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A New Chapter

In 2013, the European Parliament will adopt a new legal framework for clinical trials. This reform is urgently needed to stop the decline of clinical trial activities and to create a common governance area for clinical research within Europe

On 17th July 2012, the European Commission adopted a proposal to revise the existing legal framework for clinical trials with medicines in the European Union (EU). The Commission’s proposal to replace the existing Clinical Trials Directive with a new Regulation aims to circumvent the problem of divergent interpretation and implementation at EU member state level. The proposal still requires review and adoption by the European Parliament and the European Council. The European Commission expects the new rules to fully come into effect in 2016 after a transitional period of two years.


The European Commission proposal was prompted by massive criticism over the existing Directive, expressed by multiple stakeholder groups, since it came into force in May 2004. The obvious pressure from commercial and academic trial sponsors, as well as from patient advocacy groups, led the Commission to concede that: “The Clinical Trials Directive is arguably the most heavily criticised piece of EU legislation in the area of pharmaceuticals.” Stakeholder criticism over the last few years was intense and comprised numerous position statements and memorandums, as well as detailed policy outcomes analyses, documenting a continuous decline of clinical trial activities in Europe, especially in terms of the number of trials initiated by the academic community. Patient organisations, especially those formed of patients affected by rare diseases, also expressed their concerns about the decreasing number of trials and treatment opportunities. Many parties hold the Directive responsible for causing a sharp increase in administrative burdens to trial sponsors and investigators, with costs exploding and the feasibility of conducting trials being dramatically reduced for many trial sponsors. National regulatory authorities also expressed their concerns, as staff and budget increase did not always keep pace with the highly increased authoritative and supervisory duties. However, criticism from ethics committees and the clinical research service provider sector was less pronounced, as the missed harmonisation of processes across Europe provided, in many cases, a right to exist as well as multi-faceted business opportunities.

Major Objectives

Recognising stakeholders’ votes and preferences, the European Commission outlined three major objectives which served as a leitmotiv for the legislative overhaul:

● creation of a modern regulatory framework for the submission, assessment and regulatory follow-up of applications for clinical trials, taking into account the multinational research environment
● adaption of regulatory requirements to practical considerations, constraints and needs, without compromising the safety, wellbeing and rights of participants in trials and without compromising data robustness

● consideration of today’s global dimension of clinical trials, putting additional weight on global acceptance of and compliance with good clinical practice (GCP)

Deduced from these overall principles are several operational objectives which guided the Commission in its revision process: reducing administrative burdens and operational costs; reducing delays for the launch of a clinical trial; revising the concept of obligatory insurance/indemnification; and ensuring compliance with GCP of trials conducted in non EU-countries but constituting pivotal trials for marketing authorisation procedures.

Proposed Recommendation

In practical terms, the planned new Regulation is intended to overcome most of the widely bemoaned shortcomings of the current EU Clinical Trials Directive. The 52 pages – comprising legislative text, flanked by five annexes – already provide a clear vision of what future clinical drug research in Europe may look like.

The conduct of trials should be faster, easier and cheaper through harmonised rules regarding the authorisation and conduct of trials. Therefore, a split of the authorisation dossier into two parts is envisaged. The first, the so-called ‘Part 1’ would be made up of all scientific, methodological and technical information required to allow one or several authorities from different member states to assess the application in parallel. In analogy to the marketing authorisation procedures in the EU, a ‘reporting member state’ will be chosen to coordinate the trial authorisation procedure. In ‘Part 2’ of the application, all information which addresses issues of preliminary national competence should be bundled together: issues related to informed consent; patient recruitment and subject/investigator compensation; data protection and the collection, storage and future use of biological samples of subjects; damage compensation; and suitability of sites and personnel involved in the given trial. Tight timelines for the review process and transparent opt-out rules in cases of divergent opinions between authorities of different member states should bolster Europe’s competitiveness in terms of short trial approval times.

