The New European Union Regulation for Clinical Trials

Clinical trials can be defined as investigations made in humans to discover or verify the positive and/or negative effects (effectiveness and safety) of one or more investigational medicinal products.1 Currently, the conduct of clinical trials in the European Union (EU) must conform with the Directive 2001/20/EC of the European Parliament (the Directive), a document providing trial requirements and guidelines aimed mainly at guaranteeing the highest possible patient safety, enforcing the use of good clinical practice (GCP), and striving for high scientific value and usefulness of the data generated, among other goals.

Upon its initial release, this document was considered an important step toward harmonization of laws in the EU; however, it was each Member State’s responsibility to implement the contents of the Directive in their own national laws. Thus, different interpretations of the document resulted in slight discrepancies between the laws of each Member State. Also, the authorization of a clinical trial was specific for each Member State.

Thus, applying for a multicenter trial across different Member States involved, for sponsors, sending largely similar dossiers to each of the concerned Member States and dealing with the different applicable fees in each country. While the 2001/20/EC Directive had noble aims, the results were unsatisfactory, partly because it introduced requirements that ultimately resulted in higher costs for sponsors, and because adequate harmonization had not been achieved.

According to the Council of the European Union, between 2007 and 2011 the number of applications for clinical trials decreased by 25% in the EU.2 This is partially attributed to the Clinical Trials Directive of 2001, which ensured a high level of patient safety, but an unfavorable regulatory framework not only for pharmaceutical companies, but also for academic research in general. The Directive caused, for example, increases in staff requirements for sponsors, insurance fees, and administrative costs. As a result, many pharmaceutical companies and academic researchers felt discouraged to submit new applications within the EU.

Clinical Trials Today

The number of clinical trials worldwide is increasing rapidly. The total number of registered studies at ClinicalTrials.gov was 5,633 studies in 2000. A decade later in 2010, this number had increased 20-fold to a total of 101,157 studies, and as of May 26, 2016, no less than 216,408 were registered at the portal.3 However, while the number of clinical trials is increasing globally, some regions of the world benefit from the trend more than others, if at all.

When considering data from ClinicalTrials.gov, the number of new registered clinical trials per year in Europe (see Figure 1; green line) shows an apparent stagnation, whereas the global tendency is growth (top blue line). In contrast, the number of new clinical trials registered in East Asia (China, Hong Kong, Korea, and Taiwan; orange line) grew considerably. New clinical trials in East Asia went from a modest 7.3% of global registrations in 2006 to 16.2% in 2015.

These numbers suggest that East Asian countries are becoming increasingly attractive options for pharmaceutical companies that wish to conduct clinical studies. This could be due to a sufficiently developed scientific community, robust expenditure for health research, and easy access to a large population, as is the case of China.4,5 Another interpretation is that European countries have a higher growth potential than is currently being explored when it comes to clinical studies.

Addressing the issues of the law concerning the authorization and conduct of clinical trials in Europe could help in achieving its full potential of growth. The data on the numbers and geographic distributions of clinical trials shown in Figure 1 are derived from the ClinicalTrials.gov database, which means that these results only apply to U.S. companies and studies under U.S. jurisdiction. Although most pharmaceutical companies submit details about their global clinical trials to this database as well, it still under-represents the number of global trials worldwide.

Figure 1 Chart
FIGURE 1: New Clinical Trials Registered Per Year*

The New Regulations

The approximation of laws between Member States of the EU is foreseen by the very treaty that establishes the functioning of the EU. In Article 114 of the treaty, it is defined that the European Parliament and Council shall “adopt measures for the approximation of the provisions laid down by law, regulation or administrative action.” Meanwhile, the treaty also implies, in Article 168, that a high level of human health protection is paramount when defining and implementing a new policy or regulation.6

The “new Regulation EU No 536/2014 of the European Parliament and of the Council on clinical trials on medicinal products for human use, and repealing Directive 2001/20/EC” (the Regulation) was adopted by the European Parliament (on April 2, 2014) and by the Council of Ministers (on April 14, 2014) and signed off on April 16, 2014. This document specifically mentions and respects the previously cited articles. The new Regulation aims to simplify current rules, streamline the application procedure for new clinical trials, provide more transparency in general, and harmonize the process of performing clinical trials throughout all the Member States of the EU. The changes aim to make the EU more attractive for future clinical trials and turn around the decreasing number in new clinical trials observed in recent years.2

