Streamlining Clinical Trial Applications: An Overview of the New EU Clinical Trial Authorization Process

The EU Clinical Trials Regulation (CTR) is reshaping the landscape of clinical trials in Europe. It introduces practical changes such as a centralised submission system, fixed timelines, and a streamlined approval procedure for multinational trials. Understanding these changes is important for sponsors navigating the updated regulatory framework for clinical research in the EU ensuring smoother trial progress, meeting compliance standards, and advancing research objectives.

Previously, clinical trials in the EU were governed by the Clinical Trials Directive, which established some common standards, but application processes still differed notably between the member states. Sponsors submitted separate applications to the national competent authority and ethics committee in each country using diverse formats, procedures, and timelines which led to inefficiencies and delays setting up multinational trials across Europe.

To address these issues, the European Commission developed the new Clinical Trial Regulation that came into force in 2022 with the aim to simplify and harmonise the clinical trials application and assessment process within the EU.

One of the most significant changes introduced by the CTR is the requirement for a harmonised dossier in all Member States. The dossier is divided into two parts, Part I and Part II. For Part I, a Reporting Member State (RMS) is selected to lead the assessment of that part of the application with input from the other member states included in the initial application. The RMS will issue an assessment and although it is not binding on the other member states concerned (MSC), it is expected that they will accept this assessment. However, the other MSCs do have the option to not accept the RMS assessment of Part I, if they determine it does not meet specific criteria for acceptance as defined in the CTR.

Each MSC conducts their own review of Part II as this part of the dossier is Member State specific and assessment is performed nationally. Once an assessment of Part I and Part II is available in a given Member State, a single decision on the clinical trial is then issued by each individual MSC. There are no longer separate assessments and approvals provided by the national competent authority and ethics committee within each member state, but both are still involved in the member state assessment of the clinical trial application (CTA).

Part I contains the scientific aspects of the trial application, including details on quality, non-clinical and clinical data supporting the proposed trial. Sponsors must provide thorough documentation around the IMP's composition, manufacturing methods, quality control testing, non-clinical and early clinical experience (if any) data. Assessment of the proposed trial design and study protocol are also conducted as part of the Part I assessment. Additional information on the sponsor is furnished, including contact information. An overview of the investigational product is also provided with details on aspects like its name, ingredients, and pharmaceutical form.

Part II contains details for conducting the clinical trial at the national level. Specifically, Part II includes site and investigator information as well as recruitment plans and informed consent forms are also provided.

The application process under the CTR provides some flexibility in terms of submission timing for Parts I and II of the dossier. Part I can be submitted independently to initiate the review process. Applicants then have up to two years to also submit Part II. However, both parts must be submitted and approved for the application to be considered complete and for the final clinical trial authorisation to be granted in a given Member State.

Sponsors submit the application electronically via the new Clinical Trial Information System (CTIS), which serves as the EU's centralised clinical trial application and oversight portal. All correspondence with regulators is then handled through CTIS.

According to the CTR, non-EU based sponsors must appoint a legal representative located in the EU. The legal representative, whether appointed or the sponsor itself, must ensure compliance with CTR obligations and notify the sponsor immediately of any non-compliance.

The CTR has established well-defined timelines for the clinical trial application and the review process. Rigid periods for CTA assessment ensure transparency of maximum timelines for sponsors across the EU. Full process from submission to final decision can vary from 60 to 106 days depending on whether requests for further information (RFIs) are issued during the validation and assessment periods and assuming Part I and II are submitted in parallel. It is worth noting that there are no options for the sponsor to request extensions when responding to RFIs and also no option for the MSC to extend timelines for assessment.

In addition to streamlining timelines, increased transparency of clinical trials is another core goal of the CTR. The public can access a part of the CTIS clinical trials portal for information on on-going trials, trial protocols, investigational products, and summarised clinical trial results will be published on the database within 12 months of study completion. Precautions are also in place to protect sensitive patient or commercial data from publication.

To expand the trial to additional MSCs following the initial authorisation process, sponsors can submit further requests through the EU portal to extend the trial into other Member States. The additional MSCs then have strict timelines of between 52 to 83 days to provide their authorisation decision depending on whether RFIs are issued during the review process.

The new centralised application process under the CTR allows sponsors to obtain coordinated assessment and approval across multiple EU countries in a significantly more efficient manner than under the previous decentralised system of the CTD.

What factors must sponsors carefully consider when planning their clinical trial application under the EU CTR?  Important questions include resourcing needs depending on whether both parts of the application will be submitted concurrently or sequential with Part I staged first. Trial complexity, requiring greater documentation preparation time for more intricate protocols, also demands consideration. The country scope of submissions, with decisions on simultaneous filings to multiple EU states compared to a staggered approach, is another important planning factor. Adequate resources and qualified experts must be confirmed to provide support during the application process to ensure continued trial and regulatory oversight and compliance throughout the clinical trial lifetime.

Assessing contingencies for unexpected complexities or delays is highly important, as they may jeopardise deadlines without room for adjustments. A thorough self-assessment helps choose the best submission strategy, considering expertise, timelines, finances, and stakeholder collaboration to maximize efficiency and avoid regulatory missteps.