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, Swissmedic and Swissethics have summarized the main current challenges of DCTs with medicinal products and show under which conditions such clinical trials could be conducted in Switzerland. The paper is addressed to researchers and sponsors as well as all those interested in clinical research.

See “Position paper on decentralized clinical trials (DCTs) with medicinal products, v2.0, 15 Dec 2022”.

7.3 What is the overall acceptability of DCT elements by the Polish Regulatory Authorities and Ethics Committees?

The Swiss authorities are very receptive to DCT elements. The existing legal framework already regulates many aspects of DCTs with medicinal products in Switzerland, although researchers are recommended to liaise closely with Swissmedic and the Ethics Committees beforehand in order to clarify specific questions relating to the conduct of DCTs. The aim of prior consultation/clarification is to identify ways in which DCTs can comply with the ethical and legal standards mandated by the existing regulatory environment and can therefore be carried out in Switzerland.

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, not that we have been able to determine.

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

No, not that we have been able to determine.

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

The Swiss position paper on DCT highlights four main aspects:

1. Optimal medical care and the rights and safety of subjects must be ensured at all times.
2. The IMP must be safely dispensed, ingested/administered, and returned.
3. The data recorded during the clinical trial must be credible and reliable.
4. The data protection requirements must be met in full.

Re 1: Since the clinical trial is performed virtually, there is a risk that the personal relationship with the physician, which is the basis of mutual trust, cannot be established as personally and in the same way as in conventional clinical trials. The optimal care and treatment of subjects in the trial setting is a fundamental requirement for any form of research involving human beings and is therefore essential in the performance of DCTs, too. Optimal patient safety must also be ensured, even if subjects are not regularly physically present at the trial site. 

Re 2: The IMP must be suitable for delivery to the subjects and for being ingested/administered at and returned from their homes. All the requirements regarding the quality of the IMP must be fulfilled during delivery and storage.

 Re 3: Given the modalities of recruitment and selection, there is a risk that it will mainly be technically-versed individuals who decide to take part in the trials. A representative sample of trial participants must be ensured in order to avoid a selection bias. The data-recording tools (e.g. wearables) must generate correct and valid data. 

Re 4: Data protection - Special attention must be paid to ensuring the highest security standards during data transfer, for example within a larger network and between all participants. This means that health-related data must be protected from unauthorized access at all times.

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

It is important to take into consideration the guidance on eConsent published by Swissethics “Conception and application of an electronic informed consent, last updated 23 Aug 2019”. Within the eConsent guidance, the following recommendations are given:

“It is recommended that the investigator, project leader, or the sponsor of the research project discuss plans for using an eIC with the Ethics Committee prior to finalizing the development of the eIC to ensure that the Ethics Committee agrees that the format may be used to convey the information to the subjects. 

The requestor must submit the same eIC materials to the Ethics Committee that will be presented to the subjects to obtain their consent for participation in the clinical investigation. i.e. copies of all forms and informational materials in PDF format, with a link to the eIC Web page to access videos and Web-based presentations. The requestor should also provide transcripts in PDF format of the eIC audiovisual presentations. If the eIC is available as an Application (App) for smartphones or tablets, the requestor should provide the link to the Web page for downloading the App.”

The Swiss DCT position paper also established additional aspects that need to be taken into consideration when using eConsent: 

"If the discussion about participation between the investigator, i.e. the trial physician, and the patient during the informed consent process is done via electronic platforms, several additional aspects have to be considered. Ethical principles like autonomy and ethical requirements like time to think about trial participation must be addressed. The requirements of the Swiss Data Protection Act, e.g. with respect to server location, must be fulfilled (Art. 7 FADP). The protection of personal data from unauthorised or accidental disclosure must be safeguarded, in particular by ensuring that during any data transmission, these personal data are adequately protected from unauthorised or accidental disclosure to the sponsor or companies involved in this process (ICH GCP E6 (R2) 2.11; Art. 7 para. 1 FADP).”

7.8 Considerations/Requirements for the Use of eSignatures 

The Swissethics’ Guidance on eConsent includes the statement that “Currently, in Switzerland, the eIC can make use of electronic media (e.g. video, podcasts, interactive Websites, applications for tablets and smartphones, etc.) to convey the information, while the subject’s consent must still be documented on paper with a hand-written signature of both the patient and the investigator. That is electronic and/or digital signatures are not yet permitted”.

