Navigating the transition: Implementing the new EU CTR in the pharmaceutical industry
Keywords – Clinical Trials Information System, EU Clinical Trials Regulation, harmonization, stakeholder communication, transition
Introduction
Clinical trials are the cornerstone of medical advancement, providing essential evidence on the efficacy and safety of new treatments. The clinical trial regulatory landscape in the EU and European Economic Area underwent a significant transition from the EU Clinical Trials Directive (EU CTD) to the EU CTR, also known as Regulation (EU) 536/2014. The EU CTR, which applies to interventional clinical trials with medicinal products, was adopted in 2014. However, the regulation was not implemented until the CTIS became available on 31 January 2022, triggering the start of a three-year transition period, which ran until 30 January 2025.The first year of the EU CTR transition period was designated as a voluntary phase for initiating new trials under the new regulation. This was followed by a two-year period in which all new trials had to be submitted according to the EU CTR. Any ongoing clinical trials predicted to run beyond the transition period were required to transition to the EU CTR by the end of the three years to comply with the new regulation. By 31 January 2025, all trials were required to follow the EU CTR (Figure 1).
Figure 1. Timeline for the implementation of the EU Clinical Trials Regulation1
Created by Houtzager et al
The EU CTR aims to make the EU a more appealing and competitive environment for clinical research by harmonizing regulatory and ethics committee processes across member states.2 A key feature of the EU CTR is the streamlined submission process through the CTIS, which allows sponsors to submit a single
application for approval across multiple member states.3 This feature intends to reduce delays, lower costs, and provide predictable assessment timelines, benefitting global clinical trials by ensuring earlier enrollment and consistent trial conduct across the EU.
However, transitioning thousands of clinical trials from the EU CTD to the EU CTR involved many operational and regulatory challenges as requirements changed throughout the transition period. A successful transition required stakeholders to align expectations, share best practices, and jointly address emerging issues through close partnership and extensive dialogue.
This article provides insight into the transition experience for the industry, including commercial trial sponsors and contract research organizations. It elaborates on the challenges encountered during the transition journey and the ongoing efforts between industry, regulators, and legislators to optimize the evolving regulatory environment for clinical trials in the EU.
Transition from directive to regulation
The EU CTR defined the timeframe for transitioning trials in Article 98.1 However, the first practical guidance on the implementation of the EU CTR was not available until April 2018: four years after its initial publication.4 Additionally, only a small portion of the initial versions of this guidance addressed transitional arrangements.Although it was initially estimated that approximately 6,000 trials would need to be transitioned, CTIS received fewer than 100 transition applications in the first transition year,5 prompting regulators to release additional guidance. The Heads of Medicines Agencies’ Clinical Trial Facilitation Group and Clinical Trial Coordinating Group (CTCG), the Clinical Trial Advisory Group, and the European Commission began publishing guidance and Q&A documents in 2018, increasing the frequency of new documents and versions as time went on during the three-year transition period.6-8 Figure 2 shows that the CTCG, European Commission, and European Medicines Agency (EMA) published 19 regulatory guidance and best practice documents from April 2018 to July 2024. During the transition to the EU CTR, industry representatives held six meetings in response to the submission of the same number of industry position papers.
Figure 2. Transition from the EU CTD to the EU CTR1,4,6,8,9
CTCG, Clinical Trials Coordination Group, EU Comm, European Commission; EFPIA, European Federation of Pharmaceutical Industries and Associations.
*This document has been superseded by a newer version.
Created by Houtzager et al
Regular analysis of these guidance documents by clinical trial sponsors, contract research organizations and trade associations – together with sponsors’ experiences during the transition of clinical trials – indicated various operational challenges regarding compliance with the transition application requirements. These challenges became the subject of regular discussions and frequent correspondence between trade associations, regulators, and legislators, resulting in the regulators agreeing on new iterations of guidance documents that simplified administrative procedures while abiding by EU CTR legal requirements. Some of the most impactful challenges experienced by sponsors and applicants are described in this article.
