2. General Questions

2.1 Name of Regulatory Authority

Health Canada (HC), a federal government department, is the federal regulator of health products in Canada. HC's mandate is to ensure the provision of high-quality health services and seeks to reduce health risks while helping Canadians maintain and improve their health. As part of that, HC is responsible for the regulation of clinical trials involving a wide range of products, including drugs and biologics, natural health products (NHPs), and medical devices.

HC assesses clinical trial protocols to evaluate participant protection and safety, reviews drug quality, assures institutional ethics committee review, verifies principal investigator qualifications, and monitors and reviews adverse drug reactions.

2.2 Name of Ethics Committee 

The common abbreviation in Canada to qualify the ethics committee is either Institutional Ethics Committee (IEC) (or EC for Ethics Committee) or Research Ethics Board (REB).

Research Ethics Boards (“REBs”)

Canada has a decentralized process for the ethical review of clinical trial applications. A sponsor must obtain Institutional Ethics Committee (IEC) or Research Ethics Board (REB) approval for each participating trial site.

REBs are tasked with protecting trial participants, balancing the risks of research with the need to conduct it, and balancing the potential harms with the potential benefits.

The Health Canada-Public Health Agency of Canada (PHAC) – Research Ethics Board (REB) serves as an independent ethics review board to help ensure that all proposed or ongoing research involving human participants or communities carried out by, funded by, or otherwise under the auspices of Health Canada or PHAC, meets the highest ethical standards.

The Health Canada-PHAC REB does not review research that is not carried out by, funded by, or otherwise undertaken in association with HC or PHAC. Research projects not associated with HC or PHAC should be referred to the REB at the lead investigator’s institution and/or REB at the institution(s) where the research is being conducted.

Health Canada-PHAC REB does not oversee or regulate other REBs in Canada. Like other Canadian REVs, the Health Canada-PHAC REB is guided by the principles of the second edition of the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (TCPS 2).

2.3 Clinical Trial Application Language

English or French.

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

Yes. Review and approval of a clinical trial application by both Health Canada and the REB at each clinical site must be obtained prior to the initiation of any clinical trial/study. 

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

Yes. Review and approval of a clinical trial application by both Health Canada and the REB at each clinical site may be conducted in parallel. However, Health Canada will not authorize to start the clinical trial (or study) until the sponsor submits an IEC/REB approval (or submission) for each participating trial site.  

A few case scenarios may differ at the time of the submission wherein HC approval could be issued prior to EC or in few cases EC approval could be issued prior to HC. However, in both situations, the applicant needs to specify that the study was submitted to HC (and REB) with the name and address of the REB (when submitted to HC) and the date of submission (when submitted to EC). REB and HC may ask for proof of submission/approval from each.

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

Yes. The importation of the investigational product (IP) is discussed in detail in Section 5.10 of this guidebook.

2.7 Biological Specimen Export Requirements

According to the HC guidance on “Importing and Exporting Health Product for Commercial Use (GUI-0117)”, HC does not have jurisdiction over human biological materials to be imported or exported for testing or research purposes. Blood samples as well as cultures, diagnostic specimens, or research tissue are considered to be potential carriers of human or animal pathogens and are regulated by the Public Health Agency of Canada (“PHAC”) and the Canadian Food Inspection Agency (“CFIA”).

PHAC’s Centre for Biosecurity oversees the licensing process under the authority of the Human Pathogens and Toxins Act, SC 2009, c24 (“HPTA”) and the Human Pathogens and Toxins Regulations (SOR/2015-44) (“HPTR”). 

The HPTA states that a license must be issued by the Minister that authorizes the import or export of human pathogens or toxins. As all human biological materials are potential carriers of human pathogens, these materials are categorized by risk group based on risk to the individual/animal and risk to the community. 

• Risk Group 1 consists of microorganisms, nucleic acids, or proteins that are unable or unlikely to cause human or animal disease, so they are generally not considered to be pathogens, and are therefore exempt from the HPTA and Regulations licensing requirements. 
• Risk groups 2 through 4 are considered to be pathogens or toxins with moderate to high individual risk and low to high community risk and are subject to the HPTA and Regulations licensing requirements.

Individuals planning to conduct controlled activities (including producing, possessing, handling, using, storing, providing access to, transferring, disposing of, releasing, abandoning, or importing/exporting) with a human pathogen or toxin, whether imported or domestically acquired, must obtain a license.

Chapters 1 and 2 of the Canadian Biosafety Standard (CBS) contain detailed information and instructions on how to obtain a license for activities associated with Risk Groups 2 through 4.

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

Yes, though subject to certain conditions.

GMOs may be used in health products in Canada such as biologics (including vaccines), radiopharmaceuticals, pharmaceuticals and medical devices, and diagnostic tests. Their use is subject to conditions imposed by Health Canada which fall into three main categories: review and evaluation, compliance and enforcement activities, and monitoring and tracking. 