However, the Swissmedic position paper on “Decentralized clinical trials (DCTs) with medicinal products in Switzerland” indicates the following: 

“To date, a handwritten signature (“wet-ink”) is required in Switzerland, unless the trial participant can provide a qualified electronic signature that meets the legal requirements of the Federal law on electronic signatures (ZertES, SR 943.03). The original handwritten signed informed consent form or the certified proof of the e-signature signed by the trial participant must be archived in the “investigator site file” (ICH-GCP E6 (R2) 8.3.12). Whether the electronic signature of informed consent forms will be acceptable in Switzerland in the future is currently being clarified. The position paper will be updated accordingly as new information becomes available.”

If a sponsor wishes to use electronic signatures on the eConsent, we suggest discussing it with the involved ECs prior to submission.

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

Section 2.4 of the Swiss DCT Position paper - “Data Capture outside the Trial Site using Mobile Technologies” - indicates:

“Where the intention is to use mobile technologies to record data outside the trial site, it must be ensured that the trial subjects have been informed and agreed (consented) to data being recorded by the device (e.g. wearables) or entered by the trial subjects, e.g. electronic patient-reported outcome (ePRO). This information is included in the written study informed consent form, i.e. a separate specific informed consent form is not required. The trial subjects must also be trained in the correct use of the mobile technologies. If source data are recorded directly in Page 7 of 8 of the CRF, this must be identified as such in the protocol. If data are recorded automatically, e.g. by wearables, it should be ensured that only trial-specific data are recorded by the mobile technology being used. The data which are considered to be source data must be stated in writing before the clinical trial begins, e.g. if data are only stored for a short time on the mobile technology.”

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

Section 2.2 of the DCT Position paper provides clarification on trial-related information conducted outside the site:

“If trial-related interventions are performed outside the trial site with the trial subjects’ consent, e.g. in their homes, these tasks may be performed by commissioned service providers who supply the corresponding trial nurses, known as “mobile nurses”. Each person who performs these interventions – at the responsibility of the investigator as part of the study team – must have appropriate training and proven knowledge and experience with regard to the relevant specialist field and the conduct of a clinical trial (Art. 6 para. 4 ClinO, ICH GCP E6 (R2) 4.2.4). In this situation, it is the responsibility of the investigator in Switzerland to monitor that the trial nurses carry out and document the study-specific interventions on the patients at home in accordance with the protocol. Some medical examinations cannot be performed by the trial nurses or at home (e.g. specific neurological examinations, computed tomography). These must be performed at the trial site or at a suitably equipped facility by qualified personnel or in the course of a personal visit to the patient’s home by the investigator or a delegated physician.

The trial nurses who perform the trial-related interventions outside the trial site have access to uncoded personal data by virtue of their activities in the trial subjects’ homes. Suitable technical and organizational measures must therefore be taken to ensure that these personal data are protected from unauthorised or accidental disclosure to the sponsor or, when data are transmitted to involved companies (Art. 18 para. 1 ClinO; Art. 3 let. c no. 2, Art. 7 para. 1 FADP).”

7.11 Considerations/Requirements for HHC - Home Lab Collection

Within the Swiss DCT position paper, there is no specific mention of biological samples collected at home. However, we recommend for the following to be taken into consideration:

• The participant must be informed and consent that the procedures involved do not cause any additional risk to the trial participant or the reliability of the data.
• The person performing the task is qualified and/or trained to perform the task.
• Personnel taking the sample/s are qualified and allowed by their local legislation to take the sample, this is particularly relevant in Switzerland as regions may have different requirements.
• Adequate handling and storage conditions for the samples throughout the entire process should be assured.

There may be additional requirements at the country level, such as IATA training for handling infections and biological material.

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

Section 2.3 of the Swiss position paper on DCTs covers the dispensing and administration/ingestion of the IMP outside the trial site:

“IMP whose stability and safety profile has not yet been adequately characterized due to an early stage of development is unsuitable for dispensing and administration to the trial subjects at home. IMPs which require preparation, e.g. in a sterile environment, before administration, or those that are associated with a high risk of possible adverse reactions (e.g. anaphylactic shock) are not suitable as well. Precautions must be taken to ensure the medical care of trial subjects should adverse reactions occur during or after the administration/ingestion of the IMP by the trial subject at home (ICH GCP E6 (R2) 4.3.2).

