EU Clinical Trial Regulation 536/2014: Real-World Learnings, Best Practices For Successful Document Submissions In An Evolving System

Contributed Commentary by Chris Bamford, IQVIA and Shirley Rutter, IQVIA Biotech  

November 10, 2023 | The European Union Clinical Trial Regulation 536/2014 went live on January 31, 2022, with the purpose of harmonizing clinical trial document submission processes within the European Union member states and improving transparency to the public. Since then, trial sponsors and clinical research organization partners have collected real-world experience with the CTR and its Clinical Trial Information System (CTIS) registration portal. In closely monitoring the CTR—from design through current use—there are notable differences, learnings, and best practices in navigating the system as it evolves in real-time.  

Ideally, the system aims to streamline the application submission and routing process to accelerate drug development in the EU. However, the slightest error in the unified submission process can have significant consequences in time, cost, and resources for trials. Since launch, approximately 27% of trial applications submitted into the CTIS portal have been either withdrawn, non-validated, lapsed or rejected as of June 2023. Also, the EMA has publicly noted how the portal is one of the “most complex and ambitious IT developments carried out” by the organization, leaving room for technical unknowns and malfunctions that sponsors need to consider.  

Current EU CTR System: Potential Roadblocks  

Like anything new, end users will have questions and concerns about steps in the submissions process within the revised CTR. Leveraging tangible takeaways from the successful application submissions for multiple Phase 2 and 3 studies in 24 EU/EEA countries into the new system to date, there are intricacies for sponsors to be aware of, including the below.  

Country-By-Country Variations 

In potentially working with up to 27 EU member countries and three European Economic Area countries, it is possible to receive different feedback to questions per country regulators when submitting documents into CTIS. Though sponsors and CROs should closely follow the EU CTR Q&A guidance that all member countries have agreed to, individual responses to specific questions regarding submissions can still vary. As countries are still adapting to the revised CTR themselves, sponsors and CROs will need to plan for potential inconsistencies in direction and how to best address them. For example, authorities in some countries have deviated from EU-level guidance to either authorize or reject applications, with other EU countries taking a different position. This makes it difficult for sponsors to anticipate what an assessment outcome may be, especially as approaches to harmonization continue evolving. 

Effective Document Uploading 

The CTIS represents a wholly-new approach to clinical trial applications, and the EMA has provided a wealth of training resources to help sponsors and CROs adapt to the new system. This presents a challenge, given the many months of training and process adaptation necessary for users. Also, the EMA, regulatory authorities and sponsors have all faced challenges with the technical effectiveness and stability of CTIS, such as activities performed in other time zones not reflecting appropriately in CTIS.   

Staying Prepared And Agile  

Though the EMA is working tirelessly to resolve the above issues and progress has been made, sponsors need to continue anticipating challenges and unknowns and have a clear strategy for mitigating the risk of impact (e.g., do not leave activities that involve CTIS to the last minute). As this CTR system will continue to change and may have technical glitches and inconsistencies to overcome, staying prepared with a comprehensive strategy for effective CTR submissions that includes the following components will be key.  

Open Lines Of Communication  

Outlining a clear communication plan, involving study start-up managers and regulatory experts from an experienced CRO partner, will help sponsors understand how best to lay out solutions for an optimized submissions process for their specific trial, optimizing start-up time. Regular discussions can help sponsors better understand the regulation and potential challenges to keep in mind and prepare proactively.   

One way study start-up managers play a critical role in submissions success is working closely with local country-specific study start-up specialists to secure ground level insights into local regulatory requirements and nuances to consider during planning stages. This has always been important, but at a time of regulatory changes and related expectations, it is even more critical that country-level experts are available to help prepare submission documents and content per country templates, including the preferred language and formats.  

Like all else in drug development, maintaining open dialogue with the EMA and country-specific regulatory agencies to ensure compliance per guidance provided is critical to resolve issues at the individual study level and keep submissions on track. An initial first step is for sponsors and CROs to familiarize themselves with the EMA Service desk, who can help with technical issues in CTIS if they arise. As an example, the first 35 clinical trial applications our teams submitted for sponsor partners required support from the Service desk.    

