2. General Questions

2.1 Name of Regulatory Authority

Federal Agency for Medicines and Health Products (“FAMHP”)

The FAMHP is the Belgian competent authority in charge of ensuring the quality, safety, and efficacy of medicines and health products (medical devices and accessories, raw materials, blood and blood components of human origin, and human tissue material), for human and veterinary use, in clinical development and on the market.

FAMHP is also designated as the national contact point under the EU CTR, it handles all communications via the Clinical Trial Information System (CTIS) for Belgium. 

Please see Article 4, Law of 2017.

2.2 Name of Ethics Committee

There are multiple recognized Ethics Committees in Belgium. However, the involvement of and coordination between all Ethics Committees is managed by the Clinical Trial College (CT College). 

As per Article 3, Law of 2017, a ‘College’ is defined as “an independent body which coordinates the operation of the Ethics Committees and ensures their quality. It also acts as a single point of contact for the Ethics Committees and the FAMHP”.

The CT College is an independent body set up within the Belgium Federal Public Service (FPS) for Public Health, Food Chain Safety and Environment (FPS HFCSE).

The mission of the CT College is to ensure that the ethical assessment of both clinical trials on medicinal products for human use and clinical investigations with medical devices is carried out in Belgium:

• within the harmonized European approval process;
• with the required quality; and
• independently of the sponsor, the clinical trial or investigation site, the investigator involved, and any other undue influence.

There are currently 15 Ethics Committees (ECs) recognized under the Law of 2017. 

The CT College does not take part in the clinical trial evaluation, that is done by the applicable Ethics Committees.

2.3 Clinical Trial Application Language

The Clinical Trial application within the CTIS portal can be submitted in French/Dutch/German/English.

The Law of 2017 has the following relevant provisions:

“Art. 49. § 1. In accordance with article 26 of the [EU CTR], the clinical trial authorization, subsequent extension and substantial modification files for a clinical trial are written in one of the three national languages or in English…”

"Art. 50. By way of derogation from article 41 of the laws on the use of languages in administrative matters, coordinated on 18 July 1966, the FAMHP may respond in English to sponsors established abroad, when the latter have submitted their file application referred to in Article 49 in English, or use English in their communications."

Additionally, language requirements for each of the documents required for submission of Part I, are specified within the Q&A Document, i.e., annex II (available under EudraLex-Volume 10- Chapter V-Additional Documents>Questions and Answers Document - Regulation (EU) 536/2014) 

FAMHP has created a document listing the requirements for all documents in Part I and Part II.

2.4 Is regulatory approval required from both regulatory authorities and/or EC?

Yes, approval from both the Ethics Committee and the Regulatory Authority (i.e., FAMHP) is required. 

Article 21, Law of 2017, states as below:

“The Minister or his delegate makes the decision relating to the clinical trial pursuant to section 8 of the [EU CTR].

The clinical trial can only be authorized if the FAMHP and the Ethics Committee have both issued a favorable opinion to this effect.

The clinical trial can only be authorized subject to conditions if the FAMHP and the Ethics Committee have issued one or the other, one or more conditions. In the event that the conditions issued respectively, following their examination, by the FAMHP and by the Ethics Committee are incompatible with each other, the FAMHP notifies the Minister of this in the report referred to in article 18, § 1. In this case, the test cannot be authorized.

The Minister cannot derogate from the joint conclusions of the FAMHP and the Ethics Committee, issued by means of the report referred to in Article 18, § 1.”

2.5 Can regulatory authority and EC submission be done in parallel?

Yes. A single application submission for Part I (intended for FAMHP review) and Part II (intended for EC review) can be submitted in parallel through the EMA CTIS portal.

Please see the relevant provisions of Law of 2017 below:

“Art. 16. The FAMHP and the Ethics Committee are jointly responsible for evaluating the aspects covered by parts I and II of the evaluation report, within the meaning of articles 6 and 7 of the [EU CTR].

The King determines the respective missions of the FAMHP and the Ethics Committee in this context, whether Belgium acts as rapporteur Member State or Member State concerned.

Art. 18. § 1. The FAMHP is responsible for consolidating the evaluations of the FAMHP and the Ethics Committee in a report. The College informs the FAMHP of the position of the Ethics Committee.

