2. General Questions
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2. General Questions
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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.
https://www.canada.ca/en/health-canada.html
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).
Canada has a decentralized process for the ethical review of clinical trial applications. A sponsor must obtain IEC or 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) - 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.
Each of the REB board members needs to be available and willing to commit time and actively participate in discussions and provide input to research applications/protocols.
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 a 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 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 IP is discussed in detail in section 5.12.
2.7 Biological Specimen Export Requirements
Health Canada 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 HPTA and the HPTR. The Human Pathogens and Toxins Act, SC 2009, c24, 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 Human Pathogens and Toxins Act 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 Human Pathogens and Toxins Act 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) https://www.canada.ca/en/public-health/services/canadian-biosafety-standards-guidelines/third-edition.html and Chapter 21 of the Canadian Biosafety Handbook https://www.canada.ca/en/public-health/services/canadian-biosafety-standards-guidelines/handbook-second-edition.html, 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
- Monitoring and tracking
Each of these categories of conditions is described in detail at the following link:
2.9 Is in-country sponsor presence/representation required?
No.
A sponsor may be domestic or foreign (Part C, Division 5, Food and Drug Regulations). A foreign sponsor is required to have a senior medical or scientific officer who is residing in Canada who will represent the sponsor, and sign and date the application and the clinical trial attestation form. 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 / local chief / coordinating investigator or can the PI be based in a foreign country?
As per Health Canada requirements, a PI is referred to as a “Qualified Investigator” or QI. A local Qualified Investigator (“QI”) is required to be identified and present in Canada. See section 2.9 above.
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 right and welfare of human subjects are most likely to continue acting like this. Sometimes, regardless of the experience, training is required before the ethics committee's approval.
2.11 If the applicant is a CRO or a third party, does the regulatory authority need any authorization or transfer of obligations from the sponsor? Is there any standard template available? Does the authorization letter need to be notarized and/or apostilled?
In accordance with the Food and Drug Regulations, 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.
The ICH Guidance provides that the sponsor may transfer any or all of its trial-related duties and functions to a CRO. However, the sponsor retains ultimate responsibility for approval of the CT application, and for the quality and integrity of the CT data. Any trial-related responsibilities transferred to a Contract Research Organization (CRO) should be specified in a written agreement. 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.
2.12 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 (https://www.canada.ca/en/health-canada/services/drugs-health-products/drug-products/applications-submissions/guidance-documents/clinical-trials/clinical-trial-sponsors-applications.html) 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.
2.13 What is the local requirement for clinical study documents archival, minimum years for the archival, and the specific format followed (electronic/paper and/or both)?
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.
Provincial law, institutional policies, and contractual agreements with Qualified Investigators, Research Ethics Board, or others may require the sponsor to maintain records for a different period of time and/or under different circumstances. Where it's not possible to comply with both sets of requirements, the federal regulations would govern and the record must be retained for 15 years.
2.14 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. (See appendix A in the reference below)
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.
2.15 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 there are any significant changes affecting the trial or risk to participants. The sponsor is required to submit annual reports to Health Canada. The sponsor can justify the need (or not) to have interim reports during the conduct of the clinical trial.
Upon completion of the trial, the investigator is required to submit a final report to the REB and the Regulatory Authority (i.e. HC) summarizing the trial’s outcome.
2.16 Do the country regulations allow the Decentralized Clinical Trial (DCT) model (e.g., eICF, ePROs administration, remote investigator site, etc.)?
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.
Canada's centralized clinical trials and vast geography create barriers to trial participation for patients/participants in remote and rural settings. There is a proposed framework for DCTs participation in Canada called "The Canadian Remote Access Framework for Clinical Trials (CRAFT)" that represents a risk-based approach used by site investigators and includes specific recommendations to ensure research experience, regulatory compliance, and patient safety.
There is a paper that can be visited at https://pubmed.ncbi.nlm.nih.gov/34677247/ for more information.
The notice on the Management of Clinical Trials during the COVID-19 Pandemic: Notice to Clinical Trial Sponsors (Health Canada, May 2021)- updated 27 Jan 2023 displays some of the DCT components allowed in Canada (e-consent and IP supply) whereas no regulation is found for example for e-signature, ePRO, etc.
Please refer to the discussion of Remote Monitoring in section 7.
2.17 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.
From the research conducted, clinical trials with DCT elements have been conducted in Canada. It is uncertain whether a full DCT has been conducted.
2.18 Are there any non-regulatory DCT initiatives in the country, such as where investigator sites and local CROs founded an alliance?
From the research conducted, this has not been established.
2.19 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol (that is a breach that is likely to affect to a significant degree either the safety or physical or mental integrity of the subjects of the trial; or the scientific value of the trial)?
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.
2.20 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?
Yes.
The Food and Drug Regulations do 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
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.
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