Clinical Trials Regulation (CTR) 536/2014: What Changed and Why It Matters

The transition from the longstanding Clinical Trials Directive (2001/20/EC) to the Clinical Trials Regulation (EU) No 536/2014 (CTR) represents the most significant procedural and governance shift in European clinical research in a generation. For sponsors, investigators, and site staff, this is not merely a change in paperwork; it is a fundamental redesign of how trials are authorised, supervised, and reported across the European Union. The Regulation became directly applicable on 31 January 2022, and since that date, all new clinical trial applications must be submitted via the Clinical Trials Information System (CTIS). While the Directive allowed divergent national processes and variable transparency standards, the Regulation establishes a harmonised framework with common criteria for assessment, binding timelines, and a default posture of transparency. This article explains, in practical terms, how the system now operates, what has changed for sponsors and investigators, and how compliance is evidenced in the new environment.

From Directive to Regulation: The Systemic Shift

The Clinical Trials Regulation replaces a patchwork of national implementations of the Directive that produced inconsistencies in submission formats, ethics review processes, and timelines. The Regulation is directly applicable, meaning it binds Member States without the need for national transposition, although it does permit limited national specifications where the Regulation explicitly allows. The central mechanism of change is the creation of CTIS, a single entry point for the submission, assessment, and supervision of clinical trials across the EU/EEA. Through CTIS, sponsors interact with a single set of digital workflows that coordinate the Competent Authorities (CAs) and Ethics Committees (ECs) in all Member States concerned.

Under the CTR, the assessment is divided into two parts: Part I (scientific/ethical assessment at the level of the Trial) and Part II (national and site-specific aspects). This structure replaces the previous dual national submissions and enables a harmonised evaluation while preserving the role of national authorities and ethics committees for local considerations. The Regulation also introduces binding timelines for assessment, with clock stops for questions, and a default transparency rule that makes trial-related information publicly accessible unless justified otherwise.

Scope and Applicability

The CTR applies to clinical trials conducted in the EU/EEA involving investigational medicinal products (IMPs), including advanced therapy medicinal products (ATMPs). It sets out harmonised rules for the conduct of trials, including the requirements for the Investigational Medicinal Product Dossier (IMPD) and the Investigator’s Brochure (IB), as well as the content of the application dossier. The Regulation also establishes rules on the composition of the Ethics Committee and the coordination of assessments across Member States.

Importantly, the CTR applies to all new trials from 31 January 2022. Ongoing trials approved under the Directive benefit from a transitional period and must transition to the CTR and CTIS by 30 January 2025. After that date, all trials, including those approved under the Directive, must be managed via CTIS under the CTR framework. This transition is not a mere administrative step; it requires sponsors to reorganise documentation, update procedures, and ensure that the trial data in CTIS reflects the current trial status.

Key Changes at a Glance

• Single entry point: CTIS replaces national portals for CTR-regulated trials.
• Two-part assessment: Part I (Trial level) and Part II (National/site-specific).
• Binding timelines: Default 45-day Part I assessment with clock stops for questions; 45-day Part II assessment.
• Transparency by default: Trial-related information is public unless an exemption applies.
• Harmonised dossier: Common structure for IMPD/IB and application content.
• Coordinated supervision: Reporting of safety data and protocol amendments centralised and harmonised.

CTIS: The Authorisation Hub

CTIS is the operational heart of the CTR. It is a secure, web-based system managed by the European Medicines Agency (EMA) in collaboration with Member States. Sponsors create a user account, prepare a dossier, and submit an application for one or more Member States. The system then distributes the dossier to the relevant CAs and ECs and coordinates the assessment process.

For sponsors, CTIS introduces a new workflow and a new vocabulary. The “Member State Concerned” (MSC) is any Member State where the trial is intended to be conducted. The “Reporting Member State” (RMS) is the Member State that leads the Part I assessment for a given investigational medicinal product. In multi-product trials, there may be multiple RMSs. The “Coordinating Member State” (CMS) coordinates the Part II assessment across MSCs. The system enforces synchronised timelines and provides a single place to respond to questions, upload revised documents, and record decisions.

Part I and Part II: How Assessment Works

Part I: Scientific and Ethical Assessment at Trial Level

Part I assesses the trial as a whole, focusing on scientific validity, ethical acceptability, and the suitability of the investigational medicinal product. The RMS leads this assessment, consulting other MSCs. The initial assessment must be completed within 45 days from the date of validation of the application. If the RMS raises questions, the clock stops until the sponsor responds, and the 45-day assessment period resumes upon receipt of a complete response. The outcome is a single decision for all MSCs: either a favourable opinion or a refusal.

Practical point: The 45-day timeline is binding but not guaranteed if the dossier is incomplete. Sponsors should anticipate iterative questions and ensure that the Part I documentation (e.g., protocol, IB, IMPD, patient information and informed consent) is robust before submission.

