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European Pharmaceutical Contractor

All Change

The EU pharmaceutical regulatory environment is undergoing a period of significant change, primarily driven by evolving legislation. Much of this – particularly pertaining to clinical trials and medical devices – has been accelerated by attempts to obtain full agreement of all member states before the end of the European Parliamentary term in April 2014. Additionally, progressive licensing schemes enabling earlier access to medicines, and efficiency efforts by the EMA – such as long-term restructuring – have resulted in a changing regulatory landscape.

This article focuses primarily on recent EU legislative updates, with particular emphasis on the new EU Clinical Trial Regulation.

Streamlining Trials

Clinical trials are an indispensable part of clinical research, facilitating patient access to innovative and effective treatments under stringent safety and ethical standards. In the EU, approximately 4,400 clinical trials are applied for each year (1).

A regulation that will streamline the rules governing clinical trials across Europe has moved closer to becoming effective, following its approval by the European Parliament on 2 April 2014.

The Regulation was approved in essentially the same form as the proposed draft Regulation endorsed by the Committee of Permanent Representatives of the European Union on 20 December 2013, and was formally adopted by the EU Council on 14 April 2014. At the time of writing, it was expected to be published in the Official Journal in May 2014. This Regulation will enter into force 20 days following its publication in the Official Journal, and apply six months after an EU portal and EU database (currently being developed by the EMA) have become effective (but not earlier than two years after the regulation’s publication). It is therefore expected to come into effect mid-2016.

The Regulation will replace the current Clinical Trials Directive, and will be binding in its entirety and directly applicable in all member states.

Old versus New

The existing Clinical Trials Directive (2001/20/EC) improved the conduct of trials in the EU, particularly in relation to safety, ethical conduct and reliability of data. However, this Directive has come under heavy criticism by patients, industry and academia for its lack of harmonisation of procedures across the EU (for multinational trials) and inconsistent requirements determined at individual country level. Furthermore, its direct effects on the cost and feasibility of conducting clinical trials reportedly led to a decline in activity in the EU (1). Between 2007 and 2011, the number of applications for trials in the EU decreased by 25% (2). The 2001 Directive will be repealed from the date of application of the new Regulation – however, a three-year transition period will allow the existing Directive to govern clinical trial applications, including amendments, submitted prior to the date of application of the new Regulation.

The Regulation aims to remedy the shortcomings of the 2001 Directive by, among other things, establishing a uniform framework for the authorisation of clinical trials by all the member states concerned with a single assessment outcome. Recognising that future clinical trials will target more specific patient populations – such as subgroups identified through genomic information, requiring involvement of multiple member states – the new Regulation aims to simplify and harmonise administrative provisions by establishing procedures that stimulate the inclusion of as many member states as possible. In addition, less red tape, simplified reporting procedures, European Commission controls, standardised authorisation timelines, tacit approval, strengthened rules governing the protection of patients and increased transparency are among the Regulation’s key innovations.

Sponsors of clinical trials in the EU will need to ensure awareness of the new process and their new responsibilities, in particular regarding the EMA portal and EU database. Registration via the portal will be a prerequisite for the assessment of a clinical trial application in any country in the EU; communication regarding the trial will be via the portal; and the sponsor will be notified by the reporting member state whether the trial is authorised, subject to conditions or refused. Data and information submitted through the EU portal, including full clinical study reports, will be stored in the database, controlled by the EMA and kept distinct from the current EudraCT and Eudravigilance databases. Information contained in the database, with the exception of proprietary confidential data, will be free, publicly accessible and easily searchable.

In short, the new Regulation is good news for sponsors as it will allow for a harmonised evaluation procedure across the EU. It is also beneficial to patients, as it will enable direct access to information and clinical trial data, as well as potentially being a major boost to Europe’s competitiveness, positing the EU as an attractive location for clinical trials.

New EMA Structure

Following the EMA’s organisational changes of September 2013, its has now expanded to operating processes in its efforts to implement more efficient and consistent scientific assessment procedures.

The agency recently announced plans to introduce a new operating model for managing medicines through their entire lifecycle, focusing on scientific and procedure management. This model aims to strengthen the support provided by EMA staff – in terms of regulatory science and overall procedural management – to its scientific committees, thus enabling these committees to focus on their core expertise while ensuring consistency and streamlining of applications.