Request For Information Plan Of Action  

Through the CTR, the EMA has set a standard review time for submitted applications to improve approval timelines across EU member states and hopefully speed up study start-up timing. Within this review time, sponsors receiving a “Request for Information” from regulators need to plan to respond within 12 calendar days of receiving the question(s) to avoid re-starting the application process.  

Sponsors will need a well-coordinated plan in place to provide an adequate response within this short timeframe. During planning stages, based on the individual study, CRO partners can help map out a timetable of assigned responsibilities and roles for each day after receiving a question. Staying ready with this strategic scenario planning option in case a need arises helps all stakeholders involved—sponsors, CROs and study teams—stay on the same page, knowing what to expect within those 12 days and what their specific action items are within the process. A harmonized approach to the issuance of questions also enables organizations to gather intelligence on the types of questions that may be expected, further facilitating a sponsor’s ability to respond swiftly.  

Knowledge Sharing  

Given the evolving nature of a live system, equipping internal teams integral to CTR submission plans and processes with updated resources and knowledge is one of the keys to success.  

For one, as the new regulation has such broad implications, it requires broad awareness within organizations. A designated internal lead can help manage an easy-to-access database of collective learnings and insights from study submissions and share relevant information (tips, best practices, lessons learned, frequently asked questions, etc.) via internal discussion forums and newsletters to keep those working on submissions informed and updated.  

The plan can also account for dedicated and regular monitoring of both industry news regarding CTR submissions and EMA responses to specific questions from other companies and stakeholders to include in the database. 

Keeping teams informed on the latest and greatest in redaction guidance, common issues experienced in submissions, EMA-specific updates, how to communicate updates to sponsors, transition related challenges and queries, etc. through ongoing training sessions improves the overall operational process. Engaging team members also provides a chance to understand where they have questions and may need additional support or details.  

Growing Base Of Knowledge For Future Submissions 

In less than two years since CTR went live for use, industry stakeholders are learning daily what the EMA and EU member states are looking for and needing to streamline submission packages and increase information transparency for patients. Sponsors and CROs must account for variables in feedback, direction and needs, from the EMA and EU Commission to EU member states, and for potential technical issues with the portal process. However, through firsthand experience, we know it is possible to successfully and efficiently submit study applications abiding by the CTR and receive regulatory authorization accordingly despite an evolving live system. Underpinning strategic planning with key experts, such as study start-up managers and regulatory leads, staying equipped with updated CTR information (e.g., process requests and changes) and knowing how to effectively respond to EMA or country requests for information in a tight timeframe can make a world of difference.  

As fine-tuning of CTR continues by the EMA and participating countries, building upon the foundation of knowledge regarding potential challenges and tangible pathways to resolution will help sponsors successfully submit study applications and ultimately, optimize trial timelines for patients in the EU area. All in the industry can aim to stay in the know as more updates and changes are inevitable.  

Chris Bamford, Director, Clinical Trials Regulatory, Clinical Trial Regulatory Management, IQVIA, has represented the IQVIA Regulatory Affairs team in EMA stakeholder groups regarding the development of the EU CTIS since 2014, contributing from the perspective of both sponsors and CROs, on behalf of the Association of CROs. This has enabled IQVIA to support pharmaceutical companies in developing processes and adapting roles and responsibilities related to the new Regulation, including incorporation of newly-required aspects (e.g., redaction) and an understanding of the CTIS user management framework. To date, IQVIA has submitted more than 70 new clinical trial applications via the CTIS, allowing the team to gain an in-depth knowledge of how the system is intended to operate and how to navigate the ‘growing pains’ of the system in its earlier phases. Chris can be reached at


Shirley Rutter, Associate Director, Strategic Quality Lead, Global Quality Management, IQVIA Biotech, has 24 years’ experience in the pharmaceutical industry, managing global projects across all phases of clinical development. She is responsible for leading strategic initiatives, such as EU CTR implementation, process improvement, strategic communication, change management, establishing Quality Management Systems and preparing for various regulatory inspections. Her experience spans clinical operations, study start-up, project management, Quality Assurance, Quality Management and training. Shirley is an ISO9001-Certified Lead Auditor.