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. 

A single application is made under the CTIS portal for the coordinated review by EC and RA. 

A list of all documents required to be submitted under Part I is provided by FAMHP.

Furthermore, in Belgium, there are some special requirements regarding the content of the CTR dossier for clinical trials. 

Part I

• Protocol synopsis must be submitted in the three official languages, Dutch, French, and German, as a minimum requirement.
• Labels must be submitted in the three official languages: Dutch, French, and German, with exceptions as described in the law of 7 May 2017.

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

The timelines are set out in the table below, based on Art 5 (Application), Art 6 (Assessment report – aspects covered by Part I) & Art 7 (Assessment report – aspects covered by Part II), of the EU CTR 536/2014:

• 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.

CTIS evaluation timelines have also been published by the EMA. 

4.3 Does the regulation support electronic submission?

Yes, all documents are to be submitted electronically through the CTIS portal.

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

No, submission of clinical trials as per the EU CTR 536/2014 can be done by the Sponsor or authorized representative.

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

A Clinical Trial Application needs to be made through the EMA CTIS portal. The CTIS Sponsor Handbook is helpful in this regard.

Thereafter, the Ethics Committee appointed by the CT College as well as the FAMHP are jointly responsible for reviewing and assessing the application. 

Relevant provisions of the Decree of 2017 include:

Art. 32. “During any request for authorization, subsequent extension or substantial modification of a clinical trial, the FAMHP and the Ethics Committee are jointly responsible for the evaluation of the aspects falling under Part I, as referred to in article 6, § 1, of the [EU CTR]. The FAMHP is primarily responsible for evaluating the documents relating to compliance with good manufacturing practices (GMP) for the investigational medicinal product, the investigational medicinal product dossier (DME), the auxiliary medicinal product dossier and the content of the labeling for investigational medicinal products, respectively referred to in Annex I, F., G., H. and J., of the [EU CTR].

During any request for authorization, subsequent extension or substantial modification of a clinical trial, the Ethics Committee is primarily responsible for the evaluation of the aspects falling under Part II, as referred to in Article 7, § 1, of the [EU CTR].”

Art. 33. “The FAMHP is responsible for consolidating the observations of the other Member States concerned for the finalization of part I of the evaluation report or of the evaluation report when Belgium acts as rapporteur Member State within the framework of a request for authorization or substantial modification of a clinical trial, in accordance with Articles 6, § 5 and 18, § 4, of the [EU CTR]. The FAMHP may seek the opinion of the Ethics Committee in this context.”

Art. 34. “The FAMHP is responsible, either on its own initiative or at the request of the Ethics Committee, for asking the sponsor to provide additional information based on the observations of the other Member States concerned, for extending the evaluation period and to consolidate the observations of the other Member States concerned concerning the request for the finalization of part I of the assessment report or of the assessment report when Belgium acts as rapporteur Member State in the context of an application for authorization, subsequent enlargement or substantial modification, in accordance with Articles 6, § 8, 14, § 6 and 18, § 6, of the [EU CTR]. The FAMHP may seek the opinion of the Ethics Committee in this context.”

Art. 35. “The FAMHP is responsible for extending the evaluation period when Belgium acts as rapporteur Member State in the context of an application for authorization or substantial modification of a clinical trial involving an experimental therapeutic drug. innovation or a medicinal product referred to in point 1 of the appendix to the regulation, in order to allow the consultation of experts, in accordance with articles 6, § 7, and 18, § 5, of the [EU CTR].”

Art. 36. “The FAMHP is responsible, at the request of the Ethics Committee, for asking the sponsor to provide additional information and to extend the evaluation deadline relating to part II of the report when Belgium acts as a State member concerned or new Member State concerned in the context of an application for authorization, subsequent enlargement or substantial modification of a clinical trial, in accordance with Articles 7, § 2, paragraph 2 and § 3, 14, § 7, 20, §§ 5 and 6 and 22, §§ 2 and 3, of the [EU CTR].”

Art. 37. “The FAMHP is responsible for contesting, either on its own initiative or at the request of the Ethics Committee, the conclusion of the reporting Member State, in accordance with Articles 8, § 2, paragraph 2, 14, § 2, paragraph 2, 19, § 2, paragraphs 2 and 3, and 23, § 2, paragraphs 2 and 3, of the [EU CTR].”

These provisions are in alignment with the articles of EU CTR 536/2014.

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

Yes, the RA/CA provides a written acknowledgment of the submitted application within six days of submission of the application.

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.)

As of Feb 2024, the FAMHP has indicated that “No payment will be requested at the moment, for the submission dossier. Therefore, no proof of payment must be provided for Belgium in the CTIS submission dossier”. This statement can be found within the FAMHP “List of documents for CTR submission” under “Additional Clarifications- Fee for Belgium”. 

However, the fee related to the safety follow-up of CTIS dossiers (as stated in the “Loi de financement” from February 2022) will be requested by means of an invoice to the sponsor. This invoice will be applicable for all CTA applications (initial dossiers and substantial modifications) submitted in CTIS for Belgium. A fee will also be requested (only once) by means of an invoice to the sponsor for GCP inspections (also stated in the “Loi de financement” from February 2022). For the details of these invoices, please follow the link here.

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 information is expected to be received by the sponsor at the time of an invoice generated by FAMHP in relation to the CTA. 

In one of the guidance documents by FAMHP on the matter of fees, the account number, along with the IBAN Code and Swift code, are provided. However, it does not mention anything about the acceptable mode of payment.

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 Clinical Trial application is made by the centralized EMA CTIS portal. 

Sponsors wishing to use CTIS must have an EMA account. Users who do not have an EMA account can register through the EMA account management facility.

Organizations may need to go through additional registration steps based on the user management approach that was used for CTIS. The organization-centered approach enables user management by an administrator at the organization level, rather than at the level of an individual trial. This is intended for organizations that run various trials through CTIS. To make use of this organization-based approach, organizations must ensure that they are registered in the EMA Organization Management System (OMS) and must register a CTIS High-Level Administrator through the EMA Account Management webpage. 

Below are some of the documents made available by EMA:

1. Getting started with CTIS – Sponsor Quickguide
2. CTIS Sponsor handbook
3. Reference Materials for Clinical Trial Sponsors

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 unless participant-facing material is linked to the endpoints of the clinical trial, and those shall be provided together with the protocol in Part I of the clinical trial application. However, there is no indication as to how those documents should be provided.

Please refer to section 3.11 of this guidebook for more information.