Simplified Reporting and Labelling Rules
The facilitation of the conduct of trials also relates to new provisions to simplify the safety reporting in clinical trials and to reduce, at least in specific situations, the labelling requirements for investigational medicinal products. For trials with investigational medicinal products, as well as auxiliary medicinal products already authorised in the EU, the usual labelling of the commercially available product shall be sufficient, if no specific patient safety or data reliability issues are identified during the authorisation process. The perpetual concern of protocol amendments, causing so much red tape under the current legal framework, is handled in 10 comprehensive articles within the new proposal – aiming to set a concise set of rules for how substantial modifications of a clinical trial should be assessed under the auspices of the reporting member state.

Risk-Proportionate Trial Monitoring and Supervision Processes
Aspects of risk-proportionality have been taken carefully into account in the proposed Regulation, which introduces a differentiation of clinical trials, into three risk categories: low-intervention clinical trials, clinical trials, and trials with advanced therapy medicinal products. The proposed timelines for the review of authorisation dossiers are staggered accordingly. As a truly new legal species, low-intervention trials are clearly distinguished from non-interventional clinical studies that remain outside the scope of the Regulation. By using authorised interventional medicinal products in accordance with the terms of the marketing authorisation, low-intervention clinical trials should “not pose more than minimal additional risk or burden to the subjects compared to normal clinical practice.” Focusing on therapy-optimisation trials and trials that investigate the value of a (innovative) therapeutic intervention in closely related patient populations, this definition addresses the situation of trials typically run by academic sponsors. In conjunction with the proposed new definition, a number of practical alleviations for such low-risk trials is outlined too. The extent and nature of monitoring figures among these matters, but is not restricted to low-intervention clinical trials: the objectives and the methodology of a clinical trial and the degree of deviation of the observed intervention from normal clinical practice constitute further hazard variables which sponsors should appraise.

Single Regulatory Framework
The numerous proposed changes for the trial authorisation, conduct and supervision process all contribute to a single goal: the establishment of a truly harmonised framework for clinical drug trials in Europe. A portal for electronic submission of all applications, including those of purely national trials, the so-called ‘EU-portal’ will constitute a central element for any regulatory action in the future. Choosing the legal instrument of a Regulation, the Commission made clear that it will omit any situation in which member states set up differing requirements for a multitude of procedural and technical aspects. Future guidelines on such issues will therefore be worked out by the Commission itself, and should in the medium-term not only contribute to harmonised guidance, but also to the convergence of views and opinions among regulators. Apart from the aim to streamline the core trial authorisation and supervision process, the proposed measures also intend to foster the good manufacturing practice (GMP)-conforming manufacturing of investigational medicinal products and to singularise importation rules in the EU.

Liability and Research Ethics
However, two relevant issues remain outside the scope and competence of the Commission: civil liability and research ethics. Both fields fall outside the Lisbon Treaty and, in principle, are not subject to European law.

In terms of civil liability, the Commission has generated a remarkable idea. In its documents accompanying the proposed Regulation, the Commission acknowledges the harsh criticism from all trial sponsors about the dramatically augmented insurance costs for clinical trials. Arguing that trial insurance constitutes a very small and, from the competition perspective, problematic ‘market’, and agreeing that this situation today results in “aberrantly expensive insurance/indemnification coverage creating a disincentive to conduct trials in the European Union”, the Commission attempts to prevent insurance companies from drawing exaggerated profits from clinical trials in the future. Instead, it proposes national indemnification mechanisms provided by the member states. These mechanisms shall be run on a not-for-profit basis and be free of charge for clinical trials not intended to serve for marketing authorisations.

In terms of research ethics, the Commission has elaborated on another noticeable idea. By using the term ‘appropriate body’, the Commission avoids the distinction between ethics committees and regulators (for example, national competent authorities), who are both involved in the supervision of clinical research and the protection of participants. Leaving the responsibility “to determine the appropriate body or bodies to be involved in the assessment of clinical trials” with the member states, the Commission admits it lacks the competence to regulate national authorities and ethics committees, as well as how these bodies are organised and interact at member state level.