The scope of the Regulation is extensive-it covers, in its main text and many appendices, the new authorization procedures, temporal definitions, and conditions for the start of the trial, any suspension or hold on its activities, and any early termination; the protection of subjects; informed consent; the conduct of trials; the reporting of safety issues; insurance requirements; and manufacturing practices (among other subjects). It also contains updated definitions of many key terms for the Regulation, such as the definition of a “clinical trial.”

In the new Regulation, a clinical trial is defined as a type of clinical study that fulfills any of the three following conditions: 1) the assignment of the subject to a particular therapeutic strategy is decided in advance and does not fall within normal clinical practice of the Member State concerned; 2) the decision to prescribe the investigational medicinal products is taken together with the decision to include the subject in the clinical study; or 3) diagnostic or monitoring procedures in addition to normal clinical practice are applied to the subjects.

Certain aspects are not directly covered by the new Regulation and remain country-specific considerations, including ethical issues and the involvement of independent ethics committees, legal representative of the subject not able to provide informed consent, rules of liability in the case of damages, requirements for investigators and site qualification, and requirements for country/site-specific documents (including expectations related to the form of notarization and language(s) to be used).

The new Regulation applies directly to all individuals in the EU. It was published in the Official Journal on May 27, 2014, but will only become fully applicable when its requirements are met. The time of its implementation is defined to be six months after the European Commission issues a report confirming that the required new information technology infrastructure, namely the EU-portal and the EU-database for clinical trials (discussed below), is fully functional.7,8 The portal and the database are being developed by the European Medicines Agency (EMA) in collaboration with the Member States and the European Commission, as defined in Articles 80, 81, and 82 of the 536/2014 Regulation. The current time frame established by the EMA in December 2015 sets October 2018 as the target for when the Regulation will become fully applicable.{8}

In order to prevent inconveniences for the sponsors because of the changes, there will be a transition period of one year, during which new clinical trial applications can be authorized either according to the old 2001/20/EC Directive or according to the new 536/2014 Regulation, as requested by the sponsor. Also, clinical trials already authorized in accordance with the current Directive will be able to continue following the Directive until up to three years after the new Regulation comes into effect. As established in the EMA time frame, the 2001 Directive will no longer be applicable on October 2021.

Main Changes

The first change noticeable between the 2001/20/EC Directive and the 536/2014 Regulation is the nature of the document. While a directive is a legislative act that sets out a number of goals that all EU Member States must achieve individually through changes in their own national legislation, a regulation is a binding legislative act, immediately applicable and enforceable in the whole EU, and thus has a legislative power comparable to a law.9,10 Sponsors and investigators for clinical trials taking place in multiple Member States can rely directly on the new Regulation, as opposed to dealing with each Member State’s individual approach to an EU directive.

The new Regulation establishes the creation of the EU-portal (Article 80) and the EU-database (Article 81). The EU-portal will be the single entry point for the submission of all data and information relating to clinical trials to be performed in any Member State. These data are to be stored in the EU-database and, unless confidentiality is justified, all non-personal information contained in the database, including the study protocol, will be publicly accessible after the approval of the study, in an “easily searchable format.”7

During the authorization process, official communication between sponsors and Member States, such as requests for additional information or notification as to whether a study is authorized, will be made through the EU-portal. It is also the sponsor’s responsibility to permanently update the EU-database with any new relevant information.

After a trial ends, the sponsor shall also upload, as defined in Annex V of the Regulation, a summary of the trial’s results for laypersons, describing the main aspects of the study, its findings, and comments on its outcome in an accessible way.7 In addition, inspection reports for a trial’s investigational sites from the sponsor and any contract research organizations involved will be published on the EU-database.