§ 2. The FAMHP may, after consultation with the College, establish the respective report models which are used by the FAMHP and the Ethics Committees.

§ 3. In cases where Belgium acts as rapporteur Member State for the assessment of the aspects falling under Part I and as the Member State concerned for the assessment of the aspects falling under Part II, the report referred to in § 1 constitutes the evaluation report within the meaning of the regulations.”

2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin

The legislative framework of Belgium mandates that authorization be obtained for the manufacture and import of investigational/study products. 

A copy of the application for Authorization Request (French version) is available on the website of FAMHP. The website also contains guidance in the form of FAQs on how to apply for the authorization. 

Relevant provision of the Law of 2017:

“Art. 38. § 1. Authorization is required for the manufacture and import:

1. unauthorized experimental medicinal products, in accordance with Article 61, § 1, of the [EU CTR].

2. authorized experimental medicinal products if the latter are the subject of a modification not covered by a marketing authorization, referred to in Article 64 of the Regulation [EU CTR];

3. unauthorized auxiliary medicinal products and authorized auxiliary medicinal products which are the subject of a modification which is not covered by a marketing authorization, referred to in Article 65 of the Regulation [EU CTR];

Authorization for the manufacture and import of drugs is issued by the Minister or his delegate.”

In addition to the above, the Decree of 2017 contains the procedural aspects of the authorization application. Relevant provisions of the Decree of 2017 are as under:

“Art. 39. Applications for manufacturing or import authorization referred to in Article 38, § 1, first paragraph, of the [Law of 2017] as well as requests for modification of these authorizations are sent to the FAMHP, on the basis of the forms established by it, accompanied by supporting documents certifying that the applicant satisfies the provisions of Article 61, § 3, of the [ EU CTR].

Art. 40. The procedure provided for the issuance of the manufacturing or import authorization does not last more than ninety days from the date on which the FAMHP receives a valid request.

Art. 41. When the holder of the manufacturing or import authorization wishes to modify one of the elements referred to in Article 61, § 3, of the [EU CTR], the procedure does not last more than thirty days. In exceptional cases, this period may be extended up to ninety days.

Art. 42. Within the framework of the procedures provided for in Articles 40 and 41, the FAMHP may require the applicant to provide additional information, with regard to the information provided pursuant to Article 61, § 3, of the [EU CTR] and of the Article 39 as well as with regard to the qualified person referred to in Article 61, § 2, b), of the [EU CTR].

When the FAMHP avails itself of this option, the deadlines provided for in Articles 40 and 41 are suspended until the additional data required has been provided.

Art. 43. The holder of the manufacturing or import authorization may only deliver experimental or auxiliary medicinal products to other holders of a manufacturing or import authorization within the meaning of the law, to hospital pharmacies or to open pharmacies. to the public, or to the investigators referred to in Article 2, § 2, 15), of the regulations.

When the experimental medicinal products are intended for another Member State, the holder of the manufacturing or import authorization undertakes to deliver the medicinal products only to persons holding an authorization granted by the competent national authority or to persons authorized for this purpose under the regulations of the country of destination.”

2.7 Biological Specimen Export Requirements

Yes, this is permitted, subject to the applicable national laws.

The Decree of 28 September 2009, Setting the Quality and Safety Standards For The Donation, Collection, Procurement, Control, Processing, Storage And Distribution Of Human Body Material, To Which The Banks Of Human Body Material, Intermediate Structures Of Human Body Material And Production Establishments Must Meet (“Decree of 2009”) has the following provision:

“Article 18.§ 1. Human body material may only be imported or transferred from another Member State of the European Union if this material meets the provisions of this decree.

Human body material can only be imported by an approved importing establishment referred to in the Royal Decree of 28 September 2009 setting the general conditions which banks of human body material, intermediary structures and production establishments must satisfy in order to be approved.

In the event of application of this paragraph, the human body material manager of the establishment, or of the importing establishment, ensures the necessary guarantees that the human body material transferred from another Member State or imported meets to the provisions of this decree. The importing establishment carries out appropriate controls to ensure this.

§ 2. Human body material transferred to a Member State of the European Union or exported to third countries must meet the conditions referred to in this decree.

§ 3. In the event of import or transfer from another Member State of the European Union, solely intended for transfer to a third Member State of the European Union or for export, it is sufficient that the physical material human meets the quality requirements targeted in the country of destination.