If the IMP is dispensed outside the trial site, the requirements of Good Manufacturing Practice (GMP) must be fulfilled (Annex 1 of the Ordinance on Licensing in the Medicinal Products Sector, MPLO [812.212.1]; Art. 32 para. 1 let. d ClinO). Moreover, the requirements of the Good Distribution Practice (GDP) for the IMP and the applicable cantonal provisions in Switzerland must be fulfilled. It is furthermore recommended that the details of a planned implementation in Switzerland be discussed in advance with Swissmedic and the competent Ethics Committee and, if applicable, the competent cantonal authorities. 

The following models are being discussed at the international level for the dispensing of IMP in DCTs:

• Direct delivery of the IMP to trial subjects by the trial site.
• Delivery of the IMP directly to trial subjects by a central pharmacy.
• Delivery of the IMP by a central pharmacy to a local pharmacy near the trial subject’s home. The trial subjects or trial nurses pick up the IMP in person.
• Delivery of the IMP directly to the trial nurses by a central pharmacy.

If trial subjects are supplied directly, they must be given appropriate information and agree to the personal data necessary for this being passed on. Steps must be taken to ensure that personal data are protected from unauthorised or accidental disclosure (Article 18 para. 1 ClinO). If the trial subjects are supplied directly, they must be instructed in advance about the correct storage and use of the IMP.

Until it is administered/ingested, the IMP must demonstrably be stored in such a way that its quality (protocol-compliant storage, shelf-life) is not impaired (ICH GCP E6 (R2) 4.6.4). Care must also be taken to ensure that the IMP is used only in accordance with the approved protocol (“compliance”, ICH GCP E6 (R2) 4.6.5). The sponsor must provide suitable means (e.g. using electronic tools) for performing the regular review of quality and compliance. The investigator in Switzerland is responsible for this review and must therefore be able to access these data at all times (ICH GCP E6 (R2) 8.1).

The investigator may delegate the review to the mobile trial nurses. Like the return of unused IMP to the sponsor and its disposal, the review of quality and therapy compliance must be documented in compliance with GCP and the documentation must be available for monitoring, audit, and inspection purposes.”

7.13 Considerations/Requirements for the Use of Telemedicine

Section 2.2 of the Swiss position paper on DCTs covers “Performance of trial-related interventions outside the trial site” with respect to telemedicine.

“…The sponsor must ensure that the trial subjects’ needs are taken into account in respect of doctors’ visits carried out using telemedicine. The trial subjects should be given the opportunity to see the doctor in person if needed. The investigator in turn must also be able to pay a personal visit if they consider it to be necessary for the optimal medical care of trial subjects (Art. 2 let. e ClinO). The investigator must ensure adequate medical care if adverse events occur outside the trial site and the standardised documentation and protocol-compliant reporting of adverse events (Art. 39 – 41 ClinO, ICH GCP E6 (R2) 4.3.2).

If the investigator in Switzerland instructs or performs the trial-related interventions in patients’ homes using digital platforms, e.g. video calls (telemedicine), compliance with the Swiss Data Protection Act must be guaranteed by end-to-end encrypted communication. If cloud systems are used, these must comply with the requirements of this Act.”

7.14 Considerations/Requirements for the Use of Wearables

Section 2.4 of the Swiss position paper on DCTs covers “Data capture outside the trial site using mobile technologies”. It indicates, with respect to wearables, the following:

“Where the intention is to use mobile technologies to record data outside the trial site, it must be ensured that the trial subjects have been informed and agreed (consented) to data being recorded by the device (e.g. wearables) or entered by the trial subjects, e.g. electronic patient-reported outcome (ePRO). This information is included in the written study informed consent form, i.e. a separate specific informed consent form is not required. The trial subjects must also be trained in the correct use of the mobile technologies. If source data are recorded directly in Page 7 of 8 the CRF, this must be identified as such in the protocol. If data are recorded automatically, e.g. by wearables, it should be ensured that only trial-specific data are recorded by the mobile technology being used. The data which are considered to be source data must be stated in writing before the clinical trial begins, e.g. if data are only stored for a short time on the mobile technology. 

The mobile technologies must be demonstrably validated and comply with the relevant standards for accuracy, precision, reproducibility, reliability and responsiveness (sensitivity to technological changes over time, ICH GCP E6 (R2) 5.5.3). Furthermore, the equivalence of the mobile technology used across various data-collection platforms or methods must be ensured. It must be possible to trace data entry and data changes by means of an audit trail. If the data generated this way are source data, the sponsor must ensure that they are documented in compliance with the legislation and that the statutory archiving obligation is observed. Continued access to this documentation must be guaranteed (ICH GCP E6 (R2) 8.1 Addendum). 

