7. Decentralized Clinical Trials

The Government of Canada issued temporary interim orders (“IOs”), and again on 3 May 2021, to provide flexibility in order to enable the conduct of clinical trials on medical devices and drugs related to Covid-19 during the pandemic. The application of the IOs and lessons learned from trials conducted during the Covid-19 pandemic helped Health Canada develop its proposed Clinical Trials Regulatory Modernization Initiative (“Modernization Initiative”). Part of this initiative was an invitation to national stakeholders, during Spring/Summer 2021, to comment in writing on a consultation paper and participate in interactive webinars. 

One of the key aspects of this initiative is to modernize the regulation of clinical trials in Canada, particularly DCTs. The findings of the initiative are contained in a report entitled “What we heard: Consultation on clinical trials regulatory modernization initiative (spring and summer 2021)” (“The Consultation Report”). Suggestions were submitted on how to improve the clinical trials framework, which includes the need for further clarification on technological requirements used to support DCTs.

Furthermore, the Canadian Institutes of Health Research (“CIHR”), Canada’s federal funding agency for health research, announced the launch of a Clinical Trials Fund (“CTF”) on 22 June 2022 as part of Canada’s Biomanufacturing and Life Sciences Strategy, a CAD $2.2 bn investment to develop Canada’s clinical trial infrastructure and ensure it is prepared to deal with any future pandemics. 

The Modernization Initiative to refine policy and develop regulations to modernize Canada’s clinical trial framework is currently underway. Its progress may be monitored via a website entitled “Forward Regulatory Plan 2023-2025: Enabling the Biomanufacturing and Life Sciences Strategy- Modernizing Clinical Trials to Support Innovation”.

The updated Regulation is expected to be released in early 2026 coinciding with the finalization of the ICH GCP E6 R3.

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

Yes. Canada is in the process of modernizing its regulations to enable DCTs to be conducted. At present, DCT elements are subject to conditions imposed by Health Canada and REBs, on review of CT applications. 

Under certain circumstances, following the respective guideline of a site REB, informed consent procedures for participation in a research study or a clinical trial may be conducted remotely. The informed consent process must be clearly outlined in the protocol and submitted to the REB for review and approval before any implementation. This procedure shall comply with the current version of the Tri-Council Policy Statement and where applicable ICH-GCP and the Canadian Food and Drug Regulations for Health Canada. 

HC encourages sponsors wanting to conduct a DCT in Canada to engage with HC regulators at early stages on the protocol to discuss suitability of the study design.

Sponsor can arrange a Pre-application meeting with the Review Directorates. GCP requirements can be discussed with Compliance & Enforcement Unit.

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

Health Canada has not yet published an official guidance on conducting DCTs in Canada, but DCT elements are allowed. Some DCT elements are already described in the existing regulatory framework (please see the following sections below for more information).

At provincial level, there is some DCT guidance available:

• Clinical Trials Ontario: Decentralized Trials Resource Guide
• Canadian Cancer Trials Group (CRAFT): Proposed Framework for Decentralized Clinical Trials Participation in Canada

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

Overall, DCT elements are accepted but it is important that the sponsor takes into consideration the existing recommendations provided by Health Canada. 

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. 

Yes. At least a couple of clinical trials can be found on the Health Canada Clinical Trials Database when the word “remote” is used for the search.

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 information has been found on this matter.

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

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

Sponsors 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 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 informed on information flow, and how to make contact with 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.

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

eConsent is permitted in Canada if all applicable regulatory/ICH-GCP requirements are met, including that the system must be properly validated with documented procedures and appropriate training, all required elements must be present in the ICF, and the information must be stored for 15 years. (The clinical trial records retention period for drugs has been changed from 25 years to 15 years as per section C.05.012 (4) of the Food and Drug Regulations, as of February 11, 2022.)

Art 10.2 of the “The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans - TCPS 2 (2022)” indicates the following: 

“…The consent process should be based on mutual understanding of the project goals and objectives between the participants and the researcher. The participant may perceive attempts to legalize or formalize the process as a violation of that trust. Qualitative researchers use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (a consent log, audio or video recordings, or other electronic means). Evidence of consent may also be documented via completed questionnaires (in person, by mail, or by email or other electronic means).” 

Remote consent is permitted if the communication platforms and consent approaches to be used have received prior approval by REBs, privacy, and IT departments.

Health Canada regulations note that the process for obtaining informed consent via electronic means should also be detailed in an SOP, including how the form will be explained and discussed with the clinical trial participant (e.g.: will the participant have the option to sign a paper copy, bring a copy home or have access to an electronic signed copy, etc).

