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Understanding and Navigating Changes to EU Clinical Trial Regulations – Guidance from THREAD

Cassidi Williams

A major change to clinical trial regulations (CTR) in the European Union (EU) will be implemented in early 2022. A significant regulatory revision will go into effect as the Clinical Trial Regulation (CTR) No. 536/2014 EU will become the new standard by which clinical trials in the EU must be conducted. While this change is designed to simplify the clinical trial process and make drug development more efficient, it also creates questions for sponsors on how best to move forward. Following are some insights into the new regulation and guidance for navigating the evolved regulatory landscape.

Purpose of the Clinical Trial Regulation

Under the current Clinical Trial Directive (CTD)2001/20/EC, the setting up and conducting of clinical trials in Europe remains challenging with regard to timelines, costs, and the workloads involved in application and management. With the European Economic Area (EEA) consisting of 30 member states, the current clinical trial application process involves sponsor companies having to complete individual applications to each member state’s regulatory authority, with a separate application for ethical approval, all with the requirement of multilingual documentation for the same study. This high burden has resulted in the number of applications for authorization to clinical trials in the EU decreasing by 25% between 2007 and 2011.1 It has also driven the cost of conducting trials up and increased the average waiting time for clinical trials by 90% (152 days)2. In 2012 the European Commission developed a proposal to change the legal framework by introducing a new Clinical Trial Regulation (CTR) to address the challenges and this change is now ready for implementation in 2022. Unlike the CTD, the CTR will be binding in its entirety and will be directly applicable in all EU/EEA Member States: the 27 EU countries and Iceland, Liechtenstein, and Norway.

The new CTR will help ensure better harmonization in the submission, assessment, and supervision processes for clinical trials with the implementation of consistent rules throughout the EU while maintaining the highest standard of safety for participants. Another key objective of the CTR is to strengthen requirements for clinical trial data transparency by making study outcome reporting compulsory. The hope is that these changes will make Europe a much more attractive landscape for sponsors and contract research organizations (CROs) seeking to develop new medicines.

How Will It Work?

To facilitate the adoption of the new CTR, a new Clinical Trial information System (CTIS) will go live at the end of January 2022 and will offer a 3-year transition period from launch as submissions migrate to the new system. The system will allow for a single application submission in all member states where the study will be conducted and a joint assessment by all National Authorities, guided by a Member State who will act as Rapporteur. The application dossier will be divided into two parts. Part one forms the basis for approval to run a study in the EEA and deals with the scientific elements of the clinical trial, including protocol review, risk-benefit analysis, and compliance with technical requirements. Part two deals with intrinsically national aspects, such as informed consent and the compensation of subjects, which are assessed by each state's ethical committee separately. Parts one and two can be evaluated in separate phases. The CTIS will offer searchable clinical trial information to the patient, the healthcare professional, and the general public. Clinical trial results will be available both as a technical summary and in lay language.

Benefits of the New CTR and CTIS

Effective implementation of the new CTR should reduce the burden of work associated with clinical trial submissions. The CTIS portal will provide a single-entry point for applications. This includes:

  • A single set of documents
  • Single fee
  • Single authorization with strict timelines
  • Single reports
  • A singular source to receive a decision on the application

Similarly, the ongoing management of study modifications and safety assessments will benefit from a single touchpoint.

Are You ready? Recommendations for Compliance

Big changes and a lot of work will be required to meet the new CTR, including adapting to new processes, systems, and timelines. To avoid complications with implementation, it is important that sponsors do not wait until the last minute. The following are crucial elements that sponsors and CROs should consider:

EU legal representation

Sponsor companies who are not based in Europe will be required under the CTR to appoint a representative within the EU to act on their behalf as a legal representative to ensure compliance with obligations to the CTR.

Access to CTIS

Gaining access to the secured CTIS workspace is fundamental to preparation for use and is now feasible by registering for an EMA account, registering the sponsor organization within the CTIS, and registering and assigning core personas, roles, and tasks within the system.

