2008] OJ C115/01, Art. 5.

21 Regulation, Art. 4.

22 See David Shaw and David Townsend, “Division and Discord in the Clinical Trials Regulation” (2016) 42(11) Journal of Medical Ethics 729.

23 Regulation, Art. 4.

24 Regulation, Recital 18.

25 If a trial involves medicinal products from certain technical categories, the RMS may extend the Part I assessment period by an additional 50 days. See supra note 12.

26 Regulation, Recital 1.

* Centre for Biomedical Ethics, Yong Loo Lin School of Medicine, National University of Singapore, Singapore. Corresponding author: .