The Clinical Trials Directive (CTD) came into force in March of 2004 with the objective of providing a streamlined, consistent and simplified procedure for the authorization and conduct of clinical trials within the European Union (EU) and the European Economic Area (EEA). In practice, the goal of balancing more rigorous oversight, enhanced good clinical practice, improved data quality and reporting while attempting to reduce the burden for clinical trial sponsors, standardization of trial procedures and facilitating greater collaboration between Member States was ultimately a challenging endeavor. Although its implementation was not without criticism, it was broadly welcomed as beneficial, particularly for trial participants. However, detractors of the CTD would point to more cumbersome and bureaucratic procedures that consequently increased the cost of clinical trial conduct and ultimately resulted in fewer trials launched in the years following its initial implementation. Some sources attribute the 12% reduction in clinical trials initiated in Europe between 2007 and 2010 as evidence of the negative impact and consequence following the introduction of the CTD.  

The Clinical Trial Regulation (CTR) was adopted by the European Commission on 16 April 2014 and become effective on 31 January 2022. The Regulation represents a significant evolution of the regulatory framework for the conduct of clinical trials within the EU/EEA, and its implementation is expected to help foster an environment that is favorable for conducting clinical trials with the highest standards of patient safety across all European Member States. The core objectives of the new regulation are focused on protection of the rights, safety, dignity and well-being of clinical trial participants, and the reliability and robustness of the data generated through clinical research. This legislation has taken the legal form of a Regulation thereby ensuring a consistent and harmonized set of rules across all 27 EU Member States, theoretically removing individual country nuances, as experienced under the previous CTD.  The new regulation aims to foster innovation through simplification of the clinical trial authorization process, and to increase transparency and availability of information on clinical trials and their results. It is anticipated that the new regulation will ultimately reduce the administrative burden associated with seeking clinical trial authorisations, trial lifecycle maintenance and reporting across the EU.  

 

Implementation of the CTR 

Prior to the formal implementation of the CTR and CTIS, and since its launch, regulators and other key stakeholders have provided much needed guidance and insights on understanding the application of the CTR and user requirements with the new electronic platform. Webinars, guidance documents, templates, sponsor handbooks and other supportive materials have been developed to support industry and academia prepare for the changes introduced with the new regulation. However, it should be noted that since the start of the transition phase in 2022 there have been several challenges working with the new platform, including significant technical issues experienced with the newly introduced Clinical Trial Information System (CTIS), which may have initially discouraged early adoption by industry. Alongside these initial technical challenges their remains fundamental limitations with its application and scope, including the exclusion of critical procedural steps required to support authorization for certain product types in Europe. This includes GMO based medicinal products which are also governed by the Deliberate Release and/or Contained Use Directives, and in the case of devices the Medical Device Regulation (MDR) or In Vitro Diagnostic Regulation (IVDR). Within the EU, GMO based products require additional review and authorization steps by agencies responsible for assessing the biosafety elements of these trials – these additional separate submissions for review, may require greater involvement of participating sites and in some cases include multiple agency reviews. For Investigational Medicinal Product (IMP) trials that may have a device component, although the IMP aspects will be assessed within the CTIS any device approvals currently need to be managed outside of the CTIS, requiring separate national submissions and again potential for duplication of information and separate review and approval procedures. Therefore, in both case this adds additional time, effort, duplication of activities and further costs to initiate these types of trials in Europe. 

 

Strategic Considerations  

CTIS Platform & Submission Requirements 

The Clinical Trial Information System supports regulatory submission, authorization and supervision of clinical trials. The application process utilises a single central submission portal and database to support the lifecycle, reporting and conduct of clinical trials in Europe. The database also serves as the source of public information on studies conducted in the region. Although several new requirements have been introduced with the CTR, the fundamental information required for inclusion in the trial dossier remains broadly unchanged from the CTD. However, there are a number of important changes that have been introduced with the CTR including new and revised terms, definitions and procedures, centralised reporting requirements, enhanced NCA surveillance, collaboration and transparency. This requires careful review of all core trial documentation to ensure compliance with CTR established standards, procedures and trial document expectations.  

