Health Canada

As per the CanadaFDA, the CanadaFDR, and the G-CanadaCTApps, Health Canada (HC) is the competent authority responsible for clinical trial approvals, oversight, and inspections in Canada. The G-CanadaCTApps states that the HC grants permission for clinical trials to be conducted in the country, and regulates the sale and importation of drugs for use in clinical trials in accordance with the CanadaFDR provisions.

As per CAN-29, HC is one (1) of five (5) federal agencies within Canada’s “Health Portfolio” overseen by the Minister of Health. As delineated in CAN-23, HC’s Health Products and Food Branch (HPFB) is the national authority that regulates, evaluates, and monitors therapeutic and diagnostic product safety, efficacy, and quality, and reviews the information submitted in the clinical trial application. Per CanadaFDA, if the Minister believes on reasonable grounds that the use of a therapeutic product, other than the intended use, may present a risk of injury to health, the Minister may, by order, establish rules in respect of the importation, sale, conditions of sale, advertising, manufacture, preparation, preservation, packaging, labeling, storage, or testing of the therapeutic product for the purpose of preventing, managing, or controlling the risk of injury to health.

Per CAN-16, HPFB’s activities are carried out by nine (9) Directorates, including the Pharmaceutical Drugs Directorate (PDD) and the Biologic and Radiopharmaceutical Drugs Directorate (BRDD). Per CAN-18, PDD regulates pharmaceutical drugs for human use. Specifically, PPD:

• Reviews scientific information to assess the safety, efficacy, and quality of a prescription drug
• Assesses the potential benefits and risks of a prescription drug
• Reviews clinical trial applications for prescription drugs to ensure that the studies are well-designed and that participants will not be exposed to undue risk
• Monitors the evolving safety of drugs in development through the review of adverse reaction reports
• Makes non-marketed drugs available to health professionals for patients when conventional therapies have failed, are not suitable, or are not available
• Provides Canadians with science-based medical information they need to make informed choices

CAN-17 indicates that the BRDD regulates biological drugs, radiopharmaceuticals, and cells, tissues, and organs for human use, including clinical trials.

In addition, the G-CanadaCTApps indicates that the PDD’s Office of Clinical Trials (OCT) and the BRDD’s Office of Regulatory Affairs (ORA), among others, are directly involved with the clinical trial review and approval process for pharmaceutical, biological, and radiopharmaceutical drugs. CAN-18 states that the PDD Director General's Office oversees pharmaceutical clinical trials. Per the G-MDSA, the Therapeutic Products Classification Committee (TPCC) may be consulted when it is not clear whether a product should be classified as a drug or device. The committee makes recommendations on the classification of a product as either a drug, medical device, or combination product. When appropriate, other regulatory areas of HC may be asked to participate in the committee's discussion.

As per CAN-41, HC has established a regulatory innovation agenda, which aims to provide more regulatory flexibility to support innovative research and health product development. For more details, see CAN-41.

International Alignment

Per CAN-10, Canada is an official member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). CAN-50 indicates that HC adopted the ICH Guideline for Good Clinical Practice E6(R3) (CAN-52). The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence. More generally, CAN-50 notes HC-implemented ICH guidance takes precedence over other HC guidance when they are inconsistent. Also see CAN-50 for details on all the ICH guidelines implemented by HC. For any questions or comments, contact HC’s ICH Coordinator via email at ich@hc-sc.gc.ca.

