Clinical Trial Regulation
New terms under the Clinical Trial Regulation:
Reporting Member State (RMS) – the member state who coordinates assessment of the clinical trial application.
Member state concerned (MSC) –member states other than the RMS to whom the clinical trial application is filed.
Part I – the documents submitted for scientific/regulatory review (includes protocol, IB, IMPD, GMP documents, label and translation as required per each member state).
Part II – the documents submitted for ethical review (includes trial site information, recruitment arrangements, ICF, suitability of investigator, suitability of facilities, financial arranges, GDPR documentation).
Clinical Trial Information System (CTIS) – the new portal through which all clinical trial applications and clinical trial-related submissions are made).
Request for Information (RFI) – requests received from the authorities during the clinical trial application process and during trial conduct if necessary.
When will the Clinical Trial Regulation come into effect?
The Clinical Trial Regulation (Regulation (EU) No 536/2014) (‘the Regulation’) was written into EU law on 16 April 2014, however it has not yet come into application due to delays to the new Clinical Trial Information System (CTIS), which is a key component of the Regulation. From 31 January 2022 CTA submissions under the Regulation can start; at this point Sponsors have the option of filing under the new the Regulation or the existing Clinical Trial Directive (‘the Directive’).
From 31 January 2023 CTA submission can no longer be made under the Directive and by 31 January 2025 all ongoing clinical trials under the Directive must transition to the Regulation.
For this purpose, an ‘ongoing’ trial is considered one in which the end of clinical trial in the EU has not yet occurred; for example, a global trial which has finished in the EU but ongoing in third countries after 31 January 2025 would not need to transition.
What is the Clinical Trial Information System?
The Clinical Trial Information System (CTIS) is a new database that will be used for all clinical trial-related communications with the exception of pharmacovigilance reporting which will continue to run via EudraVigilance. As such, the CTIS will be used for all clinical trial submissions (initial application, substantial modifications, annual report and notifications) and all clinical trial communication with the authorities, including receiving and responding to Requests for Modification (RFIs).
The CTIS replaces existing submission mechanisms for clinical trials, such as CESP or EudraLink. In addition to facilitating communication between the Sponsor and the authorities, CTIS will have a component accessible to the public where clinical trial information will be published as applicable (Figure 1).
Figure 1: CTIS Overview
A number of user roles have been created for Sponsor users of CTIS, depending on what responsibilities each individual has within the preparation, review or submission of each component of an application (Figure 2).
Figure 2: Sponsor Roles Within CTIS
Adapted from https://www.ema.europa.eu
What clinical trial documents will be made public under the Clinical Trial Regulation?
Under the current Directive, the clinical trial information is made public via the EU Clinical Trials Register and consists of protocol-related information from Annex 1 (CTA Form) and the results-related information input directly into EudraCT once the trial is complete. The exceptions to this are Phase 1 non-paediatric trials, for which protocol-related and results-related information is not published. This will change under the Regulation, with one of the goals of the new Regulation being increased transparency. The default option when filing the CTA will be for all information to be made public, with the following exceptions:
Quality information, including the IMPD and any quality-related requests for information (RFIs);
Draft assessment reports;
Personal information; and
Financial agreements
However, Sponsors will have the option to request a deferral of publication for certain categories of information, as summarized in the table below.
What are the timelines for assessment of an initial CTA?
Following submission via CTIS, the first step will be validation of the application, which takes up to 10 days. For a trial taking place in multiple EU member states, the Reporting Member State (RMS) will be confirmed during this period. If validation issues are identified, the Sponsor has 10 days to respond and the member state(s) concerned (MSC) will have 5 days to review the response and validate the application.
The initial assessment of Part I and Part II takes up to 45 days. If there are RFIs on Part I or Part II, the Sponsor will have 12 days to respond and MSCs will have 19 days to review.
There is no allowance in the Regulation for extension of the time allowed for Sponsors to response to RFs (12 days). For Part I, this 19-day period includes time for the RMS to consolidate the MSCs review, in the case of a multinational trial.
The final decision will be issued after the assessment period ends. In summary, the total timeline is up to 50 days from submission to approval if there are no questions or 81 days if there are questions. Any validation issues delay the procedure by up to 15 days. The total timeline can be extended by up to 50 days for an ATMP. It should be noted that these timelines are outlined as the maximum time allowed in the Regulation and MSCs may decide on a shorter respond period. The CTA is considered approved if no communication is received from the RMS by the end of the published timelines.
Must Part I and Part II be submitted at the same time?
Sponsors may choose to submit Part I and Part II sequentially or in parallel. Furthermore, for a trial in multiple member states a mixed approach can be taken, whereby Part I is submitted to all member states and Part II only submitted to some. When the sequential approach is taken, Part II must be submitted within 2 years of approval of Part I.
What is the process for a clinical trial with an ATMP or a GMO?
As discussed above, the assessment time for a clinical trial concerning an ATMP may be extended by up to 50 days.
The assessment related to GMO aspects of a clinical trial remains separate from the main clinical trial application and is therefore submitted individually to each MSC.
Can a Sponsor choose who the clinical trial application will be assessed by?
For a multinational trial, Sponsors are able to state their preference of Reporting Member State. Sponsor preference will be taken into consideration however it is not guaranteed to be accepted. The RMS for the clinical trial will be confirmed during the validation period. It should be noted that although one RMS will lead the assessment, each MSC will review the application and will issue their own decision.
Under the Regulation, it will not be possible for the Sponsor to choose which Ethics Committee assesses the application. The procedures under the Regulation aim to ensure that validation and assessment of the application will be independent of the Sponsor, trial sites and Investigators.
How can I add a new member state to an ongoing clinical trial?
Once the clinical trial is approved in one member state an application can be filed using the ‘new MSC’ pathway to add an additional country without submitting a whole clinical trial application. To add a new MSC, the key documents required are the cover letter and proof of payment along with translations of Part I documents as required per member state guidance.
A full Part II is still required. The decision on a new MSC is made within 52 days, to be extended by a maximum of 31 days in case of questions (12 days for Sponsor response + 19 days for evaluation).
What are the timelines for assessment of a substantial modification?
Following submission via CTIS, the first step will be validation of the application, which takes up to 5 days. If validation issues are identified, the Sponsor has 10 days to response and the MSC will have 5 days to review the response and validate the application.
The initial assessment of Part I and/or Part II, depending on the scope of the modification, takes up to 38 days. If there are RFIs on Part I or Part II, the Sponsor will have 12 days to respond and MSCs will have 19 days to review. For Part I, this 19-day period includes time for the RMS to consolidate the MSCs review, in the case of a multinational trial. The final decision will be issued 5 days after the assessment period ends.
In summary, the total timeline is up to 43 days from submission to approval if there are no questions or 74 days if there are questions. Any validation issues delay the procedure by up to 15 days. The total timeline can be extended by up to 50 days for an ATMP.
Must authorities be notified when the clinical trial starts?
Under the Regulation, there are a number of notifications that are required throughout the trial. The notifications summarized below must be submitted within15 days of the event occurring in each member state to the relevant authorities:
Start of clinical trial
First subject enrolled
End of recruitment
It is important to note that a clinical trial authorization ‘expired’ if the trial is not started within 2 years of the decision. In this scenario a new clinical trial submission is required.
Must authorities be notified when the clinical trial ends?
There are several end of trial notifications required under the Regulation, as summarized below:
End of clinical trial in concerned member state
End of clinical trial in all EU countries
End of clinical trial in all countries globally
The end of trial should be defined in the protocol, and is usually considered the date of the last subject’s last visit.
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