Changes on the Horizon

In several member states, such as Germany, the discussion on appropriate bodies heated up instantly after the publication of the proposal, with signs that the respective paragraphs were misinterpreted. However, the Commission’s intention was not to initiate a discussion about the necessity of ethics committees, but about the most appropriate concept of public supervision. Current models in most European member states comprise a dual supervision system, with defined but often overlapping roles for national competent authorities and ethics committees. On the other hand, a minority of member states, including the Netherlands, developed a onestop supervision system in which a professional, highly trained and quasi full-time ethics committee serves as central review instance. Here, the national authority serves either as appeal instance or as first review instance, when supposedly high-risk trials such as those with advanced therapy medicinal products are planned. It is therefore assumed that discussion on the most ‘appropriate’ system of public supervision – appropriate in terms of guaranteeing by an efficient use of review resources an adequate patient protection – will gather momentum and accompany the clinical trial community during the present decade.

Another important aspect of the legal proposal is the shift of emphasis from individual to public health benefits. The principle of GCP that “the rights, safety and wellbeing of the trial subjects are protected” is enshrined at the forefront of the proposal (see Recital 1 and Article 3). However, the other integral elements of the current ICH GCP principle, namely the notions that “the rights, safety and wellbeing of the trial subjects (…) should prevail over interests of science and society” and that “a trial should be initiated and continued only if the anticipated benefits justify the risks”, are accentuated less in the new framework (Article 28 and Annex 1 only). In contrast, the notion of ‘anticipated benefits’ has evolved to ‘anticipated therapeutic and public health benefits’, entitled as ‘relevance’ of a trial, which shall be weighted against “the risk and inconveniences for the subject”. The proposal contains numerous references to the term ‘public health’ and reflects the fact that today clinical trials are no longer regarded as isolated research endeavours, but as pieces of a continuing evidence-building process. The growing influence of health technology assessment and comparative effectiveness research is tangible: at the end of the process, trials shall whenever possible contribute to the risk-benefit assessment at community level.

In this context, a third change is noticeable. The EU legislator is highly interested in further diminishing trials of bad quality, such as those that lack scientific reliability, might not be completed due to insufficiently qualified personnel and inadequate staff and budget resources, or are conducted with disputable objectives that put the data integrity in peril. The credibility of data and its robustness will hence take an even more prominent role in the clinical research process. In conjunction with the emerging concept of risk-proportionality, this move towards the enforcement of data reliability as an objective equally ranking with patient safety will trigger momentum for improved trial conduct and supervision. It will further advance the use of quality risk management techniques in clinical research. The proposal might therefore serve as a first blueprint at legislative level to implement the quality-by-design philosophy from other industries like medical devices to pharma, and to embed clinical research in a process that is, through the ICH Q8 to ICH Q10 guidelines, already in place for control and manufacturing of medicines. Draft documents like EMA’s reflection paper on risk-based quality management in clinical trials or FDA’s draft guidance on a risk-based approach to monitoring, both posted in August 2011, underline the advent of this quality paradigm shift in clinical research.

Impact on the Pharma World

If the proposed Regulation is adopted in its present form, the implications for trial sponsors – whether big pharma, emerging enterprises, or non-commercial sponsors – will be meaningful. The maintenance of tight timelines for study approval and the promise of decreasing administrative burdens are good news for sponsors, who have to adhere to study designs of increasing complexity and – in many therapeutic indications – genotypebased patient stratification. In addition, the new framework should increase Europe’s competitiveness in clinical research, allowing sponsors to run trials with fewer resources and costs.

The warm and very positive reception of the proposal by major pharmaceutical trade associations and associations representing academic sponsors backs the assumption that the Commission has done a good job. For other stakeholders in the pharma world, decreasing regulatory complexity and an ongoing paradigm shift in compliance and quality management issues is not automatically good news. Many niche providers, as well as smaller clinical research organisations, will experience hard times once country specific exemptions regarding dossier requirements, reporting specificities or labelling particularities are really cut down. For large, globally acting clinical research organisations, the threat is less obvious and might result in a simple uptrend of European affairs. However, the only organisations which will gain strength from the situation are those which will anticipate and adapt their business models to the intended regulatory simplification. Recognising less red tape as an opportunity, transforming monitoring capabilities in clinical development knowledge, using modern telecommunication technologies for better data processing and quality: only those service providers that can streamline their services accordingly will remain successful.

