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International Clinical Trials

New EU Clinical Trials Regulation

When the European Clinical Trials Regulation (No. 536/2014) was approved on 2 April 2014 by the European Parliament and published in the Official Journal of the EU (1), the Health Commissioner Tonio Borg said: “I am convinced that the new rules will ensure a big boost for R&D in the EU for the benefit of patients, and contribute to the Europe 2020 objectives of smart, sustainable growth” (2).

The aim of the new regulation is to streamline clinical trial authorisation and harmonise requirements for trials in Europe. It will replace the existing EU Clinical Trials Directive (2001/20/EC) (3), which has often been criticised as having excessive bureaucracy (4). The earliest the new regulation is planned to come into force is May 2016, six months after the full functionality is in place of a new EU Database infrastructure and single online EU Portal created under the new legislation.

A transition period of one year will apply, during which trials can be authorised according to the current directive or the new regulation. Also, trials already authorised under the existing system will be able to continue to follow the directive until three years after the new regulation is implemented.

This article explains the scope and major requirements of the regulation, focusing in particular on clinical trial authorisation, and also provides a concise overview of other key requirements to help understand these important and complex changes.

Simplified and Streamlined

The scope of the regulation is extensive and covers the following areas in the main text and a number of appendices:
  • Authorisation of the clinical trial
  • Substantial modification
  • Protection of subjects and informed consent
  • Start, end, temporary halt, early termination
  • Safety reporting
  • Conduct of clinical trials
  • Investigational medicinal product (IMP), auxiliary medicinal product, labelling and import
When it comes to clinical trial authorisation, the regulation will provide a simplifed and streamlined regulatory and ethical authorisation process. There will be a harmonised trial application dossier that covers regulatory and EC approval, and therefore a single national decision on a clinical trial. This will replace the current separate approvals given by regulatory agencies and ethics committees in each EU member state.

Applicants will submit a single electronic application for a clinical trial via the EU Portal to all the concerned member states (cMS). The EU Portal and Database will help facilitate the application for trial authorisation to the sponsor. The application dossier will be in two parts. Part 1 will contain “scientific” study specific documents, Part 2 will feature country and site “national” specific documents.

The sponsor will propose one of the cMS to be the reporting member state (rMS) to coordinate the validation and evaluation of the dossier application. The rMS will then be selected within six days of the start of the validation part of the process. Part 2 “national” assessment – including ethical committee review – will be made by each cMS individually for its own country, according to national laws, with one contact point.

Applications Process

Generally, it is anticipated that Part 1 and Part 2 will be submitted together; however, the sponsor can decide if both parts are reviewed in parallel or whether Part 1 can be reviewed first, followed by Part 2. In practice, Part 2 can take place up to two years after Part 1 has been completed: the sponsor will have to certify that there is no new scientific information that could change the validity of Part 1 information and assessment, and that there is no disagreement in terms of safety, data reliability and robustness.

Sponsors may withdraw the application, but it has to be withdrawn from all countries. A re-submission will be considered for a new application, in which case a new clinical trial number and new protocol number will be needed for the trial.

The authorisation will consist of validation, assessment (Part 1 and Part 2) and a decision:
  • Validation of the submission to check the dossier is complete will take 10 days, although this can be extended to 25 days to resolve any issues
  • The Part 1 assessment will take 45 days (26 days for the initial assessment, 12 days coordinated review by the rMS and cMS, followed by 7 days for the rMS to consolidate the views and finalise the assessment report as to whether the trial can go ahead, or is subject to conditions or is not authorised). The assessment period can be extended by 31 days if there are questions for the sponsor. This could result in 76 days for the assessment part of the process. The same timelines apply to the Part 2 assessment phase
  • Each cMS should notify its decision to the sponsor within five days of the Part 1 assessment report being finalised, or the final date of the Part 2 assessment, if not done in parallel through the EU Portal
Review timelines have been established as a minimum of 60 days (10 days validation, 45 days assessment and 5 days decision to the sponsor), with a total maximum time of 106 days allowed for the initial submission. However, advanced therapy trials or products derived from rDNA technology can take another 50 days – bringing the total to 156 days.

The new regime will also provide greater efficiency in extending the clinical trial to another EU country. When a sponsor submits an application for authorisation of a clinical trial to the additional EU country, this country will assess only Part 2 of the assessment report. The original Part 1 will remain valid unless the additional EU country disagrees on the basis of one of the specific circumstances permitted by the regulation. The rMS remains the same, and the cMS should notify its decision to the sponsor within 52 days, or 83 days if additional information is asked for.

Other Requirements

The new regulation also brings other major requirements for clinical trials in the EU, with the following points highlighting the main issues:

The regulation introduces the concept of co-sponsorship for clinical trials. This practice is widely used in England by the National Health Service, where clinical trials are often carried out in partnership with universities. Each co-sponsor will assume full regulatory responsibility for the entire trial, unless they all agree otherwise.

Legal Representative for a Non-EU Sponsor
This is not specified; national rules will decide whether a legal representative is required, but an EU contact person will be needed.

Substantial Modifications
A 'substantial modification' in the regulation replaces the term 'substantial amendment', described in the existing Clinical Trials Directive. Substantial modification is defined “as any change to any aspect of the clinical trial which is made after notification of a decision and which is likely to have a substantial impact on the safety or rights of the subjects or on the reliability and robustness of the data generated in the clinical trial” (1). The procedure for this is similar to the Part 1 assessment: there will be 38 days for assessment after validation, and an additional 31 days for an extension if there are questions. A decision will be given within 5 days of the assessment report. For substantial amendments to Part 2 – for instance, additional investigators or study sites – a similar 38-day timeframe, including an extension for questions, is permitted.

