4. Regulatory Authority (RA)/ Competent Authority (CA)

4.1 Provide a list of documents needed to be submitted for RA/CA review and approval including the number of copies and/or translations as relevant. 

Under the EU CTR, the initial application for a clinical trial is divided into two parts:

• Part I contains scientific and medicinal product documentation (this part is reviewed by the Competent Authorities of the Member States taking part in the application, and in some cases by some of the National Ethics Committees).
• Part II contains the national and patient-level documentation (this part is reviewed by the ethics committees of the Member States taking part in the application).

4.2 Time required for RA/CA review and approval process and turnaround time if any query is raised during the review process. 

See the below table describing reviewing timelines.

• In red: Time for sponsor to respond to questions (RFIs).
• In green: Time for RMS or MSC to assess and discuss responses.
• RMS: Reporting Member State
• MSC: Member State Concerned

If the response to the RFI is not submitted within the timeframe provided, the application will lapse.

4.3 Does the regulation support electronic submission?  

Yes, the CTIS is an online portal, and therefore electronic submission is required. The Regulation supports electronic submission.

4.4 Does the regulation require the applicant to be Principal Investigator (PI)/Chief Investigator (CI)?

No, submission of clinical trials as per the EU CTR can be done by the Sponsor or authorized representative.

4.5 Please describe the process of RA/CA submission for clinical trial approval. 

• Part I of the application deals with scientific and methodological aspects of the trial and will be applicable to all Concerned Member States (“CMS”) (i.e., those EU/EEA countries where the clinical trial is proposed to take place).
• Part II of the application will be completed in a bespoke fashion for each individual CMS, to take into account the particular ethical and regulatory requirements of each individual CMS.

The Sponsor/Sponsor’s authorized representative can submit Part I for assessment in the first instance and may then, within two years of the Reporting Date of Part I, apply for an authorization for Part II for all, or individual, CMS. As part of its submission, the Sponsor proposes a “Reporting Member State”, as follows (see Art 5.1):

“The sponsor shall propose one of the Member States concerned as reporting Member State. If a Member State concerned other than the proposed reporting Member State is willing to be the reporting Member State or where the proposed reporting Member State does not wish to be the reporting Member State, this shall be notified through the EU portal to all Member States concerned not later than three days after the application dossier is submitted.” 

“If only one Member State concerned is willing to be the reporting Member State or if the clinical trial involves only one Member State, that Member State shall be the reporting Member State.” 

“If there is no Member State concerned willing to be the reporting Member State or if there is more than one Member State concerned willing to be the reporting Member State, the reporting Member State shall be selected by agreement among the Member States concerned….”. 

A Sponsor can submit a whole application (Part I and II) to some CMS (Art 5) and at the same time an application limited to Part I only (Art 11) to other CMS.

If a Part II submission is not made for a particular CMS within the stipulated time, then the application for authorization to conduct the trial in that CMS will lapse.

The Clinical Trial Regulation (EU) 536/2014 requires strict adherence to the maximum timelines allocated to each phase and has provisions for tacit withdrawal or tacit approval to ensure that delays from any party do not hold up the process, which results in an increased predictability to study start-up in the EU.

Finalization of the Application

The Reporting Member State (see Art 5.1 above) assesses Part I of the application (the initial assessment phase) and shares its draft assessment with each of the CMS so that they can make comments (the coordinated review phase). The Reporting Member State then finalizes its assessment report (the consolidation phase), taking the CMS’ comments into account. The consolidated assessment report is binding on all CMSs’, but a CMS may object to the conclusion of the report. 

The grounds for objection by a CMS are limited to three: 

1. Participation in the trial would lead to receiving inferior treatment to normal clinical practice;
2. Infringement of national rules on cells or narcotics; and/or 
3. Considerations regarding safety or data reliability and robustness raised during the assessment phase. 

On the other hand, if the Part I report is not approved, it will not be approved for any of the CMS, without further discussion, and the trial may not be conducted.

Part II is assessed by one ethics committee in each CMS, in parallel to the Part I assessment. If the ethics committee of a particular CMS issues a negative assessment report, the trial may not be conducted in that CMS. 

The procedure ends with a unique decision on Parts I and II in each CMS. The decision can be:

1. Acceptance;
2. Acceptance subject to conditions; or 
3. Refusal. 

It will only be positive (i.e., acceptance or acceptance with conditions) if the two assessment reports are positive. Upon receiving the decision, the Sponsor may start the trial in that CMS.

New Member States may be added to the trial after the initial authorization decisions have been taken. The Reporting Member State will remain the same and will submit the additional application for additional Member States to be added.

4.6 Does the RA/CA provide written acknowledgment of the submitted application? If not, describe how the application is tracked.

Yes, the Reporting Member State (RMS) will notify the sponsor as well as the other Member States concerned, through the CTIS portal, within six days from the submission of the application dossier. 

Art 5.1, Clinical Trial Regulation (EU) 536/2014.

4.7 What is the relevant RA/CA fee in local currency/USD? Please provide as much information as possible (e.g. if the fee is different for notification/approval, initial submission, amendment, study with IMPD and study without IMPD, etc.)

Each Member State sets its own fees. 

The Clinical Trial Regulation (EU) 536/2014 simply provides that Member States may levy fees for their activities. 

See Article 86 - General Principle

"This Regulation shall be without prejudice to the possibility for Member States to levy a fee for the activities set out in this Regulation, provided that the level of the fee is set in a transparent manner and on the basis of cost recovery principles. Member States may establish reduced fees for non-commercial clinical trials.”

Article 87 provides that “One payment per activity per Member State: A Member State shall not require, for an assessment as referred to in Chapters II and III, multiple payments to different bodies involved in this assessment”.

4.8 Does RA/CA accept checks or can payment be made electronically? Please provide details on (1) A/C number; (2) A/C Name; (3) Sort Code; (4) Swift Code; (5) Bank address, etc. Where can remittance advice notices be sent?

This is a matter for the individual Member State concerned (i.e., a national matter), but the expectation is that payment can be made electronically.

4.9 Is there any guidance tool available for making an electronic application? If yes, provide the link and/or step-by-step instructions.

The EMA provides training and support on the use of CTIS. See details here.

4.10 Does RA/CA require any screenshots/mock screens for participant-facing materials?

Not under Part I of the application.

Participant-facing material is only submitted within Part II of the application. Please refer to Section 3.11 for more information.