The preceding paragraph also applies to human body material imported or transferred from another Member State of the European Union, solely intended for the preparation of products exclusively intended for transfer to a third Member State of the European Union or on export.

The human body material manager of a human body material bank or of a production establishment must be in possession of the data and guarantees necessary to prove that the human body material imported or transferred from another Member State is intended for the export or transfer referred to in this paragraph, and making it possible to demonstrate that the human body material complies with the legislation referred to in the first paragraph.

§ 4. The importing establishment has concluded written agreements with suppliers established in third countries when any of the activities related to the donation, procurement, control, processing, storage, storage or export to Belgium of human body material intended for import is exercised outside the European Union.

Paragraph 1 does not apply to exceptional imports provided that:

1. traceability is guaranteed in accordance with Article 14 of the law and its implementing decrees;
2. the human body material manager ensures that the imported human body material is not applied to persons other than the intended recipients.

The written agreement between the importing establishment and the supplier established in a third country stipulates the quality and safety requirements which must be met to guarantee equivalence between the quality and safety standards applicable to human body material intended for be imported and the standards established by this order. In particular, the written agreement relates, at least, to the points listed in Annex XI.

The written agreement grants the competent authority(ies) the right to inspect the activities, as well as the facilities, of any supplier established in a third country during the period of validity of the written agreement and for a further period of two years from the expiration of the written agreement”.

2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?

Yes, this is permitted. An authorization must be obtained either under the ‘Contained Use’ or the ‘Deliberate Release’ framework. 

The applications to seek authorization under clinical trials and under GMO frameworks can be submitted in parallel (i.e. the sponsor should apply for GMO authorization but does not need to wait for the GMO authorization before submitting the clinical trial application).

Please see the guidance on “National Procedures that must be followed for the conduct of clinical trials with medicinal products that contain or consist of GMOs - Belgium” available from the European Commission- GMO Aspects for investigational medicinal products, containing further details on the subject matter:

In order to help the clinical sponsors and investigators of IMP to determine which procedural requirements should be followed for their clinical trial with GMO-medicinal products, the FAMHP together with Sciesano, have developed a practical guidance document, "Belgian regulatory guidance on the use of genetically modified organism in a clinical trial".

2.9 Is in-country sponsor presence/representation required?

Yes, as per the EU CTR 536/2014, if the sponsor is not established in the EU, the Sponsor needs to establish a legal representative within the EU. National law is silent on this matter. 

Article 74, of the EU CTR 536/2014 reads as follows: 

“1.  Where the sponsor of a clinical trial is not established in the Union, that sponsor shall ensure that a natural or legal person is established in the Union as its legal representative. Such legal representative shall be responsible for ensuring compliance with the sponsor's obligations pursuant to this Regulation, and shall be the addressee for all communications with the sponsor provided for in this Regulation. Any communication to that legal representative shall be deemed to be a communication to the sponsor.

2.   Member States may choose not to apply paragraph 1 as regards clinical trials to be conducted solely on their territory, or on their territory and the territory of a third country, provided that they ensure that the sponsor establishes at least a contact person on their territory in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.

3.   As regards clinical trials to be conducted in more than one Member State, all those Member States may choose not to apply paragraph 1, provided that they ensure that the sponsor establishes at least a contact person in the Union in respect of that clinical trial who shall be the addressee for all communications with the sponsor provided for in this Regulation.”

2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country?

Yes, a local investigator is required.

See Article 49, EU CTR 536/2014:

“The investigator shall be a medical doctor as defined in national law, or a person following a profession which is recognized in the Member State concerned as qualifying for an investigator because of the necessary scientific knowledge and experience in patient care. Other individuals involved in conducting a clinical trial shall be suitably qualified by education, training and experience to perform their tasks”.

Article 36, Law of 2017:

“In accordance with Article 49 of the [EU CTR], the investigator must be a doctor within the meaning of the law relating to the exercise of healthcare professions, coordinated on 10 May 2015.”

2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator?

No, under the EU Clinical Trial Regulation 536/2014, there is no role for Chief or Coordinating Investigator, only Principal Investigator and Investigator.  

