On January 31, 2022, the European Medicines Agency (EMA) Clinical Trial Regulation (CTR) 536/2014, came into force with the goal of improving transparency of clinical trials among the public and harmonizing submission processes within the European Union (EU). The Clinical Trial Information System (CTIS) registration portal (EU Portal and Database) is now live and available for use by trial sponsors and their clinical research organization (CRO) partners.

When properly planned the CTR’s single application submission and routing process can potentially speed pharmaceutical development in the EU. However, a slight error in the process can lead to various risks. IQVIA Biotech's in-house experts can help customers navigate the EU CTR with strategic and operational guidance.

Sponsors and CRO partners should keep two key dates in mind when planning trial programs in the EU. All new studies are required to start within the EU CTR beginning January 2023, and for currently ongoing studies that are conducted in at least one member state, they must be transitioned to the CTR by January 31, 2025. The EMA has publicly noted that the CTIS and related database portal is one of the “most complex and ambitious IT developments carried out” by the organization. Given the CTR’s complexities and potential added efficiencies, it is vital that any sponsor planning or actively running a trial in the EU fully understand the critical changes of the regulation and related submission processes and what strategic support may be needed from a regulatory compliance perspective for successful trial design and execution.

Notable submission changes

Replacing the Clinical Trials Directive 2001/20/EC, the CTR will harmonize the trial submissions process via the CTIS portal—from trial registration to continuous assessment to processes oversight—across the EU through several key requirements:

• The CTR will require one submission application (compared to up to 30 under the previous directive) to eliminate submission duplication and trial start delays.
• Through one submission, sponsors must include all information needed for Regulatory (Part 1) and Ethics (Part 2) purposes within the standard review time set by the EMA. The designated review time is intended to help improve approval timelines across the EU member states and make study start-up timing and activities more predictable. Given the set timing, sponsors will need to plan to respond within 12 days of receiving questions from regulators to help avoid re-starting the application process.
• Information submitted in support of an application, modifications, or responses to request for information are stored in the database and are publicly available. This includes study milestones, inspection reports, trial results, plain language summaries, serious breaches to the study, reasons for trial halts or early termination (if any), serious adverse event reporting and more. Commercially confidential information (CCI) such as marketing authorization status of the treatment may be deferred until the EU Marketing Authorization decision.
• Information or data meeting the following criteria will always be redacted or excluded from publication:
• Personal patient data (PPD) such as patient information and investigator signatures.
• Member state communications, including confidential discussions between states during assessments.
• Chemistry, manufacturing, and controls (CMC) information.
• Financial agreements with sites and investigators.
• All information submitted for regulatory review will contain proprietary information for the company regarding the investigational treatment and confidential information for patients and investigators. Sponsors will have an allotted amount of time to redact proprietary and confidential information. If not redacted within the allotted timeframe, it is possible the information may be published online. 
• When transitioning currently ongoing studies to the EU CTR, sponsors should note changes in the development and submission of protocol-level information and documents:
• While it is currently possible to create country-specific protocols for EU member states, under the EU CTR, all Part 1 protocol-level documents must be approved and routed through the single submission for all states.
• Prior to initiating transition activities, approved protocol documents must be consolidated. If there are substantial differences in information per country-specific protocols, an amendment must be submitted in the portal before the transition process begins to harmonize efforts.
• Generally, it is not mandatory for sponsors to submit Regulatory (Part 1) and Ethics (Part 2) information at the same time. Sponsors should plan and determine the appropriate submission strategy for its application.

Key areas of support

When appropriately planned and executed, the CTR’s single application submission and routing process can positively impact study approval and start-up timelines. At the same time, given public access to clinical trial information, there is an opportunity to increase trial awareness and enhance patient engagement. While established pharmaceutical companies may have dedicated, in-house teams to navigate the intricate nuances and details of the CTIS submissions process, smaller companies may need to lean on expertise from an external partner to ensure they are on the right track for submissions planning under the EU CTR.

A slight error in the process can lead to various risks and challenges for sponsors. Imagine the detrimental effects if inaccurate or proprietary information is published online due to lack of timely response, inappropriate redaction of CCI and PPD, or errors in uploading the wrong documents. These errors can cause significant delays in the approval process, as sponsors would have to restart the application submission.

At IQVIA Biotech, the team is working closely with our in-house experts who have in-depth experience with the CTR requirements, transparency rules and CTIS portal submissions process to ensure we can provide the appropriate guidance and education of the portal system to our customers, partner vendors, site teams and internal team members supporting projects in the EU. To date, the team has prepared and updated training modules to help key stakeholders understand how to effectively plan and execute the submissions process like appropriate portal registration and set up, change of information and guidance documents related to CTIS.

Internally within IQVIA Biotech, there have been detailed discussions around the following and more:

• Impact analysis
• Process mapping
• Defining roles and responsibilities
• System enhancements to track compliance to the regulations
• Updates to the Standard Operating Procedures
• Operational guidance

Additionally, the team has prepared reference guides for sponsors, site teams and internal teams regarding redaction principles, Organization Management Service (OMS) registration, serious breach handling and reporting and the impact of the EU CTR.

To better understand the inner workings of the submissions process or the portal itself, our experts have conducted several submissions for mock trials in the CTIS Sandbox, a training environment. These educational insights can be shared with our customers, teams, and partners to ensure all are equipped with knowledge from real world usage. Also, working within the portal system before it went live was helpful to share constructive feedback with regulatory experts focused on the development and launch of CTIS.

With stringent timelines throughout the process, our team’s experience, thorough coordination, clear direction, and quality checks can help sponsors effectively move forward in the submissions and review process.

Contact us to discuss how we can help you navigate clinical trial regulations in Europe.