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Posted 24 April 2017 | By Siegfried Schmitt, PhD, Federico Bonacci, MD, Daniela Lisini, PhD, Viviana Mascilongo, PhD
Clinical Trial Regulation EU No 536/2014 will come into effect in 2018. This article reports on aspects of the revised regulation and evaluates its potential impact on clinical trials conducted to assess medicinal products for human use. It discusses changes impacting the critical role of the Ethics Committees in the approval process for clinical trials as well as the planned, centralized data reporting channel, referred to as "the portal." While revisions to the regulation are still underway, readers will benefit from the assessment of its current status and anticipated developments.
Clinical Trial Regulation EU No 536/20141 of the European Parliament and of the Council of 16 April 2014 pertaining to clinical trials on medicinal products for human use is a revision of the original Good Clinical Practice (GCP) Directive 2001/20/EC.2 This revision impacts clinical trials in the EU and various stakeholders who have responsibilities for clinical trials oversight.
The International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) brings together both regulatory authorities and members of the pharmaceutical industry to discuss scientific and technical aspects of drug registration.3 Since its inception in 1990, the ICH mission has been to achieve greater regulatory harmonization worldwide to ensure that safe, effective and high quality medicines are both developed and registered in the most resource-efficient manner. While clinical trials regulations have been harmonized internationally since 1996 based on the ICH harmonization and the European Union (EU) has developed a Good Clinical Practice (GCP) regulatory framework, it is the responsibility of the European Commission (EC) to issue regulations and directives. Because GCP regulations change and evolve they require updates or revisions and these changes are made by the EC.
As legal instruments, regulations are immediately enforceable. Conversely, directives must be converted into national law by the Member States.4 Directives specify results to be achieved and each Member State may decide how to transpose directives into national laws. Regulations, on the other hand, are legally binding for every Member State and enter into force on a set date in all Member States, as described below.
The ethical review shall be performed by an EC in accordance with the law of the Member State concerned. The review by the EC may encompass aspects addressed in Part I of the assessment report for the authorization of a clinical trial, as referred to in Article 6 and in Part II of that assessment report, which covers the provision for indemnity or compensation for the trial conduct and it also covers the amounts and arrangements for rewarding or compensation trial subjects for participation as referred to in Article 7 as appropriate for each Member State concerned. Member States shall ensure that the timelines and procedures for the review by the EC are compatible with the timelines and procedures set out in this regulation for the assessment of the application for authorisation of a clinical trial.
Regulation EU No 536/2014 states that any clinical trial is subject to a scientific and ethical review by an EC in accordance with the law of the Member State. A key objective of the regulation is to shorten approval times for clinical studies. However, the reduced evaluation time, together with the need to produce robust and reliable data, requires a radical change in the current complex operating modes of ECs as the complexity of the EC review process depends on the nature of individual member states' bureaucracy. Overcoming bureaucratic procedures currently in force, and radically simplifying them, is the central challenge in implementing the EU clinical trials revised regulation.5
However, the revised regulation does not address some important clinical trials issues and their resolution is entrusted to the individual Member States. Also, the regulation does not regulate the activity of an EC, nor does it affect the insurance coverage for either profit or not-for-profit studies.
The European Network of Research Ethics Committees (EUREC) published the new "Regulation No 536/2014 on Clinical Trials on Medicinal Products for Human Use," which repeals Directive 2001/20/EC. The new regulation became effective 16 June 2014.6 Directive 2001/20/EC will be repealed on the day of entry into application of the new Clinical Trials Regulation 536/2014; however Directive 2001/20/EC will still apply for three years.