Document harmonization and submission planning
One key challenge of the EU CTD that the EU CTR aimed to address was the diversity of requirements and assessment outcomes in multinational trials. Under the EU CTD, many countries had different requirements, which led to the creation and approval of numerous member-state-specific protocols, investigator’s brochures, and investigational medicinal product dossiers for a trial. For these studies to transition to the EU CTR, country-specific documents had to be harmonized or consolidated into a single version, and the regulatory agencies and ethics committees of all member states involved had to approve any substantial changes.
An additional complexity lay in the requirement that clinical trials with ongoing assessments in any member state were ineligible for transition.6 Identifying the silent period necessary to transition, around four months, posed a particular challenge for multinational clinical trials with multiple investigative medicinal products and amendments. This requirement often posed difficult decisions about whether to submit or hold planned or urgent amendments before the transition or to withdraw ongoing amendments to enable timely transitions, which would introduce uncertainties regarding approval timelines and the ability to continue the study.
Overall, seemingly straightforward requirements in the transition guidance8 resulted in operationally challenging situations. These situations involved reorganizing and rescheduling the required submissions and delays in implementing amendments, which resulted in setbacks of up to several months in transition applications.
Discussions with the CTCG revealed that EU regulatory agencies recognized these challenges. During the second year of the transition period, sponsor guidance evolved to introduce several simplifications to document harmonization and consolidation, reducing the number of activities required before the transition. This simplified the transition process and reduced the number of documents necessary, further evidencing the importance of the close interactions between sponsors and regulatory agencies through this period.
CTIS platform operation
The introduction of the CTIS platform enabled centralized clinical trial applications in the EU for the first time. However, functionality issues created a very challenging environment for transitions. CTIS issues featured significantly in the EMA’s annual surveys on the EU CTR, with more than 50% of respondents to the agency’s 2024 survey citing issues.9 Adopting the CTIS system required considerable investments for sponsor companies, and users had to continuously adapt and learn as the system evolved with new iterations and functionality fixes. In addition, the CTIS system was not set up to meet the requirements for the transition procedure. Therefore, the EMA needed to develop workarounds in the system in order to comply with the database's technicalities and allow sponsors to fulfill the requirements for the transitions.
Sponsors' efforts to overcome this steep learning curve were supported by an extensive training library, regular communications, and forums hosted by the EMA.
Transparency and guidance updates
One of the cornerstones of the EU CTR is increased transparency of trial activities in the EU. Under the EU CTR, trial information and the release of clinical trial documentation are mandated. The regulation was intended to provide open access to scientific documentation to help treating physicians and patients make informed decisions, fostering trust in innovation and medical research in the EU.
The European Commission has established mechanisms that allow sponsors to protect personal and confidential company information. The first transparency guidance10 issued described the transparency rules in the CTIS database. Over the next seven years, guidance on the disclosure rules evolved. It became apparent that a change to the publication requirements was necessary, and in October 2023, the EMA issued revised transparency rules.11
The revision of the transparency rules changed the mechanism for protecting confidential commercial information in submission documents. It also reduced the number of records to be made public, focusing on those most relevant for physicians and patients.11 Overall, the revised rules were welcomed, as they reduced the administrative effort associated with protecting sponsors' sensitive information and increased immediate transparency to the public. However, the timing of the release of the different transparency guidelines introduced further complexity and uncertainty for those planning the transition of trials, as the CTIS was not updated until several months after the revised rules were released. This required sponsors to implement temporary solutions to be corrected once the CTIS update was made available.
The modified transparency procedures were implemented in June 2024, only seven months before the end of the three-year transition period. The corresponding Q&A document was released in December 2024, providing long-awaited simplifications and clarity for sponsors.12
Timelines of acceptance of the transition dossier
Recognizing the complexity of the transition process, which contributed to a delay in sponsor companies transitioning clinical trials, the EMA and CTCG regularly interacted with stakeholders to devise solutions that would retain rigor and appropriate oversight of clinical trial conduct while facilitating the transition of all trials to the EU CTR.