Another aspect introduced with the new Regulation is the possibility of co-sponsorship (Article 72). This can benefit informal networks of researchers or research institutions that may desire to conduct a clinical trial together. It is defined that, unless decided otherwise in a written contract, all sponsors shall have the full responsibilities of a sponsor as defined in the Regulation. Co-sponsors can jointly establish which sponsor shall be responsible for compliance with the obligations of a sponsor in the authorization procedures; which sponsor will serve as a contact point for receiving all questions from subjects, investigators, or Member States; and which sponsor will carry out corrective measures taken by Member States, such as modification, suspension, or revocation of a clinical trial.

Complying with Chapter II of the new Regulation, the authorization procedure for new clinical trials will be as follows:

  • First, the sponsor shall submit the application dossier to all intended Member States through the EU-portal, while proposing one of the Member States to be the “reporting Member State” (see Figure 2). The proposed Member State will be the reporting Member State unless it does not wish to be, or another concerned Member State specifically wishes to be considered for that duty.
  • The reporting Member State will, within 10 days of submission of the application dossier to the EU-portal, validate that the application dossier falls within the scope of the 536/2014 Regulation and is in complete accordance with Annex I (application dossier specifications) of the Regulation. It then notifies its decision to the sponsor through the EU-portal. If the application dossier is deemed inappropriate, the sponsor has 10 days to comment on or complete the application through the EU-portal. In this scenario, following the sponsor’s action the reporting Member State will have five days to validate the dossier.
  • After validation of the application itself, the reporting Member State shall provide Part I of the Assessment Report, as defined in Article 6 of the Regulation. This report shall contain the reporting Member State’s conclusion as to whether 1) the conduct of the clinical trial is acceptable, 2) it is acceptable but subject to compliance with specific conditions that will be listed in the conclusion of the report, or 3) it is not acceptable. This report has to be submitted through the EU-portal to the sponsor and other concerned Member States within 45 days from the validation date. For trials involving multiple Member States, the assessment report will consist of an initial phase as described above, a coordinated review involving all Member States concerned, and a consolidation phase again performed by the reporting Member State.
  • Simultaneously, in the case of multicenter trials, each other concerned Member State will assess the application for its own territory and draw up Part II of the Assessment Report, with a conclusion as described above, and submit it to the EU-portal within 45 days of the validation date of the dossier. During these 45 days, each concerned Member State, or the reporting Member State, may ask the sponsor for information when deemed necessary. These requests, and the information provided, shall also be submitted to the EU-portal.
  • Finally, within five days of the submission of the complete Assessment Report, or on the last day of the assessment time limit (whichever is later), each Member State shall individually notify the sponsor through the EU-portal as to whether the clinical trial is authorized or refused. It is important to note that if the reporting Member State fails to provide the necessary validation of the application dossier, or to provide the Assessment Report, the study is deemed authorized. This concept is called “tacit approval.” Likewise, if the sponsor fails to provide additional information or change its application upon request within the defined time limits, the application is automatically deemed to have lapsed in all Member States.
Figure 2 Chart
FIGURE 2: The New Clinical Trial Authorization Process*

Note: MSc = concerned Member States; repMS = reporting Member States; ATMP = advanced therapy medicinal product
Source: Implementation of the Clinical Trial Regulation at National Level, Late Breaking Clinical Trials News Conference, Brussels, Belgium, October 16, 2014

Discussion

The new 536/2014 Regulation represents changes that are being welcomed by pharmaceutical companies and academic researchers in the EU, and seems to have been elaborated with special consideration toward them. It eases the costs associated with conducting a clinical trial, especially in multiple Member States, in that it reduces the required paperwork, staff, and fees, and simultaneously simplifies the authorization process.

The harmonization of laws was also conducted with consideration given to the future of clinical trials. It is recognized in the new Regulation that, in the near future, studies may be required in specific subgroups of people identified through genetic information. In order to achieve this, it would be vital to include as many Member States as possible for the best possible results. All the changes in the new authorization procedure seem to make multicenter trials an unprecedentedly viable option.

All in all, simpler rules, increased cost effectiveness, and easier access to the European population will probably make the EU more attractive for companies seeking to perform large studies. This change could possibly reverse the recent tendency of pharmaceutical companies to turn to developing countries with large populations, such as China (see Figure 1), as locations for clinical trials.