The sponsor must define measures in order to ensure that the recorded data actually originate from the trial subjects or were generated by the trial subjects (and not, for example, by a third person). Here it must be ensured that the sponsor has no access to personal or identifiable information relating to the trial subjects.

To ensure the protection of personal data from unauthorised or accidental disclosure, the sponsor must protect these data from any form of intervention from outside, whether accidental or intentional. This protection applies to all personal, identifiable information, to all personal health-related data, and to devices and mobile technologies used to collect, store, or transmit data. Compliance with the Swiss Data Protection Act must be guaranteed.”

Section 2.5 - “The question of CE certification of the technology employed” - clarifies further when mobile technology is considered a medical device; see below:

“A distinction must be made for mobile technologies according to whether they are used solely for research purposes or whether they have an additional medical purpose. Mobile technologies with an additional medical purpose (i.e. medical devices) are regulated by the medical devices legislation. A medical purpose exists if the data generated by the medical device influence medical decisions. It is forbidden to dispense non-compliant devices for a medical purpose (Art. 1, Art. 6. para. 1, Art. 8 para. 2, Art. 14, Art. 21 para. 2, Art. 23 of the Medical Devices Ordinance (MedDO) [SR 812.213]).

If the medical devices employed, including apps and software, are marked with a CE label for medical devices and are employed according to the approved intended use (not off-label use), the trial is purely a trial of a medicinal product (IMP). If, on the other hand, the medical devices employed do not bear a CE label for medical devices, or if they are employed for an off-label use, Swissmedic will assess both the IMP and the investigational medical device as part of the approval procedure. Information on submissions can be found in an information sheet (BW600_00_015e_MB > Combined trials with multiple types of products).

If the mobile technologies are not medical devices, the data are not considered to be trustworthy for individual medical purposes. The sponsor must ensure that such data does not erroneously influence medical decisions by mistake. In particular, these data must not be filed in patients’ records, nor should they be communicated to trial subjects, treating doctors, therapists or trial nurses without a compelling reason.”

7.15 Considerations/Requirements for Remote Monitoring

Section 2.6 of the Swiss position paper on DCTs covers “Remote source data verification” and indicates the following:

“If persons commissioned by the sponsor (“Monitors”) review uncoded personal data from trial subjects (e.g. medical records) in the course of source data verification and this review is not performed in person at the trial site but by employing electronic tools outside the trial site (remotely), suitable technical and organizational measures must be taken to ensure compliance with the Swiss Data Protection Act.

If the trial site sets up separate electronic access for the Monitors to the trial patients’ source data for the purpose of verifying the source data, measures must be taken to ensure that this application is protected appropriately, e.g. with two-factor authentication and a VPN (virtual private network). The Monitor may only be granted read-only rights.

The Human Research Act (HRA) regulates the export of health-related data to foreign countries and distinguishes between export of non-genetic data versus genetic data/biologic material. Swiss law allows the export of non-genetic data without a written informed consent when the requirements of Art. 6 FADP are met (Art. 42 HRA). In contrast, a written informed consent is obligatory for the export of genetic data/biological material. However, since most clinical trials process both non-genetic and genetic data, a clear-cut distinction between the two is not satisfying and therefore not really possible from a practical perspective. Moreover, there are ethical justifications to inform the persons in a transparent manner according to ethical standards that are higher than the legal minimum. Therefore, whenever uncoded personal data, regardless of whether non-genetic or genetic, are reviewed (monitored), the trial subjects must be informed comprehensively about this and must give their explicit consent to it.

DCTs must comply with the applicable law, in particular the provisions of the HRA, TPA, and FADP. In clinical trials, personal data or health data requiring special protection are regularly processed as clear data, pseudonymised or anonymised. In the latter case, there is no need to qualify as personal data or to be subject to the HRA and FADP, provided that the requirements for anonymisation are met. The Federal Data Protection and Information Commissioner, FDPIC, explains the law to be complied with and publishes guidelines, e.g. on the transfer of personal data abroad (cf. Transborder data flows (Home page (admin.ch))). The area of health data processing is subject to rapid technical, economic, political and legal changes nationally and internationally, which may have an impact on the assessment of DCT.”

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

Please refer to Section 7.14 above as it covers data capture outside the trial site using mobile technologies.