Briefing paper on the EU Clinical Trials Regulation

Briefing Paper on the EU Clinical Trials Regulation Key outcomes and impact on clinical research

Introduction Clinical trials are essential for the development of new and safe medicines and in improving medical treatments. Clinical trials are also important for patients enabling faster access to innovative medicines.

Following months of negotiation between the EU institutions, the adoption of the Clinical Trials Regulation by the European Parliament and the Council in April 2014 is a positive step towards enhancing Europe’s attractiveness as a location for clinical research and development.

According to Commissioner Borg, “the new measures should save research institutions and companies conducting clinical trials in the EU € 800 million per year in regulatory costs”, thus ensuring “a big boost for research & development in the EU. With over € 20 billion spent annually in the EU on pharmaceutical innovation and health-related research & development, it is vital for the EU economy that we remain major players in this booming sector”.1 With this briefing paper, EuropaBio wishes to clarify the requirements that will apply to all clinical trials conducted in Europe in the coming years. It is important that healthcare biotech companies, especially SMEs, fully understand the provisions of the new Regulation and its implications for clinical research, and prepare adequately.

EuropaBio remains committed to ensuring the best regulatory environment for its members to conduct clinical trials in Europe.

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Nathalie Moll

Christiane Abouzeid

Secretary General EuropaBio

Head of Regulatory Affairs UK BioIndustry Association Chair of EuropaBio’s Topic Group on Clinical Trials

Statement by Health Commissioner Tonio Borg following the vote in Parliament on the Clinical Trials Regulation, 2 April 2014

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1. Why does the Clinical Trials Regulation matter for the healthcare biotech industry?

The Clinical Trials Regulation2 comes at a critical time for clinical research and the development of innovative medicines in Europe.

While the Clinical Trials Directive3 (2001/20/EC) adopted in 2001 was intended to create a harmonised environment for clinical trials in Europe, the inconsistent implementation of the Directive in EU Member States has instead led to an increase in administrative costs and delays for starting a trial.

The patchwork of multiple and divergent requirements created unnecessary complexity and uncertainty for sponsors, particularly in managing multinational clinical trials in Europe. The number of clinical trials conducted in the EU fell by 25% between 2007 and 2011.

Following months of stakeholder consultation, the Commission published a legislative proposal for a Regulation on clinical trials in July 2012.

Two objectives for the Commission The objectives were to: • Improve Europe’s attractiveness as a location for clinical research and development of new and innovative treatments; • Ensure that the rules for submission, assessment and approval of clinical trials are identical throughout the EU, with greater cooperation between regulatory authorities in EU Member States.

The proposed Regulation is expected to restore Europe’s attractiveness for clinical trials and achieve greater harmonisation, efficiency and transparency in the approval and conduct of clinical trials, whilst maintaining high standards of patient safety and robustness of clinical data.

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2. What is in store for the healthcare biotech industry?

Building on the Clinical Trials Directive, the regulation provides for harmonised rules for the approval and conduct of Clinical Trials in Europe.

A new regulatory framework for clinical trials The new Clinical Trials Regulation will apply to all clinical trials.

A clinical trial is defined as a clinical study which fulfils any of the conditions outlined in Article 2(2).

Clinical trials are therefore covered by this Regulation, while noninterventional studies are exempted, falling outside of the scope of the Regulation.

A new category of low-intervention clinical trials has been introduced. These trials involve investigational medicinal products that are already authorised and pose only minimal risk to subject safety compared to normal clinical practice.

What are low-intervention clinical trials?

Low-intervention clinical trials relate to investigational medicinal products that are already authorised and pose only minimal risk to subject safety compared to normal clinical practice.

A streamlined application process for all clinical trials With the new Regulation, sponsors will only have to submit electronically one application dossier via a single entry point – the EU portal. This will replace the current situation of separate submissions to regulatory authorities and ethics committee(s) in each Member State.

A single authorisation procedure for all clinical trials Each application will go through a single assessment and decision on the conduct of a trial per Member State, thus replacing the current separate approvals by the regulatory authority and ethics committee(s) in each country.

Concerned Member States individually review the application with regard to national aspects (including informed consent). This includes a review from an independent ethics committee. Based on both parts of the assessment, concerned Member States will approve/refuse the clinical trial to take place in their country, without impacting the conduct of the clinical trial in other Member States.

In conjunction with other Member States where the trial is to take place (concerned Member State), the Reporting Member State (RMS) validates the application and then assesses the scientific, ethical and regulatory aspects of the application.

PART II MEMBER STATES’ INDIVIDUAL REVIEW

PART I REPORTING MEMBER STATE’S REVIEW

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The sponsor proposes one of the concerned Member States as RMS. However, Member States can agree to appoint another RMS. If this Member State refuses, the Member State initially proposed by the sponsor is appointed RMS. Importantly, the new Regulation retains the possibility for sponsors to add further Member States to an already authorised clinical trial. In this case, the application will only be reviewed by the new Member State(s).

Concept of tacit approval Tacit approval applies throughout the authorisation process, except for Part I of the assessment report prepared by the RMS. This means that approval is presumed where a RMS or concerned Member State does not notify the sponsor via the EU portal within the required timeline. Tacit approval will give sponsors and researchers.

Involvement of ethics committees – a national responsibility According to the new Regulation, individual Member States can appoint the relevant bodies including ethics committees to review the clinical trial application.

The ethics committees review processes are not harmonised at European level and therefore follow individual national laws of the concerned Member States. The review by ethics committees may encompass aspects related to Part I and Part II of the assessment as appropriate for each concerned Member State.

