5. Investigator and Investigational Product

5.1 Does local regulation require PI/CI to be approved/registered by any health authority (e.g., RA/EC)?  

Yes. The investigator must be a doctor.

See 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. The investigator may also have the status of dental practitioner within the meaning of the same law, for clinical trials relating to dentistry.”

See Art 49 of the 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”. 

5.2 Does local regulation require any specific documents if PI/CI is based outside the country?

Not specified by national regulations.

It is not clear what the position is if the PI is located outside of the EMA, but unless qualified as per the Belgian laws, a person is unlikely to qualify as an investigator.

5.3 Does local authority allow electronic ICF administration, including electronic signatures?

Yes. The College has issued a guidance document on the use of electronic informed consent in interventional clinical trials in Belgium.

5.4 Does local regulation require ICF to be administered as audio/visual and do these need to be recorded?

Informing a participant in advance shall always happen via a face-to-face interview or virtually through a video conference, but not only via a phone call (audio). The same should be recorded in the ICF.

5.5 Is there any specific information/requirement on data capture/management (e.g., privacy regulations, etc.)?

See the EMA’s final Guideline of 09 March 2023 on Computerized Systems and Electronic Data in Clinical Trials which includes the following:

“6.1. Data capture and location 

The primary goal of data capture is to collect all data required by the protocol. All pertinent observations should be documented in a timely manner. The location of all source data should be specified prior to the start of the trial and updated during the conduct of the trial where applicable. 

6.1.1. Transcription 

Source data collected on paper (e.g. worksheets, paper CRFs or paper diaries or questionnaires) need to be transcribed either manually or by a validated entry tool into the EDC system or database(s). In case of manual transcription, risk-based methods should be implemented to ensure the quality of the transcribed data (e.g. double data entry and/or data monitoring).

6.1.2. Transfer 

Trial data are transferred in and between systems on a regular basis. The process for file and data transfer needs to be validated and should endure that data and file integrity are assured for all transfer. 

Data that is collected from external sources and transferred in open networks should be protected from unwarranted changes and secured/encrypted in a way which precludes disclosure of confidential information. 

All transfers that are needed during the conduct of a clinical trial need to be pre-specified. 

Validation of transfer should  include appropriate challenging test sets and ensure that the process is available and functioning at clinical trial start (e.g. to enable ongoing sponsor review of diary data, lab data or adverse events by safety committees). Data transcribed or extracted and transferred from electronic sources and their associated audit trails should be continuously accessible (according to delegated roles and corresponding access rights). 

Transfer of source data and records where the original data or file is not maintained is a critical process and appropriate considerations are expected in order to prevent loss of data and metadata. 

6.1.3. Direct capture 

Direct data capture can be done by using electronic data input devices and applications such as electronic diaries, electronic questionnaires, and eCRFs for direct data entry. Where treatment-related pertinent information is captured first in a direct data capture tool such as a trial participant diary, a PRO form or a special questionnaire, a documented procedure should exist to transfer or transcribe information into the medical record, when relevant.

Direct data capture can be done by automated devices such as wearables or laboratory or other technical equipment (e.g. medical imaging, electrocardiography equipment) that are directly linked to a data acquisition tool. Such data should be accompanied by metadata concerning the device used (e.g. device version, device identifiers, firmware version, last calibration, data originator, time stamp of events). 

6.1.4. Edit checks 

Computerized systems should validate manual and automatic data inputs to ensure a predefined set of validation criteria is adhered to. Edit checks should be relevant for the protocol and developed and revised as needed. Edits checks should be validated and implementation of the individual edit checks should be controlled and documented. If edit checks are paused at any time during the trial, this should be documented and justified. Edit checks could be either run immediately at data entry or automatically during defined intervals (e.g. daily) or manually”.

Clinical trials conducted in Belgium must comply with the General Data Protection Regulation (GDPR) No 2016/679 and the Belgian Act of 30 July 2018 on the protection of natural persons with regard to the processing of personal data, which outlines clear responsibilities for organizations processing personal data.

5.6 If a clinical study involves the study product as OTC and this is provided via pharmacy/Amazon, etc., are there any specific regulations for IP management that need to be followed?

The EU CTR 536/2014 does not mention OTC but instead, they are using the term of Auxiliary Medicinal Product (AMP), which is defined in Art 2 (8) as “ a medicinal product used for the needs of a clinical trial as described in the protocol, but not as investigational medicinal product”.

Art 2. (10) goes further on the AMP clarification indicating: “a medicinal product authorized in accordance with Regulation (EC) No 726/2004, or in any Member State concerned in accordance with Directive 2001/83/EC, irrespective of changes to the labelling of the medicinal product, which is used as an auxiliary medicinal product”.