As a member of ICH, Europe adopted the GCP guidelines E6(R1) in 1996. These guidelines have since been converted into national law by EU member states. In 2016, the Integrated Addendum to GCP E6(R2) was adopted by the EU.7
A direct effect of the GCP implementation was the establishment of Ethics Committees (ECs). Regulation EU No 536/2014 defines an ethics committee as "an independent body established in a Member State in accordance with the law of that Member State and empowered to give opinions for the purposes of this regulation, taking into account the views of laypersons, in particular patients or patients' organisations."8
The independence of an EC is guaranteed by the absence of hierarchical subordination within its structure. Independence is supported by the presence of an adequate number of members who are not bound by an employment relationship, nor members whose interests' conflict with those of the EC members with respect to the clinical trials they oversee. As independent bodies, ECs are responsible for ensuring the rights, safety and welfare of the subjects participating in a clinical trial are subsequently charged with the tasks of expressing a preliminary opinion on the study; assessing the adequacy of the protocols; examining the suitability of the investigators and ensuring the quality of information given to clinical trials patient participants.
In 2001, the EU issued Directive 2001/20/EC9 with the purpose of harmonizing within its Member States the application of GCP in the conduct of clinical trials on medicinal products intended for human use. The directive sets fixed deadlines for the release of an opinion by the EC as well as the release of additional elements, such as the relevance of the study; the benefit-risk ratio; the quality of health facilities involved; the adequacy of insurance liability; the remuneration of investigators and patients; and the subject selection mode. Special protective conditions—both in the conduct of preclinical research and in the procedures of consent acquisition—are reserved for clinical trials enrolling subjects who are minors or those unable to give consent due to psychiatric diseases or dementia. For multi-center clinical trials limited to a single Member State, only one opinion from an EC is required.
It is left to the Member States to determine the appropriate body or bodies to be involved in the assessment of the application for conducting a clinical trial and to organize the involvement of EC within the authorized timelines set out in the Directive.
There are a number of conceptual differences between EUREC, RECs and an EC. Established in 2005, the European Network of Research Ethics Committees (EUREC) represents national associations and bodies of Research Ethics Committees (RECs). The EUREC promotes co-operation and harmonization of best practices to support training and also seeks to provide unified material across the European Ethical Committees. Since 2006, EUREC has been cooperating with the European Medicines Agency (EMA) in the implementation of EU regulations and the establishment of the EU portal, a conduit through which data and information is stored in an EU database.
According to the EUREC website, "EUREC is a network that brings together already existing national Research Ethics Committees (RECs) associations, networks or comparable initiatives on the European level. The network promotes capacity building and assistance for local RECs to cooperate in the EU European Research Area. As an umbrella organisation the network interlinks European RECs with other bodies relevant in the field of research involving human participants like the European Commission's ethical review system and the European Medical Association (EMA). EUREC cooperates with organisations that support research ethics. Such a network forms the infrastructural basis to promote awareness of specific working practices of RECs across Europe, to enhance the shared knowledge base of European RECs, to support coherent reviews and opinions and to meet new challenges and emerging ethical issues. EUREC has been founded in 2005. EUREC Inc. is listed in the register of associations since 2012."10
RECs review proposed studies involving human participants to ensure conformity to internationally and locally accepted ethical guidelines. They also monitor studies once they have begun and where relevant, take part in follow-up action and surveillance after the research has been concluded. RECs have the authority to approve, reject or stop studies, as well as require modifications to research protocols. They also may perform other functions, such as setting policies or offering opinions on ethical issues in research.
Some RECs operate within research institutions, where they may be known by different names, such as Institutional Review Board (IRB), a US-specific term. Others, operating within the EU, do so on a regional or national basis. The advantage of research ethics committees operating within research institutions is that they may be more familiar with local conditions and with closer proximity to those conducting clinical trials, can more closely monitor on-going studies.
"An EC is … a group of individuals formed to protect the interests of patients and address moral issues. It normally includes a board member of the institution, a lay person and an administrator. A member of the clergy may also be included, as well as an ethicist if one is available. Most ethics committees work in an advisory capacity; they can help patients and families reach informed decisions and work with health care providers in order to make complex and difficult decisions. The ethics committee often reviews hospital policies and procedures for potential problems and may also reduce the potential for litigation against the institution."11
Figure 1 shows schematically the principal entities involved in the conduct of a clinical trial, highlighting the differences between the Directive 2001/20/EC and the Regulation EU 536/2014.