A stepwise timeframe for assessment A strict timeframe for the assessment of applications has been defined, thus providing sponsors with more certainty on the process:

60 • Assessment should normally take up to 60 days. This timeframe covers three phases (validation, days

assessment, decision) with defined timelines.

31 • However, this timeline may be extended by 31 days if one or more Member States require extra

days

information on the trial.

50 • For advanced therapies (ATMPs) and novel biotech products, an additional 50 days apply to allow days

Member States to consult appropriate experts on these technologies.

52 • The assessment for the subsequent addition of a Member State takes up to 52 days. days

The overall assessment timelines can be summarised as follows:

VALIDATION 10 days Reporting Member State’s review

ASSESSMENT 45 days • Reporting Member State prepares initial assessment (26 days) • Concerned Member States review the assessment (12 days) • Coordinated review (7 days) • Request for additional information 31 days • Expert consultation on ATMPs 50 days

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DECISION 5 days

Subsequent addition of a Member State 52 days

Towards more transparency for clinical trials data EU portal linked to EU database The European Medicines Agency (EMA) will set up and maintain a portal and a database at EU level in order to facilitate communication and exchange of information between the sponsor and Member States, and enable citizens to have access to information about clinical trials with medicinal products.

The database will contain data and information submitted through the EU portal. All trials should be registered in the database and receive a unique EU trial number.

The EMA, in collaboration with EU Member States and the European Commission, is drawing up the database’s functional specificities and timeframe for implementation.

What are the rules governing the disclosure of clinical trial data?

The following information should be publically available on the database:

Summary of results of the clinical trial to be submitted one year after the end of the trial.

Layperson summary to be submitted one year after the end of the trial.

Clinical study report to be submitted 30 days after the marketing authorisation is granted, the decisionmaking process is completed, or the application is withdrawn.

As stated in the recitals, the data included in clinical study reports should not be considered commercially confidential once a marketing authorisation has been granted, the decision-making process is completed, or the application is withdrawn.

Confidentiality may be respected on the following grounds:

Protecting personal data.

Protecting confidential communication between Member States.

Protecting commercially confidential information (CCI), taking account of the status of the marketing authorisation for the medicinal product (unless disclosure is in public interest).

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Ensuring effective supervision of the conduct of a clinical trial by Member States.

Enhanced protection of subjects and informed consent Overall provisions stipulate that participants in clinical trials (or their legal representative) must give their informed consent at all times, based on available information. Once the trial is over, participants must receive a summary of the results of the trial. These results should be understandable for a layperson (further details to be defined in a delegated act).

Informed consent not only applies to a particular trial but also to the use of the data outside of the trial “exclusively for scientific purposes”. This provision should be aligned with the Data Protection Directive4 (95/46/EC) currently under revision.

3 specific rules The regulation lays down specific rules in a number of cases: • For cluster and low-intervention trials taking place in only one MS, simplified informed consent can be considered.

• Similarly to the US Federal Drug Administration’s (FDA) recommendations, a subject may be included in a clinical trials without his consent in “emergency situations” if the trial is expected to have a “direct clinically relevant benefit” for the subject. Similar provisions apply for incapacitated subjects.

• A clinical trial involving pregnant and breast feeding women is only possible if the trial “has the potential to produce a direct benefit for the pregnant or breast-feeding woman concerned, or her embryo, foetus or child after birth, outweighing the risks and burdens involved”.

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3. What are the next steps?

The regulation will not enter into force earlier than 2 years after the publication of the Regulation.

The application of the Regulation is linked to the full functionality of the EU portal and the EU database (as verified by EMA Management Board) which are required for the authorisation procedure.

The Regulation will apply six months after the EU portal for the submission of clinical trial applications and the EU database have become fully functional.

The Regulation is therefore expected to enter into force mid 2016 at the earliest. Until then, all clinical trials should comply with the Clinical Trials Directive (2001/20/EC). It is worth noting that the new Regulation foresees transitional provisions allowing the submission of clinical trial applications under the current Directive until 2019.

The Clinical Trial Regulation, including its effect on Europe’s competitiveness of clinical research, will be reviewed every five years.

In the meantime, a number of aspects will be developed in the coming years:

IT infrastructure: Development

Implementation at national level: As a number

of EMA clinical trials portal and EU database, including rules of procedures for the database and guidance on access to data to ensure consistency.

of aspects of the Clinical Trials Regulation are left at the discretion of the Member States, national legislation will be required concerning: • Ethics committees; • Standards for informed consent; • Enforcement (penalties for infringement of the Regulation);

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• Fees related to clinical trial assessment; • Damage compensation; • Appeal procedure for a decision refusing to approve a clinical trial.

Development of secondary EU legislation on Member States cooperation in assessing safety data, GMP principles and modalities for inspection. Guidelines are also expected (GMP, sharing data on a voluntary basis).

2015-2016 Update to Annexes by delegated acts to adapt them to technical progress and improve protection of subjects, taking account of international regulatory developments.

From 2016

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This briefing paper has been developed by EuropaBio’s Topic Group on Clinical Trials.

We wish to acknowledge the assistance provided by the BioIndustry Association (BIA), and in particular Christiane Abouzeid, Head of Regulatory Affairs at BIA, for the constant support and expertise provided during the legislative process and the drafting of this paper.

About EuropaBio EuropaBio is the European Association of BioIndustries. Our members are involved in research, development, testing, manufacturing and commercialisation of biotech products and processes in human and animal healthcare, diagnostics, bioinformatics, chemicals, crop protection, agriculture, food and environmental products and services. EuropaBio also counts a number of National Biotech Associations in its membership who in turn represent more than 1800 biotech SMEs.

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April 2014 Printed on recycled paper.

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