Article 73, EU CTR 536/2014, indicates the role of the Principal Investigator as:

“A principal investigator shall ensure compliance of a clinical trial at a clinical trial site with the requirements of this Regulation. The principal investigator shall assign tasks among the members of the team of investigators in a way which is not compromising the safety of subjects and the reliability and robustness of the data generated in the clinical trial at that clinical trial site.” 

Article 2.17 of the Belgian Law 07 May 2004- Law in human research, defines Investigator as:

“A doctor or any other person exercising a profession covered by the Royal Decree No.78 of November 10, 1967 relating to the exercise of health care professions, qualified to carry out research. The investigator is responsible for conducting research on a site. If, on a specific site, the research is carried out by a team, the investigator is the direct responsible for the team and the latter can be designated as principal investigator”.

2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled?

A written contract is required between the sponsor and the CRO, delegating authority. The contract does not need to be notarized and/or apostilled, so far as we are aware, at an EMA level, now that applications are made electronically.

Article 71, EU CTR 536/2014, provides clarification on the sponsor's role :

“Sponsor

A clinical trial may have one or several sponsors.

Any sponsor may delegate, in a written contract, any or all of its tasks to an individual, a company, an institution or an organization. Such delegation shall be without prejudice to the responsibility of the sponsor, in particular regarding the safety of subjects and the reliability and robustness of the data generated in the clinical trial.  The investigator and the sponsor may be the same person.”

2.13 Is there a requirement to register clinical trials on a local registry or database?

Yes, clinical trials must be registered on the EU database of clinical trials, as well as the FAMPH clinical trials database.

As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS. EU CTR continues to display information on EudraCT trials. EudraCT remains available for amendments to EudraCT trials, creation of PIP/Art 46 third country files (see FAQs), updating of EudraCT trials’ statuses, and relevant submission of results.

In Belgium, the FAMHP has created an online clinical trials database to hold information on all clinical trials in Belgium approved by the agency and that have not yet been completed. FAMHP does not specify how the data on this database is updated or maintained.

2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?

25 years from the end of the clinical trial. The specific format is not prescribed, but it must be traceable, legible, and accessible upon request. 

See Article 58, EU CTR 516/2014:

“Archiving of the clinical trial master file

Unless other Union law requires archiving for a longer period, the sponsor and the investigator shall archive the content of the clinical trial master file for at least 25 years after the end of the clinical trial. However, the medical files of subjects shall be archived in accordance with national law.

The content of the clinical trial master file shall be archived in a way that ensures that it is readily available and accessible, upon request, to the competent authorities.

Any transfer of ownership of the content of the clinical trial master file shall be documented. The new owner shall assume the responsibilities set out in this Article.

The sponsor shall appoint individuals within its organization to be responsible for archives. Access to archives shall be restricted to those individuals.

The media used to archive the content of the clinical trial master file shall be such that the content remains complete and legible throughout the period referred to in the first paragraph.

Any alteration to the content of the clinical trial master file shall be traceable.”

2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.

Relevant provisions on periodic safety reporting are a part of the EU CTR.

Articles 41 & 42, EU CTR 516/2014, relate to this.  

Art 41 CTR: “Reporting of adverse events and serious adverse events by the investigator to the sponsor

1.   The investigator shall record and document adverse events or laboratory abnormalities identified in the protocol as critical to the safety evaluation and report them to the sponsor in accordance with the reporting requirements and within the periods specified in the protocol.

2.   The investigator shall record and document all adverse events, unless the protocol provides differently. The investigator shall report to the sponsor all serious adverse events occurring to subjects treated by him or her in the clinical trial, unless the protocol provides differently.

The investigator shall report serious adverse events to the sponsor without undue delay but not later than within 24 hours of obtaining knowledge of the events, unless, for certain serious adverse events, the protocol provides that no immediate reporting is required. Where relevant, the investigator shall send a follow-up report to the sponsor to allow the sponsor to assess whether the serious adverse event has an impact on the benefit-risk balance of the clinical trial...”