Contact Information

According to the G-MDSA and CAN-18, Health Canada PDD contact information is as follows (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

Office of Clinical Trials
Pharmaceutical Drugs Directorate
Health Canada
Holland Cross, Tower B
1600 Scott Street, 5th Floor
Address Locator: 3105A
Ottawa, Ontario, Canada
K1A 0K9

Phone (General Enquiries): 613-957-0368
Fax (General Enquiries): 613-952-7756
General Inquiries: oct.enquiries-requetes.bec@hc-sc.gc.ca
Pre-CTA Meeting Requests: oct.pre.cta-dec.bec@hc-sc.gc.ca (per G-MDSA)

Per G-MDSA, the following is the contact information for biologic clinical trials:

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Tunney’s Pasture
100 Eglantine Driveway
Address Locator: 0601C
Ottawa, Ontario, Canada
K1A 0K9

Phone: 613-957-1722
E-mail: brdd.ora@hc-sc.gc.ca

Overview

In accordance with the CanadaFDA, Health Canada (HC) reviews, evaluates, and approves applications for clinical trials using authorized therapeutic products. HC also approves the sale or importation of drugs for use in clinical trials. (See the Manufacturing & Import section for additional information on importation.) As delineated in the CanadaFDR and the G-CanadaCTApps, institutional ethics committee (EC) review is required for each clinical trial site and may occur in parallel with HC’s clinical trial application (CTA) review and approval. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. See CAN-23 for background information on how HC reviews drugs in Canada.

Per the CanadaFDA, a “therapeutic product” is defined as a drug or device, or any combination of drugs and devices, but does not include natural health products; and “therapeutic product authorization” refers to a license that is approved for the import, sale, advertisement, manufacture, preparation, preservation, packaging, labeling, storage, or testing of a therapeutic product. As per the G-CanadaCTApps, a drug is defined as a pharmaceutical, biologic, gene therapy, blood product, vaccine, and radiopharmaceutical for human use that is to be tested in a clinical trial. HC’s scope of assessment includes clinical trials (Phases I - III) using:

• Drugs not authorized for sale in Canada in development and in comparative bioavailability studies
• Marketed drugs where the proposed use of the drug for one (1) of the following is different: indication(s) and clinical use; target patient population(s); route(s) of administration; or dosage regimen(s)

Clinical Trial Review Process

As set forth in the G-CanadaCTApps and CAN-23, HC’s Health Products and Food Branch (HPFB) coordinates the CTA approval process. The G-CanadaCTApps and CAN-23 state that prior to initiating the trial, the sponsor must file a CTA to the appropriate HPFB Directorate. CTAs involving pharmaceutical drugs should be sent to the Pharmaceutical Drugs Directorate (PDD), and CTAs involving biologics and/or radiopharmaceuticals should be sent to the Biologic and Radiopharmaceutical Drugs Directorate (BRDD).

The G-CanadaCTApps indicates that upon receipt of a CTA, the HPFB Directorate (PDD/BRDD) screens the application package for completeness. If deficiencies are found, the Directorate sends the sponsor a Request for Clarification or a Screening Rejection Letter. If the Directorate finds the application complete, an acknowledgement letter is issued to indicate the 30-day default review period commenced on the date of receipt. See CAN-23 for more information.

Per the G-CanadaCTApps, once a clinical trial is authorized, the sponsor is allowed to sell or import a drug for use in a trial, if a CTA has been filed with HC and has not received an objection within 30 days. If the clinical trial is authorized, a No Objection Letter (NOL) is issued. If the CTA is rejected, a Not Satisfactory Notice (NSN) is issued. During the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. Please see the G-CanadaCTApps for special requirements regarding reviews of comparative bioavailability studies and joint reviews of clinical trials covering a combination of devices, biologics, and pharmaceuticals. See the Submission Process section for detailed application submission requirements. See CAN-23 for more information.