With the benefits of harmonization in mind, it is also important to acknowledge that there are challenges created by the new requirements laid down in the 536/2014 Regulation. Both sponsors and Phase I trial units have highlighted the potential impediments to the attractiveness of the EU for the conduct of early-phase studies, due to the requirements for increased transparency related to clinical trial design and results, both of which will be required to be published. Concern exists that sponsors may prefer the option of conducting very early-phase studies in Asia, where no such obligations exist.

The EMA has sought to alleviate these concerns by introducing functional specifications that establish extended timelines for the publication of clinical trial registration information relating to early-phase clinical trials. For such trials, sponsors can request deferral of publication of certain protocol-related information, but this information must still be made public at the time of the publication of the results of the trial (the deadline for which would be set at either 12 or 30 months following the end of the trial—as stated in EMA/228383/2015).

While this will offer some reassurances to sponsors, the approval timelines described by the EU 536/2014 Regulation (at up to nearly 100 days for a Clinical Trial Application that elicits questions from Member State authorities) appear particularly unattractive to those familiar with review timelines of less than one month for Phase I clinical trials in some Member States. However, it must be remembered that the timelines stated in the Regulation are all maximum timelines for each step of the process. There has been much communication from the EMA, Member State authorities, and ethics committees at multiple workshops, forums, and stakeholder meetings since the Regulation was published, and through these communications the representatives of some Member States have made it clear that they would hope to review applications for single-country trials within timelines that are significantly shorter than the maximum timelines described in the Regulation.

The benefits of much greater harmonization of requirements and processes are not limited to high-profile sponsors within the pharmaceutical industries, since the new Regulation also sets the ground for co-sponsorship. This new possibility of study sponsorship can involve smaller research companies or even groups of individual scientists, which should allow for new possibilities for conducting studies independently of big institutions.

In this highly competitive scenario for the EU, it is likely that competition between Member States for patient recruitment will become a priority, together with the identification of investigational sites that excel at study delivery (known as Centers of Excellence). As inspection reports will become public, investigational sites are more than ever pressured to provide high-quality data and guarantee full compliance with the new processes and systems for clinical trials.

The situation relating to the United Kingdom following the result of the referendum on EU membership will be of particular interest to sponsors, as the implementation date for the 536/2014 Regulation draws near. According to media press releases from July and August 2016, the Medicines and Healthcare products Regulatory Agency (MHRA) in the U.K. has stated that the authority will continue to contribute significantly in many areas, including the program for implementing the clinical trial Regulation, as negotiations over the future relationship of the U.K. with the EU continue. The result of these negotiations will obviously have a significant bearing on whether the requirements laid down in the 536/2014 Regulation will apply to the U.K. after implementation in October 2018.

One possible outcome that has been considered is that the U.K. and EU will establish a relationship similar to that applied to the non-EU members of the European Economic Area (EEA). It is fully expected that these EEA countries will apply the requirements of the EU Clinical Trial Regulation, and therefore participate in the approval of clinical trials via the EU-portal and registry of trials within the EU-database (much as the involvement of these countries in clinical trials is recorded in the EudraCT registry at present). This could enable a situation where the new Regulation would apply in a de facto manner across the EU, EEA, and the U.K.; however, there are significant political hurdles to address for this to come to fruition, and an outcome that necessitates the creation of distinct clinical trial submission and regulatory processes in the U.K. cannot be discounted.

Another potential factor of the “Brexit” that should not be discounted is the value of the contribution made by the U.K. authorities, past and at present, in the establishment of harmonized processes across the EU. For example, alongside the authorities in Germany, the MHRA played an active role in the establishment of the Voluntary Harmonized Process, in place for regulatory submissions across participating EU Member States since 2010.

In addition, the MHRA and U.K. Health Research Authority have taken the lead in composing two of the key draft guidance documents that have been developed to facilitate the implementation of the EU Clinical Trials Regulation (“Definition of Investigational Medicinal Products (IMPs) and use of Auxiliary Medicinal Products (AMPs)” and “Summary of Clinical Trial Results for Laypersons,” respectively). Although it is acknowledged that 27 Members States will remain involved, it will be to the detriment of the EMA and the representatives of the other Member States if they are, at some future point, forced to proceed with the implementation of the new Regulation with no contributions such as those discussed here from the U.K. authorities.