If the Commission succeeds with the intended, true harmonisation of requirements and the set-up of a single EU-portal, sponsor country affiliates might also be affected through a shift of responsibilities towards regional or global development centres. Language competencies and direct lines with national regulators might be less relevant in a new world in which investigational medicinal product dossiers will be predominantly accepted in English. In its proposal, the Commission urges member states to accept “a commonly understood language in the medical field as the language for the documentation not destined to the subject”. And it is probably by reducing such language barriers that the planned Regulation might achieve its biggest benefit. Although the role of the EMA remains quite restricted in the new governance model – with its activities restricted to the safety reporting processes and to inspections – the proposal is indirectly triggering some centralisation in the overall process through decreased national barriers and a common lingua franca.

Current Discussion

For the moment, the time of public consultations is over; the politicians now have their say. The Irish Presidency of the Council of the EU, which started on 1st January 2013, made “progress on the proposal for a Regulation concerning clinical trials” the top line in its programme for pharmaceuticals and medical devices.

In the meantime, first reactions from member states have been reported. The UK’s House of Commons, where the proposal was discussed in September 2012, acknowledged that “there is a broad consensus on the need to change the existing regulatory framework for clinical trials”, but it expressed “reservations regarding the proposed introduction of a national indemnification scheme in each member state to cover claims for damages arising from participation in a clinical trial”, and questioned “whether there is a need, and an appropriate legal base, for the Commission to carry out inspections in member states in order to verify whether there are effective systems at national level to ensure compliance with the draft Regulation.” These two examples demonstrate that intensive discussions will take place regarding those aspects in the proposal in which a shift of sovereignty from member states to the supranational level is foreseen. Regarding the EU legislative process, on 12th December 2012 the European Economic and Social Committee issued a first opinion on the proposal. In its appraisal, the Committee backs the creation of a single EU governance area for clinical trials and the creation of a single EU portal; supports the proposed coordinated assessment procedure based on review resources in EU member states; and strongly supports the concept of low-intervention trials. However, it calls for “explicit inclusion in the Regulation of assessments by independent ethics committees”, which should be eased by a “network connecting ethics committees” that facilitates cooperation and exchange of scientific information. It should be clear to everyone that the European Parliament too will introduce several meaningful changes into the Commission’s current proposal.

The next relevant date in that process will be 24th April 2013, when the appointed rapporteur from the European Parliament, UK parliamentarian Glenis Willmott, will report to the Parliament’s influential Environment, Public Health and Food Safety Committee. A first Parliamentary reading is scheduled for 10th June 2013.


At a glance, the proposed changes to the Clinical Trials Directive are very promising. The Commission has understood the stakeholder messages fed back from two previous public consultations. A stronger notion of public health benefits, an increasing focus on data robustness, reliance on the best suitable trial design, and the advent of risk-based trial monitoring and supervision schemes may constitute the most relevant long-term outcomes from this legal revision.

In the short term, some more centralisation will be achieved through coordinated assessment procedures, similar to the mutual recognition process used since the 1970s for multinational drug approval across Europe. A decrease in language barriers and the acceptance of English as lingua franca in communications not only with the EMA, but also with national authorities, would further help to establish a European governance area for clinical research.

However, it is currently not yet possible to refer to concrete changes in the new framework, as many of the proposed procedural and technical aspects are still the subject of intense political discussions. The Commission showed its readiness to go quite far and to apply innovative concepts and ideas, but will the parliamentarians, member states and the concerned national medicines agencies follow?

An open attitude towards research and innovation, a relinquishment of national vanities and a pragmatic view on opportunities created by a common clinical research governance area should guide political decision-makers over the next few months.

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Markus Hartmann, Founder and Principal Consultant of European Consulting & Contracting in Oncology, has more than 15 years of experience in the medical and regulatory affairs business, with dedicated experience in clinical cancer research and multimodal therapeutic strategy trials. His specific focus lies in regulatory and legal questions surrounding clinical research on drugs, devices and diagnostics. Markus holds a PhD in Bioinorganic Chemistry from the University of Heidelberg and an MA in Drug Regulatory Affairs from the University of Bonn.
Markus Hartmann
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