On May 28, 2016, the new EU Clinical Trials Regulation will start to replace the 2001 Clinical Trials Directive. EU regulators as well as industry specialists have high hopes for this change. The Regulation’s streamlined application process promises faster review timelines and is expected to ease administrative burdens. In this blogpost, I provide a critical overview of the structure of the review process under the new Regulation and say a few words about the role that Ethics Committees will play. (Note: In a future post, I will draw some comparisons between the EU Regulations and Singapore’s anticipated revised Clinical Trials Regulations.)
Regulation vs. Directive – what’s the difference?
Let me start by saying something about the general difference between a ‘Directive’ and a ‘Regulation’ under EU Treaties. A Directive lays out domain-specific goals for EU member states to adopt but each affected Member State has the discretion as to how to pursue these (i.e. what laws the State wants to enact or what administrative provisions to make). In comparison, a Regulation is directly applicable in all EU Member States without the need for national legislation. To put it in legal terms: a Regulation does not require ‘transposition’, but is directly applicable to all Member States. As such, it is not unreasonable to think that sponsors of multi-center trials across EU Member States would prefer having a Regulation rather than a Directive in place since this means they longer have to deal with the variety of national laws that resulted from implementing the 2001 Directive.
Let us now get to the review process for the authorization of clinical trials. The Regulation requires the sponsor of a trial to submit an application dossier through a new EU portal, operated by the European Medicines Agency. In the application, the sponsor must list the ‘Member States concerned’, i.e. all EU countries in which the trial is to take place; and the sponsor must nominate a ‘Reporting Member State’, i.e. the one state that is to take the lead role in assessing the application. (Should the trial take place in one Member State only, that state is, by default, the Reporting Member State.) The assessment of the application then splits into two parts. The Reporting Member State, through its respective health or pharmaceutical authority, conducts – what the Regulation calls – a ‘Part I’ review, which, among other things, includes a risk-benefit evaluation taking into account the “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”. In addition, each Member State concerned must conduct a ‘Part II’ review, which looks primarily at local aspects of the research protocol, e.g. the recruitment process and the (language of the) consent form, as well as the quality and suitability of the research site. This Part II review is, again, to be conducted by the respective health or pharmaceutical authorities. The two parts of the review process run concurrently and are to be concluded within 45 days after submission of the application.
Decision on application
If the Reporting Member State decides that the clinical trial is not acceptable at the Part I stage of the assessment, this decision is binding on all Member States concerned. This shows the importance of the Reporting Member State’s lead role at this stage of the review process. If, on the other hand, a Member State concerned rejects the application to conduct a trial at the Part II stage of the assessment, this rejection is valid for that Member State only. The grounds on which a Member State concerned may reject an application at the Part II stage are as follows: generally, it may issue a negative decision only “if it finds, on duly justified grounds, that the aspects addressed in this part of the assessment report are not complied with” or if the Member State’s ethics committee issues a negative opinion (more on this in a moment). Notably, even though a Member State concerned does not conduct a Part I assessment, it may also reject an application if it judges that select aspects of Part I are not complied with, specifically “when it considers that participation in the clinical trial would lead to a subject receiving an inferior treatment in normal clinical practice” or when it has concerns about “subject safety and data reliability and robustness.”
This is interesting for four reasons:
- First, it seems that, while a Member State concerned is not required to assess Part I, the Regulation recognizes a Member State’s option of doing so.
- Second, if a Member State concerned may reject a trial application on the grounds that the trial would lead to a research participant receiving inferior treatment vis-à-vis clinical practice, then the Member State may effectively reject many placebo-controlled trials. This is so if and when receiving the placebo constitutes inferior treatment over what is considered standard of care in that Member State.
- Third, a Member State may reject an application if it has concerns about subject safety and data reliability under Part I. Yet, it is curious that other aspects covered by the Part I assessment (especially the “general relevance” of the trial, or the “expected therapeutic and public health benefits”) are not mentioned as grounds that a Member State concerned may cite in its decision to reject an application.
- Fourth, if a Member State concerned rejects the application to conduct a trial on the basis of these factors (i.e. concerns about patient safety or data reliability), “it shall communicate its disagreement, together with a detailed justification, through the EU portal, to the Commission, to all Member States, and to the sponsor.” The requirement to communicate the disagreement along with the justification directly to the other Member States should be a welcome one. It may alert the other Member States to certain factors that require additional scrutiny.
The Role of Ethics Committees
Apart from the health and pharmaceutical authorities of each Member State concerned, ethics committees are also involved in the review process for trial applications. Indeed, the Regulation specifically requires Member States to set up ethics committees as independent bodies that should be “empowered to give opinion for the purposes of [the] Regulation, taking into account the views of laypersons, in particular patients or patients’ organizations.” However, the Regulation does not spell out in any further detail how ethics committees are to be set up. Instead, it merely states that they are to be established “in accordance with the law of [each] Member State.” The Regulation also does not spell out what factors ethics committees are supposed to evaluate, apart from the very broad provision that “[t]he review by the ethics committee may encompass aspects addressed in Part of the assessment report […] and in Part II of that assessment report”. On the one hand, this might be seen as affirming the independence of ethics committees and the way they structure their review process. On the other hand, an objection may be made that the Regulation, as a document directly applicable to all EU Member States, should mandate specific and uniform minimum standards for ethics review. This would have given legislative effect towards ensuring that individuals in all EU Member States receive the same minimum level of protection afforded by an ethics committee review.
In summary, the Regulation holds the promise of successfully streamlining the application process for clinical trials. However, for those who hoped that the Regulation would establish a uniform baseline level of ethical review across the EU, that is not the case. Of course, it remains to be seen whether EU Member States (and their respective ethics committees) take action on this point and agree on common standards and guidelines to supplement the EU’s formal regulations.