7. Decentralized Clinical Trials

7.1 Do the country regulations allow Decentralized Clinical Trials (DCT) elements (e.g., eConsent, ePRO administration, remote investigator site, etc.)?

Yes.

7.2 Is there any specific regulation/ guidance on the use of DCT elements within a clinical trial?

Yes. Within the European Union, the EMA published a “Recommendation Paper on Decentralized Elements in Clinical Trials” in Dec 2022.

In Belgium, the Association of Ethics Committees (BAREC) published a statement on decentralized trials in April 2023.

7.3 What is the overall acceptability of DCT elements by the FAMPH and Ethics Committees?

Overall, DCT elements are accepted but it is important that the sponsor takes into consideration the statement of the Belgian ECs as well as the recommendations by the EMA. 

7.4 Has a fully virtual trial (DCT) been conducted in the country yet? If so, please provide an example including the registration number and any link to it, whether COVID/non-COVID trials. 

No, as per our knowledge, a fully virtual trial (DCT) has not been conducted in Belgium yet. However, clinical trials with DCT elements have been approved in Belgium.

7.5 Are there any non-regulatory DCT initiatives in the country, such as where the investigator sites and local CROs founded an alliance?

Yes, BECRO is the Belgium Contract Research Organization which includes industry leaders, academic institutions, start-ups, and other CROs. Their mission is to advance clinical research in Belgium and currently are working in an innovation panel focusing on Decentralized Clinical Trials.

7.6 Are there any general considerations when using DCT elements in a study?

Yes, however, it is important that sponsors take into consideration the recommendations provided by the EMA and the BAREC organization (see section 7.2 above).

Sponsors must make sure that the study design and the DCT elements are fit for purpose, taking into consideration the intended population, the safety profile of the study drug, and that appropriate risk management is applied.

In Belgium, regulatory authorities will not allow a fully DCT when there is no contact between the site/PI/treating physician and the study participants.

The sponsor must provide to the authorities clarity, risks and benefits of using DCT elements in a study, demonstrating how participant safety (data and physical) and well-being are guaranteed, how GCP standards will be upheld, and how compliance with data privacy requirements (GDPR and Belgian Data Privacy Law) will be maintained. 

When considering a DCT/hybrid study, it must be ensured that the sponsor and investigator are able to keep oversight of trial participant safety and well-being.

Oversight: 

• Providing clear roles and responsibilities.
• Documenting which tasks are conducted: where, when, and by whom and how oversight is maintained.
• Clear communication plan between the different parties involved: sponsor, investigator, participants, and service providers.
• Trial participants were informed on information flow, and how to make contact to acute safety concerns/events, device malfunctions, and other questions.
• Training of participants and study staff in the use of any electronic platforms or devices to be used within the study.

It is important to conduct a trial-specific risk-benefit assessment when proposing a decentralized clinical trial (DCT). This assessment evaluates whether the proposed elements are suitable for the participant populations involved in the trial. Regulators typically expect this assessment to ensure participant’s safety and data integrity.

It is advisable for sponsors wishing to use decentralized elements in a clinical trial to discuss prior with the FAMHP: CTR@afmps.be 

Sponsors can also request a meeting with the FAMHP's National Innovation Office to discuss the inclusion of DCT elements in a clinical trial.

As explained in the upcoming sections, not all DCT elements may be permitted in Belgium. However, we encourage sponsors to discuss well in advance with the FAMHP, as regulators sometimes may be flexible in their approaches.

7.7 Considerations/Requirements for the Use of eConsent/Remote Consent 

The use of electronic consent and remote consent is permitted in Belgium. See the following eConsent guideline issued by the Clinical Trials College:

• Even when the sponsor provides electronic methods for informing the participant of a clinical trial, the participant has the right to refuse and ask the investigator for a physical consent process with a paper version of the ICF. This right should be mentioned in the e-ICF. 
• Informing the participant in advance via electronic means (e.g. by e-mail, via an internet portal, …) should never replace a personal face-to-face interview with the investigator. This interview may, however, also be organized via a video conference, not a phone call. It should be clearly mentioned in the (e-)ICF whether this interview occurs via a video conference or via a physical meeting. 
• In case the participant is informed via video conference, a statement must be added to the consent part of the ICF in which the participant declares he/she has understood all information given via the video conference and has had the opportunity to ask questions. 
• A trial site always has the right to refuse an electronic information process, i.e., via video conference, with their participants.
• The eConsent must be GDPR-compliant and the eConsent process must be GCP-compliant.