Health Canada covered “remote consent” under Part 3 of their Clinical Trials for Medical Devices and Drugs Relating to Covid-19 Regulations.

“PART 3. General

• Remote written informed consent

– 36 (1) If a qualified investigator is not able to obtain, in person, the written informed consent of a person to participate in a clinical trial in respect of a COVID-19 medical device for which a COVID-19 medical device authorization has been issued or a COVID-19 drug for which a COVID-19 drug authorization has been issued, the qualified investigator may obtain the written informed consent remotely.

• Non-written informed consent

– (2) In the case where the person is not able to provide their written informed consent, the qualified investigator may obtain their non-written informed consent if the following conditions are met:

• (a) the qualified investigator reads the contents of the informed consent form to the person;

• (b) the person provides their informed consent before a witness; and

• (c) an attestation by the witness that the person has provided their informed consent is provided to the qualified investigator as soon as feasible.”

7.8 Considerations/Requirements for the Use of eSignatures

eSignature is permitted if the considerations for eConsent and Remote Consent, as applicable, mentioned in Section 7.7 above, have been met. 

Subsection C.05.012(4) of the F&D Regs require a participant to have the option to access an electronic signed copy of an eConsent form, which itself is required to be obtained in compliance with the requirements for obtaining informed consent, though via electronic means. It may be assumed that eSignature may include any requirement for countersignature as required by the procedure for obtaining informed consent as followed in clinical trials.

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

This is not specifically addressed in the national legislation; however, the use of ePROs within clinical trials is accepted in Canada.

Electronic patient-reported outcomes (ePRO) devices and software are considered Digital Health Technologies (DHTs). The latest recommendations on DHTs were provided by Health Canada during the FDA-MHRA-HC Good Clinical Practice and Pharmacovigilance Symposium which took place between the 13 and 15 Feb 2024:

• Key is to ensure that GCP requirements for Data Integrity (DI) are implemented throughout the data lifecycle of all records.
• Requires adequate planning and risk assessment prior to system implementation.             
• System design and adequate control for all record formats are important.
• The right data needs to be collected with appropriate tools.

Compliance fundamentals:

• Defined and controlled data flow
• Risk identification and management procedures
• Electronic systems required validation (for intended use)
• Implementation of adequate procedures / training
• System controls / access / oversight

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

It is important to highlight that health care providers in Canada (including investigators) are required to obtain licenses in those provinces or territories where they will practice. Each province and territory in Canada has its own nursing regulatory body responsible for licensing and regulating nurses within their jurisdiction.

The use of HHC in Clinical Trials is not specifically addressed in the national legislation; however, it is being used in DCT/hybrid clinical trials. 

Below are some general considerations on the use of HHC:

• Investigator delegation and oversight must meet the same standards as traditional trials.
• Delegation of responsibilities must be well documented.
• Investigator to ascertain suitability for trial procedures to be conducted at the participant’s home.
• Inclusion/exclusion criteria should include provisions related to adequacy of participant’s home.
• Participants should be informed during the consent process about planned trial procedures conducted at their home.
• Trial-related procedures at home should only be done if the procedures do not cause additional risk to trial participant or reliability of the data and the person performing the task is qualified and/or trained to perform the task. 
• The sponsor and/or investigator should ensure that appropriate guidance and training is provided to the delegated person(s) to conduct the tasks at home correctly. 
• The insurance or indemnity or a guarantee or a similar arrangement should be in place to cover any damage resulting from trial-related procedures performed at home. 
• Investigator should monitor compliance of the trial participant considering the lack of/decrease in the number of face-to-face visits/meetings between the trial participant and the investigator and/or delegated staff. 
• Trial participants should be given the opportunity to visit the investigator in person if needed/preferred and they should be able to have a direct contact line if further support to perform a trial related task/collect data is needed. 
• There should be procedures in place for reporting and management of adverse events noticed by the trial participant or by any delegated person during home visits.
• The sponsor should provide alternatives if a trial participant is unable or not willing to use her/his/their own private device (mobile phone, tablet, etc.) to capture trial data. 

Qualifications required on the HHC will also depend on the type of responsibilities allocated to the individual HHC.

7.11 Considerations/Requirements for HHC- Home Lab Collection

The requirements for home lab collection in Clinical Trials are not specifically addressed in the national legislation; however, it is being implemented in clinical trials. 