This led to an evolving CTR guidance, with major updates to simplify the transition process and finally, in July 2023, to an expedited approval process and the introduction of a minimal dossier containing the protocol, the investigator’s brochure, investigative medicinal products dossier, relevant good manufacturing practice documents, subject information sheets, and the informed consent form. 8 In parallel, the European Commission guidance was updated to clarify that alignment of the required documents listed in Annex I of the CTR was not required before the 31 January 2025 deadline if the minimal dossier had been authorized prior to that date.6 The industry welcomed this change as an important facilitation of the transition of trials into EU-CTR, not compromising quality or compliance.
While the expedited procedure aimed to shorten timelines, its impact on timelines for authorization of transition applications was limited because of the variability in implementation by the member states. The intended 22-day timeline was rarely met, with some cases of unnecessary additional requests for information and conditional approvals causing delays. The average timeline was around 40-45 days, with some member states taking more than 80 days to approve applications. These varying timelines significantly undermined the predictability of the EU regulatory environment, particularly for multinational clinical trials. Prolonged transition procedures often delayed follow-up submissions (e.g., updated reference safety information, updated investigational medicinal product dossier to ensure supply for the clinical trial), which affected trials in the EU, as the pending approval from one member state could prevent subsequent submissions in CTIS, owing to the functional limitations of the database and EU CTR requirements.
Analysis and discussion
The transitional period from the EU CTD to the EU CTR was marked by regulatory, organizational, administrative, and strategic complexity that could only be navigated through intense dialogue with regulatory agencies, ethics committees, and other stakeholders.The evolution of the transitional guidance, including increased flexibility, simplification of the document requirements, introduction of expedited procedures, and revised transparency rules, enabled the significant rise in transition applications in the latter half of 2024, according to metrics from the EMA (Figure 313). More than 40% of transition applications were submitted in the final three months before the October 2024 submission deadline.13
Figure 3. Number of applications submitted during the EU CTD to CTR transition (February 2022 to October 2024)13
Created by Houtzager et al
Without evolution in the guidance, the influx of last-minute submissions would not have been possible, and many trials would have failed to complete the transition, potentially denying patients access to innovative new treatments. Despite challenges in implementing EU-level guidance, the proactive engagement of the EMA and CTCG with industry partners was crucial to enabling this increase, as all parties recognized the importance of working collaboratively to drive the EU CTR transitional period to a positive conclusion.
The transition journey has been lengthy and complex, with sponsor companies working to transition their ongoing trials to comply with EU CTR amid a rapidly evolving regulatory landscape. It is noteworthy that larger pharmaceutical companies, with significant investments in resources and funding, have successfully transitioned their trials within the mandated timeframe. However, it is crucial to acknowledge the challenges faced by start-ups, small and medium-sized enterprises, and academic and non-commercial sponsors, which, because of a lack of dedicated resources, found it difficult to fully implement the new regulation, monitor the evolving guidelines, and adhere to the changing requirements. Importantly, smaller organizations and academic institutions may have also found it more difficult to engage with regulatory agencies, as many interactions were mediated by industry bodies that smaller organizations may not belong to. Reaching all stakeholders is likely to remain a challenge. Still, within the Accelerating Clinical Trials in the EU initiative, the European Commission and EMA are dedicated to supporting noncommercial clinical trial sponsors as effectively as possible,14 ensuring that no organization is left behind.
Consequently, the ongoing dialogue between the CTCG, the EMA, the European Commission, industry trade associations, and other key stakeholders continues to be vital to further optimize implementation of the EU CTR and the use of CTIS.