7.8 Considerations/Requirements for the Use of eSignatures

The use of electronic signatures is permitted in Belgium.      

Belgian position on the eSignatures within the eConsent is indicated within the “Guidance for Sponsor on the Use of Electronic Informed Consent in interventional clinical trials in Belgium”:

• Identical to the signing of the paper version of the ICF, the signing of the e-ICF can only happen once the interview (face-to-face or by video conference) with the investigator has been performed. The investigator always signs the ICF last. 
• The participant has the freedom to choose to give his/her consent by signing electronically (via e-ICF) or by signing a paper version of the e-ICF.
• A trial site always has the right to refuse the electronic signing of the ICF by its participants. 
• If the participant has the option to sign the ICF via electronic methods, this method has to be adapted according to the considered trial and the context of the consent process and adapted to the patient's needs. E-signatures could involve the participant’s handwritten signature using a finger or a stylus under the condition that there is a table trail which makes it possible to demonstrate that the person making the electronic signature was indeed the participant (e.g. the check of the ID document of the person). This is a particular application for phase 1 trials during which participants are required to show an official ID at every visit. If such verification of the identity is not performed, an advanced or qualified electronic signature as defined in the eIDAS regulation should be used as they uniquely identify the individual signing. Be aware that: 
  • Only a qualified electronic signature has the equivalent legal effect of a handwritten signature (eIDAS, art 25. §2.). Signatures via e-ID or itsme® are qualified electronic signatures. 
  • The advanced signature should comply with the defined requirements as described in Article 26 of the eIDAS Regulation which gives guarantees of the identification of the individual signing. More information is available on the website of the FPS Economy (Ref. 6). 
• After signing the e-ICF by both parties, the participant and the investigator, it must be ensured that the document/PDF is locked to avoid editing after signing. The properties of the electronic document/PDF must be audit trailed, to ensure traceability of when it was signed and locked.

Access by the participant: 

If the participant and the investigator have signed the ICF via electronic methods, the participant will still receive a printed version and/or electronically locked copy of the signed and dated e-ICF. 

Access by the clinical trial site:

The clinical trial site should have access to the ICF as a PDF of the signed document or as the e-signed PDF in order to archive it electronically on-site for at least 25 years after the end of the trial.

The eIDAS Regulation refers to the Regulation (EU) 910/2014 on electronic Identification and trust services for electronic transactions in the internal market. 

7.9 Considerations/Requirements for Electronic Patient Reported Outcome (ePRO)

This is not specifically addressed in the national legislation; however, Belgian CA and EC accept the use of ePROs within clinical trials.

The EMA's “Recommendation paper on decentralized elements in clinical trials” makes some remarks with regard to ePROs, see below:

"The trial participant should be fully informed in advance on how the information transmitted via digital tools, for example, electronic Patient Reported Outcomes (ePROs), will be acted upon. It should be made clear to the trial participant that the investigator may not review such data in real-time, and that if the trial participant experiences any specific safety concern they need to directly contact the investigator to report such an issue

ePROs considerations are also reflected within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.

7.10 Considerations/Requirements for Home Health Care (HHC)- Home Nursing

Home nursing is permitted in Belgium. However, the sponsor must make sure that the use of HHCP in a clinical trial follows the recommendation provided by the EMA in their “Recommendation paper on decentralized elements in clinical trials”. 

It is important that recommendations provided by the Belgian Association of Research Ethics Committees (BAREC) on their “Statement on Decentralized Trials” are also taken into account, as there may be occasions where certain DCT elements may not be permitted.