Clinical Trial Regulation EU No 536/2014 describes the purpose and intent of the EU portal:
In accordance with Article 80 it is defined as: "The [European Medicines] Agency shall, in collaboration with the Member States and the [EU] Commission, set up and maintain a portal [emphasis added] at [European] Union level as a single entry point for the submission of data and information relating to clinical trials in accordance with this regulation. The portal shall be technically advanced and user-friendly so as to avoid unnecessary work." "Data and information submitted through the EU portal shall be stored in the EU database" referred to in Article 81.12
Here, the EU defines the need for a single entry point to an EU-wide clinical trial repository, forming an absolute prerequisite to the regulation coming into force. However, without the portal and the database, compliance with the revised regulation would be impossible. Further clarity on the design and functioning of these two elements is provided in the functional specifications for the EU portal and EU database to be audited.13 These draft specifications anticipate provisions for Member State experts, such as scientific assessors, regulatory officials, Ethics Committee members or inspectors.
There is no specific requirement in the regulation for the names of Member State experts to be included in the database and the names of Member State experts will not be included in the database except where necessary for the application of Article 81(2) of the regulation (Article 81(6)). Therefore, as stated in Article 81(4)(a), to the extent that personal information identifying Member State experts is collected in the database at all, it will not be made public.14
The current overview of the European Databases is yet to be published; however, it will be released after the publication of the new updated guidelines. While the new EU portal is still in development, the current EU Clinical Trials Register (EudraCT database) is applicable to trials conducted under the current Directive 2001/20/EC. Trials conducted under the future regulation will reside on the EU Database, which will have a publically accessible platform.15, 16
The existing data will have to be migrated into the new database and will have to be accessible through the new portal. However, through Policy 70, clinical data is made public through the EMA Clinical Data platform. EU Clinical Trial Regulation data will be published through the future EU Portal and Database. The scope is different.
The EU Clinical Trials Register contains information on interventional clinical trials in the European Union (EU) or the European Economic Area (EEA) that started after 1 May, 2004.17
Clinical trials conducted outside the EU/European Economic Area (EEA) are included if:
The Register also provides information about past pediatric trials covered by an EU marketing authorization.
Clinical Trial Regulation EU No 536/2014 will come into effect in 2018. It will impact future clinical trial authorization processes, the functionalities of the EU CT portal and database, as well as transparency and safety reporting requirements.
The following two key issues have emerged from the analysis of the regulation:
The revised regulation does not cover all of the relationships existing between the stakeholders, nor does it cover the operative way to manage clinical trials conducted by EU member states. Consequently, there is an urgent need for all stakeholders to address these issues and their cost implications. To be successful, this task will require a change in electronic systems, operational processes and organizational adaptations.
Siegfried Schmitt is a principal consultant with Parexel, providing services to the regulated healthcare industry. He is a recognized subject matter expert in data integrity. He currently serves as chair of the RAPS Regulatory Focus Board of Editors. He can be contacted at firstname.lastname@example.org.
Federico Bonacci, MD of the Forensic Toxicology Laboratory located in Catanzaro, Italy, specializes in medical legal and insurance issues. He was a member a Bioethics Committee at the Hospital Ciaccio in Catanzaro, Italy from 2010 to 2013. He can be reached at email@example.com.
Daniela Lisini, PhD, senior biologist, is director of production at the Carlo Besta Neurological Institute in Milan, Italy. She is experience in the regulation of advanced therapy medicinal products and works with the Italian Institute of Health and The Italian Medicines Agency (AIFA). She can be reached at firstname.lastname@example.org.
Dr. Viviana Mascilongo is a regulatory affairs manager and procurator. She has direct contact with EMA, FDA and national drug agencies and ministries of health in EU member countries. She is an EMA Stakeholder: EMA/136736/2016 (17), EMA/739149/2015 (nr. 52). She currently services as a technical reviewer on the RAPS Regulatory Focus Board of Editors. She can be reached at email@example.com.
Cite as: Schmitt, S., Bonacci, F. Lisini, D. And Mascilongo, V. "Impact of Revised Clinical Trial Regulation EU No 536/2014." Regulatory Focus. April 2017. Regulatory Affairs Professionals Society.
Tags: 536/2014, Clinical, EU, No, Regulation, Trial
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