Input analysis for two public consultations on the EU Clinical Trials Regulation

Revision of Directive 2001/20/EC

In April 2014, the European Parliament adopted a new legislative framework for the
conduct of clinical trials in the European Union (EU). The current Directive 2001/20/EC,
most often referred to as the Clinical Trials Directive (CTD), will be replaced by
Regulation EU No 536/201 from the end of May 2016 1], 2]. In effect since 2004, the CTD has had a deep impact on the planning and conduct
of trials in the EU and internationally, because of the EU’s prominent economic position
3], 4]. Currently, all clinical trials conducted in EU member states are regulated following
the provisions outlined in the CTD. Prior to the CTD, legislation mainly fell in the
ambit of the individual member states, creating an EU-wide patchwork of different
regulations. Though widely seen and accepted as an international standard in clinical
trials, the 1996 International Conference on Harmonisation of Technical Requirements
for Registration of Pharmaceuticals for Human Use guidelines on Good Clinical Practice
were not applied consistently throughout the EU. This created a situation where member
states differed in fundamental aspects of the application and approval procedures
for trials, including risk–benefit analysis, data protection issues, informed consent,
reporting of suspected adverse reactions, etc. In consequence, differences in the
level of patient protection occurred throughout the EU. Thus, in its aim to realize
a single market for medicinal products, the European Commission (EC) pursued a harmonized
legislative framework governing the conduct of clinical trials in all member states
5]. However, although the motivation for the CTD, as briefly outlined above, appeared
to be straightforward, its introduction and subsequent implementation was followed
by a huge wave of criticism 4], 6], 7]. This criticism was raised by a multitude of different stakeholders, and was often
more or less focused on specific parts or articles of the Directive. Some of the most
commonly raised issues in the context of the entry into force of the CTD concerned
an overall inconsistent implementation of the CTD in the different member states,
leading – among other things – to inconsistencies in the application and approval
procedures. This, in turn, resulted in an increase of costs, mainly due to an increased
need for human resources to handle the administrative workload 8].

Challenged by this critique, the EC recognized a need for action. Hence, an impact
assessment was initiated by the end of 2008 in order to assess the functioning of
the CTD and to bring forward proposals for further legislative improvements 9]. Impact assessments are an integral part of the EC’s efforts to continuously improve
the regulatory environment of the EU, and are highly formalized 10], 11]. The formal impact assessment of the clinical trials legislation was preceded by
a stakeholder conference in October 2007 12], and further accompanied by the ICREL study (Impact on Clinical Research of European
Legislation), which was conducted in the course of 2008 13]. In 2009 and 2011, the Directorate General for Health and Consumers (DG SANCO) called
stakeholders for public consultations (PCs). The PCs were each based on consultation
documents published by the EC 14], 15], which described the problems with the CTD as assessed by the EC and outlined possible
policy options to address them, thereby giving the PCs a clear structure. Furthermore,
stakeholders were asked for additional comments or suggestions. The impact assessment
finished in 2012 with an extensive two-part report 16], and was followed by a Commission proposal for revised legislation on clinical trials.
With this, the EC not only intended to fundamentally overhaul the CTD, but to replace
the whole EU Directive by an EU Regulation 17]. This proposal, however, was far from being a unanimously-accepted solution to the
regulatory problems faced by the various stakeholders. Strong criticisms were made
18]–20] and further elaboration of the Regulation was necessary before the Parliament finally
adopted the Clinical Trials Regulation (CTR) in April 2014 1]. A timeline listing the major steps in the revision of the CTD is presented in Fig. 1.

Fig. 1. Timeline impact assessment and Revision of Directive 2001/20/EC (see Additional file
Additional file 1)

Stakeholder involvement in the revision process

As mentioned above, the process of revision of the CTD, and especially the formal
impact assessment, was accompanied by extensive efforts at stakeholder involvement.
Obviously, the EC had a considerable interest in achieving input from all stakeholders
in the field of clinical research who were affected by the legislation. The two PCs
seemed to be of particular importance in the process of revision. The final impact
assessment report frequently refers to points raised by stakeholders during the PCs.
Among other data sources, the stakeholder input served as an empirical basis and a
further rationale for policy choices in the final regulation.

In this context, it is noteworthy that these deliberative efforts are in line with
the overall aim of what is called “Good Governance” as expressed by the EC in a White
Paper in 2001 21]. The White Paper marked a turning point in EU policymaking, as it acknowledged the
involvement of stakeholders in the policymaking process as fundamental to the EU’s
democratic legitimacy, and obliged EU institutions to continuously consult with stakeholders.
Therefore, the White Paper can be seen as a direct consequence of the postulated democratic
deficit 22]. With that said, it is entirely unsurprising that the EC consulted stakeholders in
the revision of the CTD. Moreover, at first glance, it seems that every endeavour
has been made to be most transparent. After completing the PCs, DG SANCO listed all
contributing stakeholders by name, and in most cases attached the individual contributions.
In addition, a summary report was compiled and published online for each PC 23], 24].

Nevertheless, the value and utility of these summary reports are questionable: the
EC states that a summary report “summarizes the responses to the PC document. In doing so, it not only reflects the
majority views, but aims to give a ‘snapshot’ of the range of responses” 23], 24]. While of course it may seem appropriate and necessary to offer an overview of the
issues addressed in the submissions, summarizing ipso facto runs the risk of losing
information. Since DG SANCO received more than 100 written submissions in each PC,
summarizing all of this input in a document of just over 20 pages seems rather unsatisfactory.
This raises concerns about the validity of the alleged “snapshot”. In addition, neither
the summary reports nor the impact assessment report describes the methodology used
to analyse the input. In an amendment to the abovementioned White Paper on Governance,
the EC in 2002 published ‘minimum standards’ for consultations 25], in which further guidance on stakeholder consultations is given. However, neither
said document, nor any other official EU document mention any methods.

Rationale and objectives

Given the reservations expressed above, instead of merely summarizing the responses,
a descriptive approach seems advisable, providing the reader with an overview of the
full spectrum of topics addressed by the various stakeholders. Thus, this study aims
to analyse the stakeholder submissions to the PCs and report on the findings.

To the best of our knowledge, this is the first study which specifically aims to qualitatively
analyse the stakeholder input expressed to an EC PC. Previous studies in this field
were limited to quantitative assessment of the number of responses per stakeholder
group, and focused instead on procedural aspects 26]–28]. Thus, this study also contributes to the general field of research on PCs, with
Regulation 536/2014 as a case study 26], 29], 30].