Art 42 CTR: “Reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency

1. The sponsor of a clinical trial performed in at least one Member State shall report electronically and without delay to the database referred to in Article 40(1) all relevant information about the following suspected unexpected serious adverse reactions:

(a) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in that clinical trial, irrespective of whether the suspected unexpected serious adverse reaction has occurred at a clinical trial site in the Union or in a third country;

(b) all suspected unexpected serious adverse reactions related to the same active substance, regardless of pharmaceutical form and strength or indication investigated, in investigational medicinal products used in the clinical trial, occurring in a clinical trial performed exclusively in a third country, if that clinical trial is sponsored:

(i) by that sponsor, or

(ii) by another sponsor who is either part of the same parent company as the sponsor of the clinical trial, or who develops a medicinal product jointly, on the basis of a formal agreement, with the sponsor of the clinical trial. For this purpose, provision of the investigational medicinal product or information to a future potential marketing authorization holder on safety matters shall not be considered a joint development; and

(c) all suspected unexpected serious adverse reactions to investigational medicinal products occurring in any of the subjects of the clinical trial, which are identified by or come to the attention of the sponsor after the end of the clinical trial.

2. The period for the reporting of suspected unexpected serious adverse reactions by the sponsor to the Agency shall take account of the seriousness of the reaction and shall be as follows:

(a) in the case of fatal or life-threatening suspected unexpected serious adverse reactions, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction;

(b) in the case of non-fatal or non-life-threatening suspected unexpected serious adverse reactions, not later than 15 days after the sponsor became aware of the reaction;

(c) in the case of a suspected unexpected serious adverse reaction which was initially considered to be non-fatal or non-life threatening but which turns out to be fatal or life-threatening, as soon as possible and in any event not later than seven days after the sponsor became aware of the reaction being fatal or life-threatening….”.

2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)? 

A safety report is required annually.

Article 43, EU CTR 536/2014:

“1. Regarding investigational medicinal products other than placebo, the sponsor shall submit annually through the database referred to in Article 40(1) to the Agency a report on the safety of each investigational medicinal product used in a clinical trial for which it is the sponsor.

2. In the case of a clinical trial involving the use of more than one investigational medicinal product, the sponsor may, if provided for in the protocol, submit a single safety report on all investigational medicinal products used in that clinical trial.

3. The annual report referred to in paragraph 1 shall only contain aggregate and anonymized data.

4. The obligation referred to in paragraph 1 starts with the first authorization of a clinical trial in accordance with this Regulation. It ends with the end of the last clinical trial conducted by the sponsor with the investigational medicinal product…”. 

2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol?

Yes, notification is required within seven days of becoming aware of the breach (see details below).

Notification of a Serious Breach allows the sponsor to inform about a breach likely to affect to a significant degree the safety and rights of a subject or the reliability and robustness of the data generated in the clinical trial. These notifications must be made without undue delay but no later than 7 days from the date on which the sponsor became aware of the breach (article 52 of the CT Regulation). 

For more information, refer to the following EMA guidance on notification of serious breaches: 

• Guideline for the notification of serious breaches of Regulation (EU) No 536/2014 or the clinical trial protocol 
• Appendix III b – Information to be submitted with a notification of a serious breach

2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?

Yes, this is required.

Please see the relevant provision of the Law of 2017 below:

“Article 12. § 1. The sponsor shall assume, even without fault, liability for damage caused to the subject or, in the event of death, to his successors in title, whether directly or indirectly related to the clinical trial. Any contractual stipulation aimed at restricting this liability is deemed null and void.
 Where a clinical trial has more than one sponsor, all sponsors are jointly and severally liable.

§ 2. Prior to the clinical trial, the sponsor shall take out insurance covering this liability as well as that of any participant in the clinical trial, regardless of the nature of the links between the stakeholder, the sponsor and the subject. 

In accordance with Article 74, § 1, of the Regulation, the sponsor or a legal representative of the sponsor is established in the European Union.

When a clinical trial has more than one sponsor, one of them is designated as responsible for taking out the insurance referred to in paragraph 1.

§ 3. For the purposes of this article, the participant or his successors in title may summon the insurer directly in Belgium, either before the judge of the place where the event giving rise to the damage occurred, or before the judge of the participant's domicile, or before the judge of the insurer's registered office.

Without prejudice to the possibility of fixing in the contract between the sponsor and the insurer maximum amounts in order to compensate the damages of the participant or, in the event of death, his successors in title, as well as to the possibility of fixing a maximum duration of coverage of the risk, no nullity, exception or forfeiture deriving from the law or the insurance contract may be invoked by the insurer against the participant or his successors in title, except in the cases provided for by the King.”