Aman Khera, Global Head of Regulatory Strategy, Worldwide Clinical Trials
January 31, 2022, marked a substantial regulatory shift for clinical trials conducted in the European Union (EU). As of that date, the new EU Clinical Trial Regulation 536/2014 (EU-CTR) begins replacing EU Clinical Trial Directive 2001/20/EC (EU-CTD), which has been in effect since 2004.
The EU-CTR is designed to improve the EU’s competitiveness in the drug development market by increasing transparency, collaboration, and harmonization within clinical trial processes. It holds considerable potential benefits, but it also carries enormous practical implications for anyone who conducts clinical trials in the EU. Thus, all industry stakeholders should start to examine some of its main objectives and plan for ongoing, comprehensive training initiatives to understand its impact.
While it is essential to grasp the EU-CTR's operational implications, sponsor companies should also pay close attention to the underlying themes of transparency and collaboration interwoven throughout the regulation.
The past few years have demonstrated just how much industry stakeholders—not to mention patients and caregivers—crave harmony and transparency. Indeed, patients and caregivers worldwide are now leveraging technology to come together and demand more openness from sponsor companies and regulatory agencies alike. In many ways, the EU-CTR’s attempts to promote harmony and transparency may set the stage for a very real and very positive paradigm shift in clinical research.
Primary Objectives of the EU-CTR
Whether or not the EU-CTR actually helps move the needle on transparency, an awareness of its objectives is crucial. Among the regulation’s most essential goals are the following:
Provide common provisions governing clinical trials across EU member states
In 2004, the EU-CTD represented an initial attempt to harmonize and standardize clinical trials in Europe.1 However, as many know, it often has had the opposite effect.
In part, that is because the EU-CTD is a directive instead of a regulation, which means each EU member state had to implement its legal requirements through national legislation. The result has been a fragmented clinical trial assessment process and a complex data submission framework. In contrast, the EU-CTR is binding on all EU member states in its entirety.2 The hope is that its regulation status will help overcome many of the past limitations of the EU-CTD as it encourages collaboration and streamlines processes.
Changes need not happen immediately for sponsor companies, though. A three-year transition period has been granted, starting January 31, 2022. From January 31, 2022, through January 31, 2023, clinical trials may be submitted using either the EU-CTD or the EU- CTR. As of January 31, 2023, all clinical trial applications in the EU fall within the purview of the EU-CTR, although any trials already approved through the EU-CTD can continue within the EU-CTD until January 31, 2025. After that date, all clinical trial activity is subject to the EU-CTR.
Harmonize clinical trial authorization processes
The EU-CTR supports a much more coordinated clinical trial assessment process among EU member states. The assessment of multinational clinical trial applications should be simplified because EU-CTR enables a single decision—National Competent Authority (NCA) plus Ethics Committee (EC)—per member state.
Furthermore, for each clinical trial’s duration, the coordinated assessment will be led by a “reporting member state.” This is a significant new development over the EU-CTD, and one that sponsor companies will need to consider carefully since they must designate which EU member state they want as their reporting member state.
The designated reporting member state must serve in that capacity— unless more than one member state is willing to assume the responsibility. In such cases, the member states will select a reporting member state and inform the sponsor. If the member states fail to reach an agreement, then the sponsor company’s proposed reporting member state must fill the role.
Serving as a reporting member state is not a function to be taken lightly. Reporting member states will drive the assessment process, and if a reporting member state refuses the Part I scientific/technical application, it is refused for all member states. Consequently, selecting an appropriate reporting member state will need to be an early and strategic consideration.
Strengthen transparency and the robustness of clinical trial data
For the first time, the EU will have a centralized, electronic portal and database called the Clinical Trial Information System (CTIS) that will serve as a single entry-point for clinical trial information across the EU.3 Sponsor companies will have to upload and submit all clinical trial data—including initial clinical trial application data and documentation—through the CTIS. The aim is to eliminate the need to make multiple electronic or paper-based submissions.
What sponsor companies must recognize is that the use of CTIS will be highly role-based. Permissions will form a crucial security function, so now is the time for stakeholders to identify their CTIS user roles, register their high-level administrators with the European Medicines Agency (EMA), and initiate CTIS training. Preparing and training on the system in advance could go a long way toward avoiding potentially costly slip-ups in a go-live scenario.