For more information, please consult the HC- “Biologics, radiopharmaceuticals and genetic therapies” page.

Additionally, HC has a guidance document: Preparation of Clinical Trials Applications for Use of Cell Therapy Products in Humans.

2.9 Is in-country sponsor presence/representation required?

Yes. The Sponsor is defined by Division 5, Part C of the F&D Reg as the individual, corporate body, institution, or organization that conducts a clinical trial. 

The HC Guidance Document for Clinical Trial Sponsor: Clinical Trial Applications defines a “Senior Medical or Scientific Officer” as “A scientific or medical officer residing in Canada, representing the sponsor, who is responsible for providing an attestation with respect to the Clinical Trial Application (CTA)/ Amendment at the time of filing, as outlined in Appendix 3 of the Drug Submission Application Form (HC/SC 3011).” 

A Contract Research Organization (CRO) and/or institutional site(s) can also represent the sponsor for any or all trial-related duties and functions and this should be specified in a written agreement and these entities should have or implement quality assurance and quality control. 

However, the ultimate responsibility for the data quality and integrity always falls under the sponsor's duties.

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

Yes. A qualified Investigator is required at each site.

The F&D Reg defines a “Qualified Investigator” as “The person responsible to the sponsor for the conduct of the clinical trial at a clinical trial site, who is entitled to provide health care under the laws of the province where that clinical trial site is located, and who is:

1. In the case of a clinical trial respecting a drug to be used for dental purposes only, a physician or dentist and a member in good standing of a professional medical or dental association; and
2. In any other case, a physician and a member in good standing of a professional medical association."

A Qualified Investigator is usually approved by an ethics committee based on their experience with a history of prior success conducting similar tasks. Researchers who have demonstrated the ability to successfully carry out research in a way that protects the rights and welfare of human subjects are most likely to continue acting like this. Sometimes, regardless of the experience, trainings are required before the ethics committee approves. 

Qualified Investigators at each participating site are required to sign the “Qualified Investigator Undertaking”. This form does not need to be submitted to HC (unless requested) but must kept by the sponsor.

There are provincial and territorial medical license requirements. Investigators must have the relevant medical license/s for those territories where they will conduct clinical research.

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

No, each site must appoint a Qualified Investigator. However, a Qualified Investigator can be appointed at more than one site.

Section 2.7.2 “Qualified Investigator” of the HC - Guidance Documents for Clinical Trial Sponsor: Clinical Trial Applications indicates the following:

“There must be no more than one (1) qualified investigator at each site. This restriction does not apply to sub-investigators.

Qualified Investigators must complete the Qualified Investigator Undertaking (QIU) or develop similar documentation that meets the requirements of the Regulations [C.05.012(3)(f)]. 

When the Qualified Investigator is conducting the trial at multiple sites, these sites may be identified by duplicating Part 3 of the QIU form as many times as necessary to capture all site addresses under the responsibility of the same QI. Only the final page of the QIU would contain the QI's signature. The additional pages listing multiple clinical trial sites are attached to Parts 1 and 2, and the complete document should be paginated (e.g., 1 of 5, 2 of 5, etc.).

If there is a change in the Qualified Investigator at a site, a new Clinical Trial Site Information Form must be submitted to Health Canada, and a new QIU form must be maintained by the sponsor.

Please note that the QIU form should not be submitted unless requested by Health Canada but must be maintained by the sponsor as per C.05.012.”

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?

In accordance with the F&D Reg, a sponsor is defined as an individual, corporate body, institution, or organization that conducts a clinical trial. This includes individuals, companies, institutions, or organizations that take responsibility for the initiation, management, and/or financing of a clinical trial.

Health Canada ICH Guidance makes the sponsor responsible for selecting the Qualified Investigator (QI) for the Clinical Trial (CT) and provides that there should be an agreement that clearly allocates responsibility between the sponsor and the QI.

In accordance with Section 5.2 of the Canadian ICH- Good Clinical Practice- (E6-R2), “the sponsor may transfer any of all of the sponsor’s trial-related duties and functions to a CRO, but the ultimately responsibility of the quality and integrity of the trial data always resides with the sponsor. The CRO should implement quality assurance and quality control.”

Pursuant to the ICH Guidance, any duty or function that is not specifically transferred to a CRO is retained by the sponsor. There are no specific legal requirements governing the choice of a CRO in Canada, and it is the sponsor’s decision whether to retain a CRO and which CRO to retain.

The Clinical Trial Agreement between the sponsor and CRO is not subject to review by Health Canada, but if the sponsor contracts a CRO to conduct the CT, the sponsor is required to provide contact information for and summarize the scope of duties of the CRO in the CT application for review by Health Canada.

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

Yes. In accordance with the Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications, sponsors should register their clinical trials on one of two publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization, ClinicalTrials.gov, and the International Standardized Randomized Controlled Trial Number (ISRCTN) Registry.

The Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans, the ethical benchmark, requires that clinical trials must be registered before recruitment of the first trial participant in a publicly accessible registry that is acceptable to the WHO or the International Committee of Medical Journal Editors (ICMJE). In addition, following registration, researchers are responsible for ensuring that the registry is updated in a timely manner with new information; safety, and, where feasible, efficacy reports; reasons for stopping a trial early; and the location of findings.

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)?

15 years

Under Part C, Division 5 of the Food and Drug Regulations, the sponsor shall maintain all clinical trial-related documents and records for a period of 15 years.

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

The following definitions provide a basis for a common understanding of Canada’s safety reporting requirements:

Adverse Event (AE) – Any adverse occurrence in the health of a clinical trial subject who is administered a drug that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.

Adverse Drug Reaction (ADR) – Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.

Serious Adverse Drug Reaction (SADR) or Serious Adverse Event (SAE) – Any untoward medical occurrence that at any dose: results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or causes a congenital anomaly/birth defect.

Serious, Unexpected ADR – A serious ADR that is not identified in nature, severity, or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.

Researchers are required to promptly report new information revealed during the conduct of the trial that might affect the welfare or consent of participants to the REB, to a publicly accessible registry, and to other appropriate regulatory or advisory bodies. In addition, when new information is relevant to participants’ welfare, researchers must promptly inform all participants to whom the information applies (including former participants). Researchers must work with their REBs to determine which participants must be informed, and how the information should be conveyed.

The reporting of ADRs is required under both the Regulations and the ICH Guidance. In general, only ADRs that are both (i) serious and (ii) unexpected are subject to expedited reporting to Health Canada. Expedited reporting for ‘expected’ reactions or reactions unrelated to the study drugs is generally not required.

During the Clinical Trial, the Qualified Investigator must notify the sponsor immediately of any ADRs, and after such report, submit a more detailed, written follow-up report to the sponsor. The sponsor is then required to inform Health Canada of ADRs, regardless of whether they have occurred within or outside Canada. A report must generally be filed within 15 days of the sponsor becoming aware of the ADR if the ADR is neither fatal nor life-threatening, and immediately or within a maximum of seven days where the ADR is fatal or life-threatening. In addition, when dealing with fatal or life-threatening ADRs, the sponsor must submit a report assessing the impact of the ADR on the CT within eight days of informing Health Canada.

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.)? 

Investigators and sponsors share responsibility for submitting interim and annual reports on the status of a clinical trial. The investigator is required to provide annual progress reports to the REB and submit interim progress reports to the REB and Health Canada if any significant changes are affecting the trial or risk to participants. The sponsor is no longer required to submit annual reports to Health Canada, under the old regulatory framework. The annual reports have been replaced by the annual update of the Investigator’s Brochure (see Q&A 14). The sponsor can justify the need (or not) to have interim reports during the conduct of the clinical trial. 

Within 12 months following the primary study completion, the investigator is required to submit a final report to the REB and the sponsor to the Regulatory Authority (i.e. HC) summarizing the trial’s outcome.

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

Yes. The QI should promptly provide written reports to the sponsor and the REB on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants. QIs must report new information that may affect the welfare or consent of participants to the REB, Health Canada, and other appropriate regulatory or advisory entities. When new information is relevant to participants’ welfare, researchers must promptly inform all participants to whom the information applies (including former participants). Researchers should work with their REBs to determine which participants must be informed, and how the information should be conveyed. New information may comprise a range of issues, including, but not limited to:

• Changes to the research design
• Evidence of any new risks
• Unanticipated issues that have possible health or safety consequences for participants
• New information that decisively proves the benefits of one intervention over another
• New research findings, including relevant non-trial findings
• Unanticipated problems
• Closure of trials at other sites for reasons that may be relevant to the welfare or consent of participants in the ongoing trial

The investigator should submit written summaries of the trial status to the REB as per their requirements.

Investigators are also required to report to the REB any protocol deviations/violations which:

• Impact the rights, safety, and well-being of a research participant 
• Jeopardize the study efficacy or data integrity
• Constitute a breach of privacy

Deviations from or changes to the protocol to eliminate immediate hazards to the study participants must be reported to the REB within 7 calendar days of their discovery. All other deviations must be reported to the applicable REB within 15 calendar days of their discovery.

Methods to report protocol violations may differ between REBs. Please check with the relevant REB for additional information. 

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

Yes. The F&D Reg does not require the sponsor to provide insurance coverage to investigators, institutions, or trial participants, but this is superseded by GCP, which guides sponsors on providing insurance. 

Compensation

Injury or Death

The Canadian regulations do not require compensation for trial participants in the event of trial-related injuries or death. GCP indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

It is standard practice for sponsors to carry liability insurance coverage on clinical trials and for sponsors and investigators/sites to enter into indemnity agreements. Some REBs may also require evidence of liability insurance coverage and an indemnity agreement to approve the study protocol. A global insurance certificate is accepted.