In March 2024, the EMA updated the recommendations on “Auxiliary Medicinal Products in Clinical Trials”. These recommendations can also be found in Chapter III- Quality section under the Eudralex Volume 10. This publication provides additional clarifications, such as:

“Examples are medicinal products used as rescue medication, challenge agents, to assess end-points in the clinical trial, or background treatment. Further, the medicinal product should be related to and relevant for the design of the clinical trial, which excludes ‘concomitant medications’. As outlined in preamble 54 concomitant medications is unrelated to the clinical trial and not relevant for the design of the clinical trial”. For further definition and examples, see Annex 1 of this document."

Therefore, an authorized or marketed medicinal product (i.e.: Auxiliary Medicinal Product) used in a clinical trial, will need to comply with the requirements set within the EU CTR and will be labeled accordingly.

5.7 For a marketed study product/OTC, can a participant be compensated after confirmation of the purchased study product, or upfront prior to product acquisition? Does compensation in any way impact how the study is viewed (i.e., RWE vs. Interventional Study)?

National provisions do not directly address this issue. However, an exception does appear in Article 47/1, Law of 2017.

Art. 47/1. “§ 1. In accordance with Article 92 of the [EU CTR], the costs of experimental medicinal products, auxiliary medicinal products, medical devices used for their administration and acts specifically required by the protocol are borne by the sponsor.

§ 2. A derogation from paragraph 1 may be made in accordance with the provisions laid down by or under the law of July 14, 1994 relating to compulsory health care and compensation insurance coordinated on July 14, 1994 if:

1. the trial is at a low level of intervention; and
2. the sponsor can demonstrate at any time that the medicinal product would have been prescribed anyway by the attending physician and that the medical devices concerned would have been used for its administration, if the patient had not been included in the trial.”

5.8 Is it permitted to pay participant stipends (i.e., is it permitted to pay the patients for their participation in the clinical trial)? If so, what is the average range?

Yes, compensation is permitted under certain conditions, subject to the applicable laws.

According to Article 31(1)(d), Article 32(1)(d), and Article 33(d) of the EU CTR 536/2014, no incentives or financial inducements, other than compensation for participation in the clinical trial, are to be given to incapacitated subjects, legal representatives, minors and pregnant and breastfeeding women. This compensation should not cover more than expenses and loss of earnings directly related to participation in the clinical trials. Examples of expenses directly related to the participation in the clinical trials are travel costs for the participating subject and the legally designated representative (if applicable) or (if applicable) the person accompanying the subject, costs for accommodation, or additional costs due to participation in the clinical trial collected by the subjects’ health insurance (compulsory patient contributions/own risk). The information on compensation shall be submitted in the application dossier (CTR Annex I, P(70)) and as such is subject to assessment. A small token of appreciation is not considered an incentive but needs to be explicitly allowed by the ethics committee.

Please see:

1. Question 9.1, Clinical Trial Regulation 536/2014, Q&A December 2023[SC1]
2. Template of ‘Compensation for trial participants’ 

Additionally, reimbursement of expenses such as transportation costs (fuel, parking fees, public transport), meals, mandatory contraception, medication needed to treat side effects, sun cream, time investment/efforts, and hotel costs, are permitted and those should be listed within the informed consent form.

5.9 Specific labeling requirements for clinical study product

Please see Article 40, Law of 2017, which deals with the labeling requirements. 

Art. 40. “The information to be given on the outer packaging and on the immediate packaging of medicinal products shall be drawn up in the three national languages. This does not preclude that this information may also be written in other languages, provided that the same information is contained in all the languages used.

By way of derogation from paragraph 1, the information may be written in a single national language or in English when the investigational or auxiliary medicinal products are administered at the site of the clinical trial and the participants do not handle the medicinal product.

By way of derogation from paragraph 1, and in accordance with Article 67, § 1, b), of the [EU CTR], authorized investigational medicinal products and authorized auxiliary medicinal products may be labelled in accordance with Article 6, § 1, paragraphs 6 to 9, and Article 6, § 1, of the Law of 25 March 1964 on medicinal products and their implementing orders.”

In addition, Annex VI of the EU CTR 536/2014 contains detailed provisions on the labeling requirements.

5.10 What documents need to be submitted (including relevant fee if any), and to whom, if a permit is needed for an investigational/study product being shipped from outside the country? Are there any specific requirements for biologics?

The legislative framework of Belgium mandates that authorization be obtained for the manufacture and import of investigational/ study products. Please refer to section 2.6 of this guidebook for further information.

The list of documents required to support each authorization request are listed within the request forms. All types of requests and forms can be found on the FAMHP website. 

The completed document, along with annexes, should be sent to: eudragmdp@afmps.be.

The amount of the fee linked to authorization is already included in the annual fee or in the cost of an additional inspection (which is not included in the annual fee). It is therefore not necessary to provide proof of payment when submitting an application for a permit.

5.11 What is the turn-around time to get an import permit?

Ninety days. 

Please see Article 40, Decree of 2017:

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.”

5.12 Does local authority allow the destruction of clinical supplies at an off-site location (e.g. third-party vendor in or outside the country) after study completion? Are certificates of destruction required?

Not stated in national regulations.