The Federal Agency for Medicines and Health Products (FAMHP), the Belgian regulating authority in the sphere of medical devices, has published updated guidelines for clinical trial sponsors. The document is intended to provide additional recommendations and clarifications with regard to the processing of applications for the authorization of clinical trials and substantial modifications on medicinal products for human use.

The document constitutes the ninth version of the guidance on clinical trials published by the FAMHP, while the initial version has been issued earlier in January 2017. The authority also mentions that the present guidance could be subject to changes and amendments reasonably necessary to reflect the appropriate changes in the regulatory approach. 

Regulatory Background 

According to the FAMHP guidance, clinical trials are regulated under the Regulation (EU) 536/2014 of the European Parliament and of the Council of 16 April 2014 on clinical trials on medicinal products for human use, repealing the Directive 2001/20/EC, and the law on Clinical Trial Regulation (CTR). 

First of all, the FAMHP mentions that there is a pilot project intended to improve the regulatory procedures related to the clinical trials and implement necessary amendments thereto. At the moment, the sponsors may participate in a pilot project on a voluntary basis. 

The new pilot project also implements special rules and procedures related to change notifications. According to the guidance, upon approval of the initial clinical trials application under the CTR pilot procedure, all substantial modifications could be submitted. At the same time, they would not be admissible in case the initial clinical trial application was not approved. 

The sponsors are not obliged to report non-substantial modifications. However, such modifications should be duly documented, and all relevant documentation should be kept and provided to the regulating authority upon request. The FAMHP also states that all notifications that have not been submitted in the course of the clinical trial application process could still be submitted by the sponsor together with the notification at the end of the trial. In order to assist the sponsors with sustaining compliance with the applicable requirements, the regulating authority also provides examples of substantial modifications and different categories of notifications. 

The FAMHP guidance on clinical trials also describes the cases actually falling outside the scope of the pilot project, such as the clinical trials associated with genetically modified organisms and safety reporting. At the same time, the scope of the pilot project additionally covers the Urgent Safety Measures to be taken by the sponsors in case of unexpected events that could affect the benefit-risk balance, and also the protocol deviations with a direct impact on the safety of the subject. Such cases should be duly notified to the regulating authority. 

Procedure For Sponsors of Clinical Trials 

A sponsor interested in participating in the aforementioned pilot project shall submit its application (dossier) in electronic format using the special online platform (CESP). Upon submission, the sponsor would be assigned with the CTR pilot project number communicated in the response to the application. 

The FAMHP provides a template of the letter of intent, which actually constitutes an application form to be submitted by the sponsor interested in participating in the pilot project. According to the present guidance, the letter of intent shall contain the following information: 

  • EUDRA-CT number of the clinical trial,
  • Sponsors trial code as stated when applying for the EUDRA-CT number,
  • Title of the clinical trial,
  • Planned submission date of the dossier,
  • Name and site of the coordinating investigator of the clinical trial,
  • Number and address of planned trial centers in Belgium as available at the moment of the submission of the letter of intent. 

The authority additionally emphasizes that the name indicated in the letter of intent should be the official name of the institution applying for participation in the pilot project. 

Once the CTR pilot project number was assigned, the sponsor shall indicate it in all further communications with the regulating authority.

According to the FAMHP guidance on clinical trials, a CTR pilot project dossier shall contain the following elements: 

  • A written statement indicating the name of the particular institution applying for participation in the pilot project,
  • CV of each principal investigator (including all relevant diplomas and information about the most important trial experience confirmed by the appropriate documents) based on the template developed by the EU Commission. 
  • A separate document with a list of all files enclosed. 
  • The protocol synopsis (both in English and at least in the official national language of the region where the trials are actually taking place).
  • Draft DSMB charter (if applicable). 
  • All other documents divided into folders and compressed into the single Zip archive. 

The FAMHP additionally emphasizes that the submission shall comply with all applicable requirements including the ones listed herein. The cover letter should be duly signed (an electronic signature could be also used). It is also important to mention that at the moment there is no fee payable by the applicant interested in participating in clinical trials for the submission of the dossier.

CTR Pilot Project: Aspects and Details

The FAMHP guidance also highlights some additional points that are important in the context of applying for participation in the CTR pilot project and further review of the application. According to the document, the responsible authority would take all reasonable steps to accelerate the review of the submission and provide the response within the shortest term. At the moment, there are two applicable timelines:

  • Short timeline (15 calendar days), which is applicable to all Phase I clinical trials, 
  • Extended timeline (28 calendar days), which should be applied in case of a mixed Phase I/II clinical trial. 

Upon completion of the review, the authority may also notify the applicant about any deficiencies found, or determine that the submission is incomplete. In such cases, the applicant would have 10 calendar days to make necessary changes and provide documents and information requested by the authority. The review of additionally provided information would take up to 5 calendar days starting from the day such information was received by the regulating authority. However, if the authority would determine that the submission still fails to meet the applicable requirements, it would inform the applicant that the review process would be terminated. 

The procedures described hereabove actually stand for the validation process, while the next step is the assessment procedure to be carried out by the regulating authority. During the assessment procedure, the FAMHP is also entitled to ask additional questions when it is necessary to assess the details of the application. It is important to mention that the current procedure provides only one round of questions. Thus, the applicant shall make its answers as clear and detailed, as possible, to address all requests of the regulating authority. 

As soon as all aforementioned procedures would be completed, the regulating authority would make one of the following determinations:

  • The CTA is “Authorised” – the applicant is allowed to commence the clinical trials,
  • The CTA is “Authorised subject to conditions” – the applicant would be able to commence the clinical trials once all the requirements communicated by the regulating authority would be fulfilled,
  • The CTA is “Refused” – the applicant shall not commence the clinical trials, while still may implement all necessary improvements and submit a new application. 

Summarizing the information provided here above, the FAMHP guidance on clinical trials highlights the most important aspects to be considered by the sponsors applying for participation in the CTR pilot project. In particular, the document outlines the scope of the information to be provided by the applicant, and also describes the procedures following the submission.

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