While considering the impact on sponsors of clinical trials, it must be understood that the changes introduced within Regulation 536/2014 will introduce dramatic alterations to the way that the regulatory authorities, ethics committees, and other bodies assess clinical trial authorizations (for example, radiological committees, bio-banking committees, and other committees established in particular Member States) and interact with one another as they do so (i.e., much greater collaboration will be required in the future). Some authorities in Western Europe have already established pilot programs that will allow them to test their processes for this collaboration, and this can be expected to serve them well as they finalize the processes they will apply when working under the new Regulation starting in October 2018.

However, many Member States are not so advanced in their planning, and it must be hoped that all are able to make progress in this regard, because it will be very difficult to implement the required processes on short notice, and collaboration within each Member State will be crucial if the authorities are to implement the laws and requirements described within the Regulation.

Finally, one can expect a benefit not only for sponsors in general, but also for the scientific community and the general population, thanks to the increased transparency provided by the new Regulation. The public availability of relevant data, presented in an easily searchable format, and the obligatory inclusion of a layperson’s summary of the study’s protocol and results, when available, will allow citizens not directly involved in the studies to benefit from the results, whether they be patients seeking new treatments or health professionals interested in the new knowledge being produced. Because the summary of the results has to be submitted irrespective of the outcome of the clinical trials, this also avoids publication bias for possibly unfavorable results of a trial.

PEER REVIEWED

References

  1. Clinical trials – General information. European Commission portal.
    http://ec.europa.eu/health/human-use/clinical-trials/information/index_en.htm
  2. Council adopts new rules on clinical trials. Council of the European Union press release (April 2014). www.consilium.europa.eu/uedocs/cms_Data/docs/pressdata/en/lsa/142181.pdf
  3. Trends, Charts, and Maps. ClinicalTrials.gov.
    https://clinicaltrials.gov/ct2/resources/trends
  4. Novak T, Payeur G, Belotserkovksy M. 2014. Decline of clinical trials in central and eastern Europe: fluctuation or trend? www.appliedclinicaltrialsonline.com/decline-clinical-trials-central-and-eastern-europe-fluctuation-or-trend
  5. Viergever RF, Keyang Li. 2015. Trends in global clinical trial registration: an analysis of numbers of registered clinical trials in different parts of the world from 2004 to 2013. http://bmjopen.bmj.com/content/5/9/e008932.full
  6. Consolidated version of the treaty on the functioning of the European Union.
    http://eur-lex.europa.eu/legal-content/EN/ALL/?uri=celex%3A12012E%2FTXT
  7. Regulation of the European Parliament and of the Council on Clinical Trials on Medicinal Products for Human Use, and repealing Directive 2001/20/EC.
    http://register.consilium.europa.eu/doc/srv?l=EN&f=PE%202%202014%20INIT
  8. Delivery time frame for the EU portal and EU database. 2015. European Medicines Agency. www.ema.europa.eu/docs/en_GB/document_library/Other/2015/12/WC500199078.pdf
  9. Regulations, Directives and other acts. https://europa.eu/european-union/eu-law/legal-acts_en
  10. EU Directive vs EU Regulation: what’s the difference? 2014. www.enhesa.com/blog/eu-directive-vs-eu-regulation-whats-difference

Yves Geysels, PhD, (yves.geysels@quintiles.com) is a professor of clinical trials at the University of Namur, Faculty of Medicine, Department of Biomedical Sciences in Belgium and president of the Belgian Association of Clinical Research Professionals.

Christopher A. Bamford, PhD, is a representative of the Association of Clinical Research Organizations (ACRO), a global CRO trade organization in Washington, D.C.

Richard H. Corr is an exchange student of the Science Without Borders program of the University of Namur, Belgium, and a medical student of the Universidade Federal do Rio de Janeiro, Brazil.

[DOI: 10.14524/CR-16-0017]

*To see all figures and/or tables published originally in this article, please visit the full-issue PDF of the February 2017 Clinical Researcher.