 

Reporting Member State 

Identification and selection of the Reporting Member State (RMS) is a key strategic consideration that requires careful assessment prior to submission. Several factors should be considered in this selection process. The choice of RMS in a multi-national trial should take account of several factors including the experience of the National Competent Authority working with the CTIS, class or type of IMP being investigated and if any prior consultation with an EU regulatory authority has been sought. However, the final acceptance and assignment of the RMS will also be influenced by the principles around CTIS workshare, which is intended to ensure balanced distribution of RMS responsibilities between all of the European regulatory agencies. 

 

Transparency & Confidentiality 

One of the more controversial features of the CTR was the formal alignment with EU transparency rules and the initial mandatory requirement for trial sponsors to have information published on the site – initially this included the majority of trial documentation and information included with the CTIS trial submission. The CTR aims to increase the level of transparency with regards to clinical trials conducted in Europe and stipulates that all data will be publicly accessible unless justified based on protection of personal data, commercially confidential information, and confidential communication between Member States – with the latter point allowing for more effective supervision of clinical trials by the Reporting and Concerned Member States. With its introduction some preliminary safeguards where incorporated, including procedures for trial categorization and deferral, designed to protect commercially confidentially information, particularly for early development trials. However, in June 2024 the EMA introduced amended guidance, which greatly reduced the level of documentation and information to be made available for publication on the platform. This has helped to minimize the additional burden and effort of redacting a significant amount of documentation during the trial dossier preparation phase. 

 

Request for Information (fixed response time) 

Another important consideration is the short response time required to address Requests for Information (RFI) during the CTIS review steps, and the lack of a system generated status notification – notifying users when queries are raised within the CTIS. This requires organizations to implement robust procedures, well defined communication plans and maintain regular surveillance of the CTIS to ensure timely confirmation of issued RFIs and to enable adequate time to respond.  The establishment of a Rapid Response team also greatly facilities effective & timely review of queries and ensures trial sponsors meet the required response deadlines within CTIS validation and evaluation steps. This is particularly important for trials that may include several member states participating as it can result in multiple RFIs being issued in close proximity with limited time to update documentation and/or draft quality responses. 

 

Challenges Still Remain 

Although the introduction of the CTR and the CTIS has positioned Europe well for handling multinational reviews for standard IMP based clinical trials there are several areas that warrant further attention, review and development.  

 

Technical Challenges & Lack of National Guidance 

Since its formal go-live in 2022 the CTIS has been plagued with technical issues that have contributed to preliminary difficulties with accessing, understanding and effectively managing trial submissions and authorizations via the new portal. Additionally, although both industry and European regulators had several years to prepare for the CTR, one of the initial challenges faced in 2022 was the lack of formally implemented or CTR aligned national legislation in some Member States – leading to a lack of clarity on country specific elements required to support submission and authorization steps for specific countries. From its initial launch date the system has encountered many technical challenges resulting in submitted trials “disappearing”, problems with submission of response to queries, and incomplete or unclear feedback during the review process. In November of 2022, a couple of months before the introduction of mandatory use of CTIS, a Working Group of Medical Ethics Committees based in Germany published an open letter titled Massive Functional Problems of the EU Clinical Trials Portal CTIS Threaten Drug Research in Europe, requesting a temporary moratorium on the mandatory implementation of the CTR and CTIS, due to take effect from January 2023. The letter highlighted that the dysfunctionality of the CTIS portal would likely impact the competitiveness of research in the region. 

 

GMOs and Devices included in IMP Trials 

With the introduction of the EU MDR and IVDR, and consequent impact on companies developing a range of products governed by these regulations (e.g., software, companion diagnostics, etc.) used in trials, the routes to approval are multifaceted, diverse and cumbersome. For example, some trials that include a companion diagnostic (CDx), require independent (national) review of the CDx Performance Study outside of the CTIS.  Although EU agencies have made considerable efforts with the harmonization, simplification and streamlining of procedures & requirements for GMO based IMPs the procedures to obtain approval for GMOs are still managed at a national level, resulting in additional steps and documentation to obtain all necessary authorizations for trials in this space. Again, as with the CDx example, there is a need to obtain separate national authorization under the Contained Use or Deliberate Release Directives for trials of this type in each individual member state.  