Continued simplification and a pragmatic approach toward a harmonized regulation are necessary, as many EU CTR challenges have not yet been resolved. Some examples of these challenges include long, substantial modification assessment periods that delay the implementation of critical changes in trials with no options to submit another substantial modification in parallel, member states continuing to request additional documentation based on national requirements that are outside the scope of the EU CTR, and the administrative burden of a complex, bureaucratic, and slow regulatory system.
In contrast, it must also be acknowledged that the EU CTR has facilitated public access to clinical trial information via the EU Public Portal created by the EMA.15 In contrast to the previous EU Clinical Trials Register,16 the new Public Portal provides additional information and places clinical trial documents at the fingertips of patients and researchers. The recently released EU Trials Map17 represents a significant further enhancement in public access to information about ongoing clinical trials in the EU.
Against the backdrop of these significant changes, the implementation of the EU CTR has not yet resulted in an increase in clinical trials in the EU based on comparison of data in the EU Clinical Trials Register16 and recent EMA metrics.13 Reflecting on the importance of promoting the EU as a location for clinical trials, the EU Commission, EMA, and member state regulatory agencies launched the Accelerating Clinical Trials in the EU (ACT EU) initiative in January 2022.18 The effective implementation of EU CTR is a critical pillar of the ACT EU initiative, and the EU remains on its journey toward attracting clinical research and drug development by simplifying and accelerating the application and approval process and enhancing the spirit of harmonization. These efforts to create an increasingly attractive clinical research environment are recognized and fully supported by industry stakeholders.
While the commission study on the implementation of the EU CTR and its impact on European clinical research is awaited, the guidance can continue to evolve, adopting pragmatic immediate solutions to eventually create a regulatory framework that benefits all stakeholders, patients, regulators, and trial sponsors, reestablishing the EU as the prime destination for clinical research.19
Conclusion
The story of the EU CTR transitional period stands as testament to what can be achieved through effective collaboration, leading to pragmatic and proportionate implementation of regulations. It serves as a reminder that a collective pan-European mindset is needed for early adoption and resourcing at the member state level. Technologically enabled solutions will also be needed to meet the European legislation's ambition to improve the whole European ecosystem, addressing the patients’ needs for innovative treatment solutions. The lessons learned could be applied in the implementation of new EU regulations in the future. Stakeholders from across the industry will need to readily embrace related endeavors and remain available for ongoing dialogue whenever future opportunities arise.Abbreviations
About the authors
Siard Houtzager, PhD, is associate director of the EMEA regulatory policy team at Johnson & Johnson and has more than 20 years of experience in regulatory clinical trial management. Since 2021, he has served as director of the regulatory clinical trial submission team for the implementation of the EU CTR at Johnson & Johnson. Currently, as a regulatory policy lead, he cochairs the EFPIA CTR team, where he focuses on driving policy changes to enhance the clinical trial environment in Europe. He holds a doctorate in molecular neuroscience from the Vrije Universiteit of Amsterdam. He can be reached at [email protected]
Chris Bamford, PhD, is director of clinical trial regulatory management at IQVIA. He has worked in regulatory affairs relating to clinical trials for 20 years. As a director in the IQVIA clinical trial regulatory management team, he has represented the team in EMA stakeholder groups focused on the implementation of the EU CTR and the development of the EU CTIS since 2014. He advises IQVIA’s clients on the regulatory requirements relating to the management of clinical trials. Bamford has a doctorate in molecular oncology from the University of Aberdeen, Scotland. He can be reached at [email protected]