Training is Key

Sponsors will need to identify core users of the CTIS and ensure they receive access to the new technology platform. They can then target training to individual users and define how they envision these users working within the CTIS. Companies will need to define “who will do what” in their organization and tailor training needs to cover the specific tasks that users will perform. Comprehensive training is available on the EMA website.


Serious thought should be given to system management needs and sponsors need to understand the resource requirements to manage these needs. Some examples of common system management needs include:

  • Managing the requirements of the highly-structured application process, overall
  • Daily monitoring of requests for information (RFI’s)
  • Safety monitoring
  • Managing rigorous timelines associated with all of these needs

Understanding Transition Period Timelines

It is vital that Sponsors review their current clinical trial portfolios and identify any trials they plan to submit under the new regulation before the transition period expires.

Before January 2022

All clinical trial applications already submitted, or active studies are governed under the current CTD.

Year One Transition Period (From January 2022 to January 2023

Clinical trial applications can be submitted under the existing CTD or under the new CTR via the CTIS. Any ongoing clinical trials can remain governed by the CTD or may be switched to the CTR at any time until the end of the three-year transition period. For trials that are expected to continue beyond 31 January 2025, sponsors will need to transition to the CTR before the transition period expires. This will necessitate the consolidation of existing clinical trials conducted across multiple member states into the new CTIS. Sponsors must ensure completion of the process early enough in the transition period to ensure continuity of the clinical trial beyond 31 January 2025.

Year Two-Through-Three Transition Period (February 2023 to January 2025)

All new clinical trial applications will need to be submitted via the CTIS and will be governed by the CTR. All ongoing clinical trials can remain governed by the CTD or may be switched to the CTR at any time until the end of the three-year transition period. This will apply to trials continuing past January 2025. 

Post Transition Period- After January 2025

All clinical trials will be governed by the CTR irrespective of the date of initial submission.

Recommendations for a Successful Regulatory Transition

Adapting Processes to Meet Stringent Timelines

Under the CTR, sponsors will need to coordinate initial applications—and all modifications—closely. Missed timelines may result in legal consequences for sponsors, such as lapsed applications. Sponsors will need a strategic plan for management and oversight around the timing of all application materials.

Understanding the Application and Approval Process

The application process and assessment are divided into two parts: part one addressing the scientific and medicinal product documentation and part two addressing the patient level documentation. Part one will require assessment by each member state concerned, a reporting member state, and all relevant ethics committees. Part two will require assessment only by the relevant national/local ethics committee(s). Both parts one and two can be submitted and assessed in parallel. The sponsor can also submit only part one initially and then submit part two within two years of part one approval. If the sponsor does not submit part two for any of the MSCs within two years, the trial in the member state will lapse. The process will require strict timelines for the sponsor to adhere to. See Table 1.

Table 1

Focus on First-Time Quality

Under the CTR, an applicant’s success depends on the first-time quality of the dossier to a greater extent than ever before. An applicant will not pass the validation phase in any member state committee (MSC) unless it receives clearance to proceed in all MSCs. The initial application authorization procedure and any substantial modification applications must be completed before additional MSCs can be involved. This greater interdependency amongst MSCs in the trial demands that sponsors get applications right the first time.

Develop a Transparency Culture

Sponsor companies need to assess the transparency requirements of the CTR and work with all necessary stakeholders (e.g., data protection officers, experts in data de-identification, etc.) to ensure all personal and commercially confidential data in the CTIS are protected. Establishing disclosure/transparency policies and procedures will be key, as will incorporating disclosure strategies into the clinical development plan and all clinical trial activities.

For additional information on how THREAD can help you optimize your clinical trials, visit THREADResearch.com.

Caroline Kelly

Senior Manager, Consulting, THREAD

Caroline brings extensive knowledge and experience in clinical research study design and conduct having worked in the field for the past 24 years. She is a qualified Nurse with a Post Graduate diploma and master's degree in Health Science with most of her career working at site level in Clinical Research.