Below are some general considerations on the home collection of biological samples:

Collection of biological samples at home may be permitted, as long as the procedures involved do not cause any additional risk to trial participant or reliability of the date and the person performing the task is qualified and/or trained to perform the task. If biological samples are collected at home, it should be considered whether persons taking the sample are qualified and allowed by their local legislation to take the sample. In addition, adequate handling and storage conditions for the samples throughout the entire process should be assured. Collection of biological samples will require to follow biosafety protocols.

There may be additional provincial and territorial training requirements, such as IATA training for handling infections and biological material.

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

It is allowed subject to certain conditions.

Direct-to-participant approaches may increase burden on patients and sites and may not be appropriate for all study populations or study types. Participants may be identifiable to the 3rd party vendor and processes must be put into place to ensure vendors do not pass the participant information to the sponsor. It is also necessary to ensure compliance with provincial privacy regulations, as well as professional and regulatory requirements for health care providers. 

According to Health Canada's “Management of clinical trials during the COVID-19 pandemic: Notice to clinical trials sponsors” (which is still in place until the framework established through the “Clinical Trials Modernization Initiative" is implemented):

“It's allowed to ship clinical trial investigational products from Canadian sites directly to patients under the F&D Regs.

Product formulations that are acceptable for direct shipment are:

• tablets and injectables that a participant may take on their own;
• medications that don't have to be administered in a hospital or clinic; and
• medications that don't have any special conditions for handling.

When transporting, handling and storing investigational products, make sure to reduce the risk of exposure to temperatures outside labeled storage conditions. Please see Health Canada's guidelines for temperature control of drug products during storage and transportation (GUI-0069).

Making sure that:

• the investigational drug has been received by the participant (verification is required);
• record-keeping complies with the regulatory requirements of section C.05.012 of the FDR;
• maintain complete and accurate records for a drug used in a clinical trial, including records for shipping, receiving, disposing, returning and destroying the drug;
• the process in the participant's study record is accurately documented.”

7.13 Considerations/Requirements for the Use of Telemedicine

From the research conducted, no specific guidance could be located which specifically regulates telemedicine as a feature of DCTs. 

Within standard medical care, the Canadian “College of Physicians and Surgeons” at each province have published guidance for “virtual care”. This article provides an overview of “Cross-Canada virtual care licensure requirements and best practices.”

7.14 Considerations/Requirements for the Use of Wearables

From the research conducted, no specific guidance could be located which specifically regulates wearables as a feature of DCTs.

However, wearables are considered as a Digital Health Technology, as this is defined as:

• Any instrument, tool or platform utilized at any point in the data lifecycle of electronic data captured and reported as part of a clinical trial.
• Any computer system, software application and input sensor/devices used to collect, manage, transmit, store or report electronic data.
• Includes remote data acquisition tool.

Refer to Section 7.9 for the Considerations for DHTs.

7.15 Considerations/Requirements for Remote Monitoring

As the sponsor may use a variety of approaches to monitor the trial, it is important to make sure that the clinical trial protocol describes the operational aspects of the trial and how it will be implemented. 

The risk assessment needs to be described in the monitoring plan which should describe how monitoring will be implemented to assess data quality and integrity and protocol compliance. The monitoring plan should also specify for reviewing the trial records and source documents with any unique aspect related to the DCT procedures. 

Monitoring and remote monitoring visits may occur and are subject to Health Canada and REB conditions. This includes the fact that the Informed Consent Form should inform the participant that their medical records and study information may be reviewed remotely by the sponsor while maintaining patient’s privacy and confidentiality, and the REB may want the ICF to be explicit on the mediums for record access. 

In the absence of regulations or guidance from Health Canada, the guidelines advise that the principles of ICH-GCP be deferred to. Additional considerations on remote monitoring are provided by Clinical Trials Ontario under their “Decentralized Trials Resource Guide.”

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

From the research conducted, no specific guidance could be located which specifically regulates the use of Digital Health Technologies as a feature of DCTs in Canada. 

Digital Health Technology is defined as:

• Any instrument, tool or platform utilized at any point in the data lifecycle of electronic data captured and reported as part of a clinical trial.
• Any computer system, software application and input sensor/devices used to collect, manage, transmit, store or report electronic data.
• Includes remote data acquisition tool.

Refer to Section 7.9 for the Considerations for DHTs.

We suggest that you refer to the US FDA Guidance “Digital Health Technologies for Remote Data Acquisition in Clinical Investigations”, as Health Canada tends to refer to US regulatory guidance for certain topics.