Wisniewska Malgorzata, MSc, is associate director and senior international clinical trial regulatory lead at Takeda, based in Glattpark-Opfikon, Switzerland. With more than 20 years of regulatory experience including CMC, MAA, and LCM, she currently specializes in EU CTR, CTA strategy, and international regulatory submissions. She holds an MSc in ergonomics and quality management from the Poznań University of Technology and postgraduate diplomas in clinical trials methodology and project management from Warsaw Medical University and Gdańsk University of Technology. Malgorzata is A RAPS member and contributor to the EFPIA CTR Pillar. She can be reached at [email protected]
Katharina Ondreka, Dipl Biol, is a senior manager of global regulatory affairs at Otsuka Pharma. With more than 10 years of experience, Ondreka specializes in clinical trial regulatory affairs. She holds a diploma in biology from Goethe University in Frankfurt, Germany, and has extensive expertise in the European Union and other regions globally. She can be reached at [email protected]
Martin O’Kane BSc, PhD, is regional head of policy and liaison for Europe at Novartis Pharmaceuticals. He has more than 20 years regulatory experience, including 17 years working for the UK Medicines and Healthcare Products Regulatory Agency, the majority of which was in the clinical trials field, including scientific assessment of trial applications and development of policy, guidance, and legislation relevant to the UK’s exit from the EU and the UK response to COVID-19. He holds a degree in pharmacy from the University of Aston, UK, and a PhD in neuropharmacology from the University of Glasgow, UK. O’Kane is a member of RAPS. He can be reached at [email protected]
Juliet Spunner, BSc Hons, is EU early assets and CTA regulatory lead at Bayer. Spunner is an experienced regulatory affairs professional with more than 35 years’ experience in the UK and EU product development as a team lead, focusing on the therapeutic areas of ophthalmology, CV therapy areas, and clinical trials. Spunner is an EU CTR subject matter expert and led a cross-functional transition task force for Bayer. She is Bayer’s representative on EFPIA CREG and associated sub-teams. Spunner holds a BSc Hons in biochemistry and pharmacology from the University of Southampton. She can be reached at [email protected]
Claudio Lorck, PhD, began his professional journey in 1989 in pharmaceutical development, focusing on formulation development and production transfer. In 1994, he became QC manager, overseeing the QC laboratories. In 2001, he transitioned to an R&D group formulating NCEs and manufacturing IMPs for clinical trials, managing QC and CMO, and acting as QP. In 2005, he served as head of clinical trial materials and QP, supplying R&D clinical trials. Lorck joined AbbVie Deutschland in July 2014 and led the EU QP team in R&D QA. In December 2018, he became associate director in regulatory policy and intelligence at AbbVie, until he retired in April 2025. He can be reached at [email protected]
Muyibat Olaleye, MSc, is an associate director of global submissions management-clinical trials at Bristol Myers Squibb (BMS). With a decade of experience, Olaleye is experienced in clinical trial regulatory strategy and submissions, including interactions with regulatory agencies across multiple regions and regulatory intelligence monitoring for clinical trials. Recently, Olaleye led the implementation of the EU CTR at BMS, steering cross-functional teams through the complex regulatory framework changes to ensure compliance and operational readiness. She earned an MSc in pharmaceutical sciences from the University of Greenwich. Olaleye can be contacted at [email protected]
Valentina Geisseler-Homann, is senior regulatory clinical trial lead at F. Hoffmann-La Roche, Basel, and has more than 15 years of experience in regulatory and clinical trial development. She led CTR process development and implementation at Roche. As global CTA process owner, Geisseler-Homann oversees the global end-to-end CTA process, ensuring compliance and driving change within the CTA landscape. She collaborates with peer companies and stakeholders within the EFPIA CTR pillar to shape the regulatory environment and enable the delivery of new medicines to patients. She can be reached at [email protected]
Disclaimer The perspectives provided in this paper are drawn from the experiences of commercial sponsors and CROs involved in clinical trials within the EU. While every effort has been made to present a balanced overview, the paper reflects the collective viewpoint of industry stakeholders engaged in the operationalization of the EU CTR.
Citation Houtzager SWJ, et al. Navigating the transition: Implementing the new EU CTR in the pharmaceutical industry. Regulatory Focus. Published online 30 July 2025. https://www.raps.org/News-and-Articles/News-Articles/2025/7/Navigating-the-transition-Implementing-the-new-EU
References
All references were last checked and verified on 30 July 2025.
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