Therefore, in these particular cases developers still face considerable challenges navigating the complex interplay between several different regulatory frameworks including for GMOs (Deliberate Release & Contained Use Directives), devices (IVDR & MDR) and standard clinical trial authorization (CTR). This situation therefore nullifies some of the potential benefits of the CTR and CTIS, leading to longer overall review timelines, duplication of effort and a lack of harmonized review. 

 

Future Direction

It is welcome to note that the EMA and other stakeholders have been very proactive in trying to address the many technical issues mentioned above and as we move from the transition to formal implementation phase many of the previous technical issues have been resolved or workarounds have been proposed. The lag in national guidance and alignment with the CTR has also progressed considerably in the last few years, ensuring that national authorities are able to provide much needed clarification on national expectations within the CTR and CTIS portal. 

As highlighted earlier in this article, issues with trials requiring review under additional regulatory frameworks including the MDR/IVDR and national GMO legislation are not currently covered within this new framework or platform. Consequently, resulting in more complex, multi-agency and multi-system reviews, potentially negating any benefit of a single unified system. However, of note, is that the current EMA ongoing pharmaceutical legislative review is accessing changes to the way GMO authorizations are managed, potentially seeking to revoke the Deliberate Release framework and integrating some aspects of the GMO authorization procedures within the CTIS. These changes also include proposals for the EMA’s Committee for Medicinal Products for Human Use (CHMP) to take the lead on Environmental Risk Assessments (ERA) review, potentially ensuring more standardized and harmonized review steps in the future. Although many of these changes are not expected to be in place for some time agencies such as the Paul Ehrlich Institute (PEI) in Germany have attempted to facilitate GMO based trials, by enabling parallel submissions through CTIS and PEI helping to potentially streamline and harmonize review steps.  

The EU’s COMBINE Project launched in June 2023 has been tasked to address the challenges faced by companies working with products that may require authorization under the CTR and MDR/IVDR frameworks. The objectives set out in this initiative are expected to help streamline and standardize review procedures for these types of trials. Some member states, such as Denmark, have already implemented guidance based on the principles set out in the Combine initiative to facilitate parallel review of trials that include an IMP and device element. The Danish procedures ensure single ethics review and broadly seek to align the validation and review steps between device and IMP reviews. Although the introduction of the CTR has been a bumpy one it is anticipated that the future of clinical trials in Europe will be more effective, streamlined and transparent ultimately ensuring that developers can get safe and effective treatments to patients faster. 

 

Conclusion 

The introduction of a standardised, simplified, transparent and universal clinical trial authorisation procedure is a welcome and long awaited change for the European clinical research landscape. Since it’s official launch in 2022, national regulators, ethics committees, academia and industry have had a steep learning curve, with considerable hurdles along the way. However, the EMA and other stakeholders have sought to provide effective flexibility and support for industry and academia to facilitate user understanding of the new systems and regulations, and to support adoption and ensure a relatively smooth transition, and procedures working with the new regulation and platform. Ultimately, the CTR and CTIS will be a paradigm shift for the way clinical trials are authorized, conducted, and supervised which should result in a safer, more open, effective and competitive environment in Europe for clinical research in the twenty first century.  

 

About TFS HealthScience CRO 

TFS HealthScience is a global CRO that supports biotechnology and pharmaceutical companies throughout their entire clinical development journey across several therapeutic areas, including Rare Diseases & Orphan Drugs, Oncology, Neuroscience, and more. In partnership with customers, we build solution-driven teams working for a healthier future. As a trusted CRO partner throughout the entire clinical development journey, we understand the importance of providing essential and diverse services to streamline clinical trials for our clients with robust FSP services and strategic resourcing solutions (SRS). Visit our website to learn more about the solutions TFS can offer for your next clinical trial or connect with a TFS representative today!