Part II: National and Site-Specific Assessment

Part II addresses national and site-specific considerations, such as local ethics, compensation rules, data protection, and site suitability. Each MSC conducts its Part II assessment within 45 days from the date of the Part I decision. The CMS coordinates this process. Again, clock stops apply for questions. The outcome is a national decision per MSC, which may be favourable or unfavourable. The trial can only start once both Part I and Part II are approved in all MSCs.

Submission and Validation

CTIS validates submissions for completeness against a checklist. If the dossier is incomplete, the application is flagged, and the clock does not start. Sponsors should ensure that all required modules are complete, including the investigational medicinal product details, labelling information, and the patient information leaflet. The system allows for modular updates: for example, a substantial amendment to the protocol may be submitted as a modification, which triggers a coordinated assessment process.

Roles and Responsibilities: Sponsors and Investigators

The Regulation clarifies and harmonises the responsibilities of sponsors and investigators. The sponsor is the person or entity who takes responsibility for the initiation, management, and financing of the clinical trial. The investigator is the medical professional responsible for the conduct of the trial at a site. The relationship is contractual, and the Regulation requires that the investigator be able to guarantee the rights, safety, and well-being of subjects.

Sponsor Obligations

Sponsors must ensure that the trial is scientifically sound, based on adequate data, and that the risk-benefit profile is acceptable. They must prepare the IMPD and IB, ensure qualified staff and adequate facilities, and provide insurance or indemnity covering liability for damages. Sponsors must also establish a pharmacovigilance system for the trial, including the collection and reporting of safety data. Under the CTR, the reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs) is harmonised and submitted via the Eudravigilance database, with CTIS providing the coordination layer.

Protocol amendments must be assessed for impact. Substantial amendments require prior approval; non-substantial amendments may be recorded and reported. The determination of substantiality is guided by the Regulation and related guidance, and sponsors should document their rationale. In practice, many sponsors adopt a risk-based approach to change management, supported by standard operating procedures that define substantial vs non-substantial changes.

Investigator Obligations

Investigators must ensure that the trial is conducted in accordance with the protocol, Good Clinical Practice (GCP), and the CTR. They are responsible for the selection of subjects, obtaining informed consent, and ensuring proper documentation. Investigators must report adverse events and safety issues to the sponsor and, where required, to the CA/EC. They must also maintain trial master files (TMF) and allow inspections.

Importantly, the Regulation reinforces the right of the investigator to directly communicate with authorities and the Ethics Committee, ensuring that there is no undue influence from the sponsor. Investigators must be appropriately qualified and have access to necessary resources. The site must be suitable, and the investigator must confirm this in the application.

Contractual Clarity and Data Protection

Sponsors and investigators must have clear agreements covering roles, responsibilities, compensation, and data protection. Under the General Data Protection Regulation (GDPR), personal data processed in clinical trials must have a lawful basis, typically public interest (Article 9(2)(i) GDPR) supported by Member State law, and must be handled with appropriate technical and organisational measures. The CTR complements GDPR by mandating transparency while allowing exemptions for personal data where disclosure would compromise privacy. Sponsors should prepare privacy notices, data processing agreements, and ensure that CTIS submissions exclude personal data that should not be public.

Timelines and Clock Stops: Practical Implications

The introduction of binding timelines is one of the most significant improvements under the CTR. However, timelines are only as reliable as the completeness of the dossier. The 45-day Part I assessment period is paused when authorities pose questions, and it resumes only when the sponsor provides a complete response. Similarly, the 45-day Part II period is paused for questions and resumes upon complete response.

Sponsors should plan for iterative queries, especially in complex trials (e.g., ATMPs, first-in-human studies, or trials with multiple IMPs). A practical strategy is to pre-emptively address common questions: provide clear justification for dosing, robust risk assessments for manufacturing and supply chain, and detailed statistical analysis plans. Early engagement with national authorities through available scientific advice mechanisms can also help, although the CTR does not provide a formal pre-submission meeting process at the EU level.

Timeline tip: Build internal review buffers. Even if the regulatory clock runs 45 days, internal sponsor review of questions and compilation of responses can add days. Ensure that subject matter experts (clinical, nonclinical, CMC, statistics) are on standby during the assessment period.

Transparency and Public Access

Transparency is a foundational principle of the CTR. CTIS publishes trial-related information, including the trial title, sponsor, investigational medicinal products, therapeutic area, trial design, status, and key results. The aim is to increase public trust and avoid duplication of research. The default is publication; exemptions are limited and must be justified.

Sponsors may request confidentiality for certain information, such as commercially confidential information (CCI) or personal data. The Regulation and related guidance specify the types of information that can be redacted and the conditions under which confidentiality can be granted. For example, detailed manufacturing processes that reveal proprietary know-how may be redacted, but the summary of the IMPD and the risk-benefit assessment are typically public. Similarly, personal data must not be disclosed; CTIS workflows include checks to prevent inadvertent publication of sensitive information.

Transparency extends to results. Summary trial results must be submitted within one year of the end of the trial (or six months for pediatric trials), and they are made public unless an exemption applies. Plain language summaries are required for trials involving investigational medicinal products, making results accessible to laypersons. Sponsors should invest in high-quality summary writing that is accurate, understandable, and compliant.