It is advisable for sponsors wishing to use Home Healthcare Professional Visits in a clinical trial to discuss prior with the FAMHP: CTR@afmps.be.

7.11 Considerations/Requirements for HHC- Home Lab Collection

In Belgium, it may be permitted to collect biological samples from study participants. However, the sponsor must make sure to follow the recommendation provided by the EMA in their “Recommendation paper on decentralized elements in clinical trials”. 

It is important that recommendations provided by the Belgian Association of Research Ethics Committees (BAREC) on their “Statement on Decentralized Trials” are also taken into account, as there may be occasions where certain DCT elements may not be permitted.

Article 2§ 2 of the Belgian Royal Decree 09 Jan 2018 on Biobanks, indicates the following: 

“The practitioners referred to in the preceding paragraph have successfully completed a training program whose content is established in writing by a clinical team specialized in obtaining and collecting human body material.
 § 2. The collection of human bodily material from a living donor is carried out in an environment that guarantees health, safety and discretion”.

7.12 Considerations/Requirements for Direct-to-Patient Study Product Delivery

According to the response provided by the Belgian authorities within the Appendix “National Provisions Overview” of the EMA's Recommendation paper on decentralized elements in clinical trials, delivering or dispensing investigational medicinal products to participants is not permitted.

The Belgian response to question 9 - "Is it possible to deliver or dispense authorized IMPs directly to trial participants from pharmacies not associated with the clinical trial site? This includes authorized investigational medicinal products not used according to their SmPC." - is NO, only a delegated pharmacy (delegated by the PI) can deliver or dispense IMPs. 

According to the RD of 21 January 2009, a pharmacy in Belgium must deliver each medication in person to a patient, with the exception in Art. 29 of medication-free of prescription. An investigator can also provide the trial participant in person with an amount of medication (IMP). 

It is advisable for sponsors wishing to deliver IMP directly to trial participants to discuss prior with the FAMHP: CTR@afmps.be

7.13 Considerations/Requirements for the Use of Telemedicine

While not specifically addressed in the national legislation, telemedicine is permitted in Belgium.

Ethics Committees tend to enquire about the privacy settings of any platform used for telemedicine purposes.

It is important to consider which are the study-specific assessments that are under the responsibility of the investigator, (such as physical, neurological examinations, etc.) and if such assessments are related to the study endpoints. There may be instances where some assessments may be permitted to be conducted remotely, for example, where a qualified nurse is physically present with the study participant and the investigator is instructing or overseeing remotely via telemedicine. However, there may be occasions where those assessments can only be performed by a physician.

7.14 Considerations/Requirements for the Use of Wearables

Not specifically addressed in the existing national legislation, but support for their use may be found in the EMA's “Recommendation paper on decentralized elements in clinical trials” which makes some remarks with regards to wearables as part of handling data. 

References to Wearables as well as Bring Your Own Device (BYOD) can also be found within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.

7.15 Considerations/Requirements for Remote Monitoring

According to the response provided by the Belgian authorities within the Appendix “National Provisions Overview” of the EMA's Recommendation paper on decentralized elements in clinical trials, remote monitoring may not be permitted.

The Belgian response to question 15 - "Is remote access to the medical records allowed by the monitor or auditor?" - is NO, “Remote source data verification is as such not allowed. This is only possible in specific cases, approved during the CTA process under the following conditions: - An agreement has been setup describing rSDV which is approved by all parties (institution, principal investigator and the sponsor or the CRO assigned). - The rSDV can be organized by the investigator’s site and is therefore technically feasible without compromising the confidentiality of the Electronic Medical Records data.” 

It is advisable for sponsors wishing to conduct remote monitoring in a clinical trial, to discuss it prior with the FAMHP: CTR@afmps.be.

7.16 Considerations/Requirements for Digital Health Technologies (such as Platforms)

Not specifically addressed in the existing national legislation/guidance, however, considerations can be found within the EMA guidance on “Computerized Systems and electronic data in clinical trials”.