Increased Transparency
All clinical trials in the EU will need to be registered. Summaries of the results of authorised studies – including a summary drafted by the sponsor in plain language – must be submitted within one year of the termination of the trial. Final clinical study reports that were submitted to support a marketing authorisation should be uploaded onto the EU Database within 30 days of the authorisation, rejection, or withdrawal of the marketing authorisation of the medicinal product. Sponsors may be subject to penalties if they fail to adhere to these transparency obligations.

Notifications of Trial-Specific Events via the Portal
The sponsor/applicant is required to notify each country through the EU Portal within 15 days, with the following important information for a trial needed to increase transparency:
  • Start of recruiting
  • First patient, first visit
  • End of recruiting
  • Last patient, last visit
  • Final end of trial (last country, including if the country is outside the EU)
  • Suspension
  • Temporary halt
  • Early termination
Low-Intervention Trials
The regulation introduces a risk-based approach – a category of “low-intervention trials” in which:
  • The investigational product is already authorised, and its use in the trial is in accordance with the terms of the marketing authorisation or based on published scientific evidence of safety and efficacy
  • Additional diagnostic or monitoring procedures do not pose more than minimal additional risk or burden, compared to normal clinical practice in a member state
Low-interventional trials are subject to less stringent requirements for monitoring and documentation.

Indemnity and insurance for low-interventional studies will be covered by insurance covering the investigator, the institution or product liability insurance, rather than being required to provide a specific insurance or indemnity for a trial.

Risk-Based Monitoring
The sponsor will determine the extent and nature of risk-based monitoring, depending on the type of clinical trial, such as its objectives and methodology, and the degree of deviation of intervention from normal clinical practice.

Protection of Subjects and Informed Consent
Changes to protection of subjects in trials are intended to harmonise requirements and also allow for national rules in some aspects – for example, who may act as a legal representative of a subject, or the legal age of consent. Furthermore, provisions have been added relating to clinical research for emergency situations, pregnant and breastfeeding women, and where clusters of subjects enter a trial.

Data Privacy
Sponsors will be permitted to seek the consent of the trial subject to use his or her data for purposes which are outside the scope of the trial protocol, for scientific reasons. Consent for use of personal data for these purposes may be sought at the same time as consent for participation in the trial. This consent may, however, be withdrawn by the trial subject at any time.

Safety Reporting Requirements
The regulation removes duplications by introducing streamlined reporting procedures based on the centralised EU Database for safety reporting. Suspected unexpected serious adverse reactions (SUSARs) can be reported by the sponsor directly to the online EU pharmacovigilance database, EudraVigilance, instead of being submitted to each EU country as well.

Serious Breaches
In the event of a serious breach of the regulation or the protocol – for instance, one likely to affect to a significant degree the safety and rights of the subjects or the reliability and robustness of the data generated – this must be reported by the sponsor to the member states concerned through the EU Portal within 7 days.

Good Manufacturing Practice
The term 'auxiliary medicinal products' replaces 'non-investigational medicinal product', referred to under the existing directive, but does not include concomitant medication. The regulation requires the updating of the “expiry date” (the period of use/retest date should be included on the immediate packaging, in addition to the outer packaging). This additional requirement will be a significant increase in work for sponsors, and brings some increased risks and costs. Increased wastage is likely because relabelling may not be possible – for example, when using small containers such as with blister packs.

Archiving Trial Master Files
There is a clearer duration for archiving these files. Clinical trial documentation is to be archived for 25 years, which is a more specific time period than the internationally accepted ICH Good Clinical Practice.

The new Clinical Trials Regulation is a signifi cant step towards harmonisation for carrying out trials in the EU. The key potential benefits are a more streamlined approval process undertaken in multiple EU countries, a single application for studies in several countries, and simplified safety reporting procedures. In order to ensure a smooth transition to the new regulatory framework – and make the most of the improvements that the legislation prompts – organisations should have a strategy to implement the changes to company processes and ensure staff are fully trained on the requirements.

1. EU Regulation No. 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC, Official Journal of the European Union, L158, Vol. 57: pp1-76, 27 May 2014
2. Statement by Health Commissioner Tonio Borg following the European Parliament vote on the Clinical Trials Regulation, 2 April 2014. Visit: STATEMENT-14-98_en.htm
3. EU Directive 2001/20/EC of the European Parliament and of the Council of 4 April 2001 on the approximation of the laws, regulations and administrative provisions of the Member States relating to the implementation of good clinical practice in the conduct of clinical trials on medicinal products for human use
4. Proposal for a Regulation of the European Parliament and of the Council, Version 17, July 2012. Visit: en_GB/document_library/Other/2014/12/WC500179339.pdf
5. Functional specifications for the EU Portal and EU Database to be audited, EMA/42176/2014, Rev 1: Compliance and Inspections, 25 March 2015. Visit: library/Other/2014/12/WC500179339.pdf

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Dr Laura Brown is Managing Director of LB Training and Development Ltd, an international quality assurance and training consultancy. She oversees and delivers a broad range of technical, management and soft skills courses and consultancy for the pharmaceutical industry, covering project management, regulation and guidelines, Good Clinical Practice, and standard operating procedures. She is also Course Director, MSc Clinical Research, at Cardiff University's School of Pharmacy.
Dr Laura Brown
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