Compliance Evidence: What Teams Must Keep

Compliance under the CTR is demonstrated through documentation and processes that show adherence to the Regulation and GCP. The Trial Master File (TMF) and Investigator Site File (ISF) remain central. CTIS does not replace the TMF; it complements it. The TMF must contain evidence of trial conduct, including approvals, correspondence, monitoring reports, and safety documentation.

Essential Documentation

• Protocol and amendments: Version-controlled, with rationale for changes and evidence of approval.
• IB and IMPD: Up-to-date, with cross-references to nonclinical and clinical data.
• Investigator information: CVs, GCP training records, site suitability evidence.
• Subject information and informed consent: Approved versions, with translation records where applicable.
• Contracts and agreements: Sponsor-investigator agreements, data processing agreements, insurance certificates.
• Safety reporting: SUSAR reports, safety management plans, DSUR (Development Safety Update Report) where applicable.
• Monitoring and audit reports: Evidence of quality control and assurance.
• CTIS correspondence: Copies of submissions, questions, responses, and decisions.

Data Integrity and Traceability

Teams must ensure that data captured in CTIS matches the TMF and the actual trial conduct. This includes maintaining audit trails for electronic systems, ensuring that changes to data are attributable, and that version control is consistent across documents. For electronic data capture (EDC), ensure that the system is validated and that user access controls are in place. For paper-based processes, ensure controlled documents and secure storage.

Quality Management

A robust quality management system (QMS) is essential. This includes standard operating procedures (SOPs) for trial management, safety reporting, change control, and CTIS workflows. Risk-based quality management should be applied to focus oversight on critical processes. Periodic internal audits and inspections by CAs verify compliance; sponsors should maintain audit readiness at all times.

Safety Reporting: Harmonised Pharmacovigilance

The CTR harmonises safety reporting across the EU. SUSARs are reported via the Eudravigilance system, and CTIS provides the coordination and visibility across Member States. Sponsors must have a pharmacovigilance system that meets the requirements of the Regulation and the Good Pharmacovigilance Practices (GVP). The DSUR remains a key periodic safety report for investigational products.

Practically, teams must ensure that their safety database is interoperable with Eudravigilance, that coding (e.g., MedDRA) is up to date, and that expedited reporting timelines are met. The CTR sets out specific timelines for reporting serious adverse reactions, and sponsors should have automated workflows to avoid missed deadlines. Safety signals should be assessed, and protocol amendments should be considered if new safety information changes the risk-benefit profile.

Advanced Therapies and Complex Trials

Advanced therapy medicinal products (ATMPs), gene therapies, cell therapies, and tissue-engineered products, often involve complex manufacturing and supply chains. The CTR applies to these products, and the assessment may involve additional expertise. Sponsors should anticipate more detailed questions on manufacturing controls, vector shedding, long-term follow-up, and patient monitoring. For pediatric trials, additional requirements apply, including pediatric investigation plans and specific transparency rules.

For trials involving devices or combined products, the regulatory interface can be complex. The CTR applies to the medicinal product component; device aspects may fall under the Medical Device Regulation (MDR). Sponsors should ensure that the regulatory strategy addresses both frameworks and that CTIS submissions reflect the combined nature of the intervention where relevant.

National Implementations and Local Nuances

While the CTR is directly applicable, Member States retain some discretion in areas explicitly permitted by the Regulation. This includes local requirements for compensation, liability, and data protection, as well as the composition and procedures of Ethics Committees. Sponsors should expect variations in how ECs operate, the depth of local ethical review, and the requirements for translations of patient-facing documents.

For example, some countries may require additional assurances regarding insurance coverage or specific consent wording. Others may have stricter rules on the involvement of vulnerable populations. The CTR harmonises the core process, but local compliance remains essential. Engaging experienced local partners and maintaining a country-specific regulatory intelligence database is advisable.

Transition and Legacy Trials

The transition from the Directive to the Regulation is governed by specific provisions. Trials approved under the Directive may continue under the old framework until 30 January 2025, provided they remain compliant with the Directive. However, any substantial amendment or extension after 31 January 2022 may trigger the need to transition to the CTR and CTIS, depending on the nature of the change. Sponsors should plan early for transition, as the process requires preparing a CTIS dossier that aligns with the current trial status and may involve reconciling documentation.

Transition planning should include:

• Mapping current trial documentation to CTR requirements.
• Preparing CTIS user accounts and roles.
• Updating SOPs to reflect CTIS workflows and CTR obligations.
• Training staff on new processes and terminology.
• Coordinating with investigators and sites to ensure readiness.

Practical Compliance Checklist

Teams can use the following checklist to ensure readiness and ongoing compliance under the CTR:

• CTIS readiness: User accounts created, roles assigned, and SOPs for CTIS submissions and updates established.
• Dossier completeness: Protocol, IB, IMPD, labeling, and patient information documents are up to date and cross-referenced.
• Timelines: Internal processes to meet 45-day assessment windows, including rapid response to questions.
• Transparency: Documented rationale for confidentiality requests; plain language summary templates prepared.
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