There will be four new divisions: Human Medicines Research and Development Support; Medicines Evaluations; Procedure Management and Business Support; and Inspections and Human Medicines Pharmacovigilance. There will also be a new division for stakeholders and communication, intended to provide support to pharma companies during the R&D of new medicines. The current entities responsible for veterinary medicines, IT and administration will remain unchanged.

The EMA has advised role changes will involve replacing the existing Product Team Lead with two new roles: a Procedure Manager who will have responsibility for overseeing all aspects of management of specific procedures; and an EMA Product Lead, responsible for maintaining oversight of a medicine as it moves through its lifecycle.

Applications and Procedures

Effective from 1 April 2014, the EMA has implemented changes to how it handles the submission and approval of changes (variations) to approved products (Type 1A, 1B and 2 variations), periodic safety update reports, and certain administrative procedures such as transfers, Article 61(3) notifications and corrigenda.

Product licence holders should note the main change involves the EMA’s contact persons. The agency has confirmed all applicants will be notified of variations directly by product and procedure if and when their contact person changes, and none will occur prior to this notification. The EMA has established a dedicated service in which applicants can contact them by email for all pre-submission queries related to the post-authorisation measures listed above. A transition plan has been established for ongoing procedures, and further changes to other post-approval evaluation procedures are planned for later in the year.

Final Steps

The EMA launched a final round of targeted consultations with key stakeholders on its draft policy on proactive publication of, and access to, clinical trial data at the beginning of May 2014. This should give key stakeholders and the EMA the opportunity to address any outstanding issues before the final policy is presented to its management board for endorsement in June 2014.

The consultation is designed to clarify and fine-tune specific aspects, and achieve the broadest possible consensus and understanding of the policy. The targeted discussions should focus on the presentation by the EMA of the principles set for the possible redaction of the clinical study reports to be published.

Adaptive Licensing

In recent years, numerous proposals for adaptive approaches to get a drug to market have been in discussion, such as staggered or adaptive approval, managed entry and progressive authorisation.

The EMA is currently inviting companies to participate in its adaptive licensing (AL) pilot project, launched in March 2014. This pilot aims to provide a framework for informal interactions to understand how future AL pathways might be designed and identify potential hurdles. The EMA intends to include as many programmes as necessary in this pilot phase in order to gather sufficient knowledge and experience, address a range of technical and scientific questions, and further refine how the AL pathway should be designed for different types of products and indications. Ongoing development programmes submitted to the pilot project should be in the early stages of clinical development, prior to the initiation of confirmatory studies.

Building upon existing regulatory processes within the EU legal framework, AL is intended to enable reductions in drug development timelines, as well as earlier patient access to treatments that show promise in treating serious conditions for which there is no current therapeutic option available. This proposed licensing approach would involve a step-wise authorisation process, whereby an initial authorisation of a medicine would be granted based on studies conducted in a restricted patient population; then, in collaboration with the EMA, a series of further investigations into the safety and efficacy of the drug would be conducted; and a subsequent regulatory evaluation would result in adaptations to the marketing authorisation to expand access to broader patient populations.

In comparison to current procedures, the aims of AL are to improve the quality of knowledge and timelines of knowledge generation – especially during early stages of drug development – while still maintaining regulatory oversight, scientific rigour and commitment to patient safety.


The limitations of the current pathway to take a product to market are generally acknowledged; it is hoped that, in time, and based on collaborative pilot projects such as this, the progressive step-wise route to market involving a sequence of regulatory steps and concurrent buy-in by regulators, industry and other key stakeholders may become routine practice.


1. 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, 2012
2. The Council of the European Union, press release, 14 April 2014

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Daphne Smyth leads the Global Regulatory Affairs function at ICON and has over 25 years’ experience in regulatory affairs, pharma and contract research organisations, leading global teams and projects across many therapeutic areas, stages of development and regions. Prior to joining ICON, she worked for three years as an Independent Regulatory Affairs Consultant, before spending five years leading the start-up of a European office for a small Canadian pharma company in a senior management position. Daphne has been employed in various regulatory positions with both global and European responsibility for major products within Bayer AG. She holds a BSc from University College Dublin, Ireland.
Daphne Smyth
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