In addition to submission efficiencies, CTIS is expected to increase the transparency of clinical trial applications and results. Select data in the CTIS will be made public.
In fact, the default standard in the EU-CTR is always to make information public at the first opportunity (e.g., at the time of decision). Therefore, sponsor companies will need to put mechanisms in place to protect patient confidentiality at the point of submission, as well as to consider their options for deferring the publication of specific details as allowed.
The EU-CTR not only sets new rules for the public reporting of clinical trial applications and results, but it also requires sponsor companies to summarize study results using language and formats a layperson can understand.
As stated earlier, transparency is a central tenet upon which much of the EU-CTR is built. It is a tacit acknowledgment that successful clinical trials can only exist if patients have confidence and trust in the process. Viewed through that lens, instituting summaries specifically designed for public consumption may turn out to be a critical step in reinvigorating and bolstering public confidence in clinical trials.
Ensure the highest safety standards and participant protections
Sponsor companies will need to use CTIS/EudraVigilance for all safety reporting going forward, and the EU-CTR ramps up their reporting obligations as well. For example, within the EU-CTD, there is no set timeframe for reporting serious breaches. Within the EU-CTR, serious breaches must be reported within seven days, and all unexpected events which affect a clinical trial’s benefit-risk balance must be reported within 15 days.
The EU-CTR also establishes more detailed and protective informed consent guidelines at the EU level, including for those who cannot provide informed consent. It better defines informed consent requirements for several vulnerable patient populations and for various clinical trial circumstances (e.g., cluster trials and trials in emergency settings). The definition of a legally designated representative (LDR) has been updated too.
By taking a more standardized approach, the EU-CTR will help ensure a more equitable application of informed consent rules for everyone in the EU. Patients can be assured that no matter where they happen to live, their voices will be heard with regard to the consent process.
Increase the efficiency of clinical trial application submissions and assessments
It is hoped that the centralized CTIS database and harmonized authorization processes will increase efficiency. However, be aware that demands for faster information turnaround times also come into play.
For example, the EU-CTR gives sponsor companies a maximum of 12 calendar days to respond to application queries or requests for information (RFI). Failure to meet that deadline means an application will lapse by default. Although workload management tools built into the CTIS can help ensure compliance with new rules and timeframes, it will be imperative for sponsor companies to monitor the CTIS for notices and alerts.
Aggressive timelines put the onus on sponsor companies to develop a strategic, “all-hands-on-deck” approach. Deciding when to begin dipping their toes into the EU-CTR waters will take some advanced planning, so it is a good idea to lean into the recommendations of regulatory experts who are used to keeping up with the latest intelligence and guiding companies appropriately. Sponsor companies with more at risk may choose to wait and monitor the early experiences of others. In contrast, those with more products in the pipeline may find it advantageous to get faster first-hand experience with the regulation.
Time for Transformation
The industry should not underestimate the size and scope of the changes mandated through the EU-CTR. The regulation—which has been years in the making—represents the largest transformation in clinical trials in the EU in quite some time. It holds significant strategic and operational implications, meaning most stakeholders would benefit from investigating its provisions thoroughly, obtaining training, and seeking guidance.
Yet while the EU-CTR’s primary objectives appear favorable, even the best plans can have unintended consequences. The EU-CTD, for example, never really achieved the standardization desired.
In truth, we do not know precisely how the EU-CTR will impact drug development. Will it speed up clinical research as we all need? Will its technology and timelines prove restrictive? Or will its focus on transparency and collaboration result in even greater long-term impacts? It is impossible to answer such questions now, but we will know soon enough. A time of transformation is upon us.
References
- EUR-Lex. Document 02001L0020-20090807. Directive 2001/20/EC. Available at: EUR-Lex - 02001L0020-20090807 - EN - EUR-Lex (europa.eu). Accessed January 6, 2022.
- EUR-Lex. Document 32014R0536. Regulation (EU) No 536/2014. Available at: EUR-Lex - 32014R0536 - EN - EUR-Lex (europa.eu). Accessed January 6, 2022.
- European Medicines Agency. Human Regulatory: Research and Development: Clinical Trials Information System: training and support information page. Available at: Clinical Trials Information System: training and support | European Medicines Agency (europa.eu). Accessed January 6, 2022.
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