Per the G-CanadaCTApps, soon after HC issues an NOL, it will publish the following information about the clinical trial in HC’s publicly accessible database:

• Protocol number
• Protocol title
• Drug name
• Medical condition
• Study population
• Authorization date
• Sponsor name
• HC control number
• Trial start and end dates, if known

The CanadaFDR and the G-CanadaCTApps also delineate that a clinical trial application-amendment (CTA-A) is required for proposed changes to a previously authorized study when the changes to clinical trial drug supplies affect the quality or safety of the drug, or when the changes to an authorized protocol alter the risk to clinical trial participants, or both. CTA-As must be authorized by HC prior to implementation of the changes. However, if the sponsor is required to immediately implement changes because the clinical trial or the use of the clinical trial drug endangers the health of participants or other persons, the sponsor may immediately make the amendment without prior review by HC. Sponsors must notify HC of this change, provide the relevant rationale in support of the immediate implementation, and file a CTA-A that clearly identifies the change and rationale for immediate implementation of the change within 15 days after the amendment implementation date. In addition, sponsors may make the following changes immediately if it notifies HC in writing within 15 days after the date of the change: a change to the chemistry and manufacturing information that does not affect the quality or safety of the drug; or a change to the protocol that does not alter the risk to the health of a participant.

As per the G-Dcntrl, HC requires information about decentralized elements in the clinical trial application to review whether these elements were designed to minimize risk to participants, support appropriate oversight and monitoring throughout the trial, and help achieve trial objectives. Additionally, sponsors must attest that the trial, including all decentralized elements, will be conducted according to good clinical practice (GCP). Depending on the decentralized elements and activities within the proposed trial known at the time of application, HC will review how participant visits and clinical trial activities will be conducted (e.g., in person, by telephone or telehealth platform, or through third parties or vendors). See G-Dcntrl for more details about clinical trials with decentralized elements.

As delineated in the CanadaFDA and the G-Inspections, HC is authorized to implement an inspection strategy and to ensure compliance with CanadaFDA. The G-Inspections states that HC’s Regulatory Operations and Enforcement Branch (ROEB) monitors compliance, which is assessed through inspections and other compliance and enforcement activities, such as compliance verifications. Compliance verifications of clinical trials may be initiated when there are reasonable grounds to believe that non-compliance may have occurred or is occurring and that enforcement measures may be necessary (e.g., complaints received regarding specific trials, reports of adverse drug reaction(s), or reports from other regulatory authorities). The Clinical Trial Compliance Program within ROEB is responsible for clinical trial site selection for inspections in collaboration with the PDD and the BRDD. A risk-based approach is applied in the site selection process to minimize the potential health risks inherent to clinical trials involving human participants. The selection of sites for inspection is based on a variety of criteria to select sites throughout all levels of the drug assessment and regulatory approvals process. For clinical trial sites with decentralized elements, G-Dcntrl states that the main location of the clinical trial site associated with the qualified investigator (QI) is the primary point of contact for an inspection. HC inspectors may request documentation from sponsors and QIs to demonstrate adequate coordination, oversight, and monitoring of delegated parties, as well as the measures in place to protect participant safety. See the Risk-Insp for a risk classification guide used by ROEB; this guide describes how inspectors classify risk-based observations and assign a rating, promotes consistency, and provides examples of inspection observations.

Per the CanadaFDR, HC will suspend the authorization to sell or import a drug for clinical trial purposes if it has reasonable grounds to believe that:

• The sponsor has contravened any relevant laws or regulations
• Any information submitted in respect of the drug or clinical trial is false or misleading
• The sponsor has failed to comply with GCP
• The sponsor has failed to provide information or samples as required by the regulation

See the CanadaFDR for additional details on HC’s suspension and cancellation responsibilities.

Expanded Access Clinical Trial

The Expd-CTs explains that in Canada, an expanded access clinical trial is a type of clinical trial that provides access to investigational products (IPs) that have the potential to treat people living with medical conditions who do not qualify for other clinical trials or are not able to participate in one. When appropriate, expanded access clinical trials can use more flexible protocols and a decentralized model to facilitate access for a larger, potentially more diverse population of participants, in more accessible settings. Since expanded access clinical trials are a type of clinical trial under the CanadaFDR, they require a CTA for review by HC. HC will review applications for the sponsor’s evidence from previous studies that the proposed use of the IP would not endanger the health and safety of participants. HC assesses all CTAs on a case-by-case basis. CTAs for expanded access clinical trials follow the same review processes and timelines as other clinical trials. HC scientists and physicians review expanded access CTAs to assess whether:

• The risks in using the drug in the trial are considered and would not endanger health and safety
• The best interests of those taking part in the trial have been considered, including that drugs are used in the right way for the participants being studied
• The goals of the trial can be met

Per the Expd-CTs, group-level access to a drug in Canada is available only through an expanded access clinical trial and not through the individual-patient Special Access Program. Therefore, sponsors wishing to include a Canadian arm in an international expanded access program for multiple patients must do so through an expanded access clinical trial.

According to CAN-56, there are no fees to submit a clinical trial application in Canada.

Overview

As indicated in the CanadaFDR and the G-CanadaCTApps, Canada has a decentralized process for the ethical review of clinical trial applications, and requires the sponsor to obtain institutional ethics committee (EC) approval for each participating trial site. (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information.

Per CAN-35 and CAN-13, all proposed or ongoing research involving human participants carried out by, funded by, or otherwise under the auspices of Health Canada (HC) or the Public Health Agency of Canada (PHAC) must obtain approval from a joint EC representing those two (2) agencies—as well as complying with the CanadaFDR and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. This joint EC is known as the HC-PHAC REB. Further, if an institution is conducting an HC- or PHAC-funded project, the HC-PHAC REB must review and approve the research even if it has been previously reviewed and approved by another EC. See CAN-35 for details on the HC-PHAC REB’s development, responsibilities, and composition. HC’s operational policy (CAN-13) outlines policies and procedures that the joint HC-PHAC REB must follow when reviewing clinical trials.

Institutional ECs are required to comply with the provisions delineated in the CanadaFDR, the G-CanadaCTApps, and CAN-52. Note that per CAN-50, HC-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. In addition, institutional ECs are guided by the G-TCPS2. Jointly developed by Canada’s three (3) federal research agencies: the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Social Sciences and Humanities Research Council (SSHRC), the G-TCPS2 is a policy that sets the ethical benchmark for all Canadian institutional ECs. However, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guideline as a condition of funding. According to CAN-14, the CIHR, the NSERC, and the SSHRC created the Panel on Research Ethics (PRE) to promote the ethical conduct of research involving human participants. The PRE develops, interprets, and implements the G-TCPS2.

Ethics Committee Composition

As delineated in the CanadaFDR and the G-CanadaCTApps, institutional ECs must have at least five (5) members representing a mixed gender composition, the majority of which are Canadian citizens or permanent residents, and must include:

• Two (2) members from a scientific discipline, with broad experience in the relevant research methods and areas, one (1) of whom is from a medical or dental discipline
• One (1) member knowledgeable in ethics
• One (1) member knowledgeable in relevant Canadian biomedical research laws
• One (1) member from a nonscientific discipline
• One (1) community representative

The G-TCPS2 mirrors these EC composition requirements, and also requires a Chair who is responsible for ensuring that the ethics review process conforms to the requirements of G-TCPS2. The Chair provides overall leadership for the EC and facilitates the review process based on institutional policies and procedures and the G-TCPS2. The Chair should monitor the EC’s decisions for consistency and ensure that these decisions are recorded accurately and communicated clearly to researchers in writing as soon as possible by the Chair or designate. Institutions must provide the necessary resources and adequate administrative support to enable the EC Chair to fulfill their responsibilities. As mentioned earlier, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guidance as a condition of funding.

Also, see CAN-52 for additional guidance on EC composition, functions, and operations. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Terms of Reference, Review Procedures, and Meeting Schedule

According to G-TCPS2, institutions must have in place written procedures for the appointment, renewal, and removal of EC members, including Chairs. Further, institutions must have clear written policies describing the mandate of each EC. An institution may wish to use different models for the ethics review of research conducted under its auspices.

The G-TCPS2 states that an EC should have adequate expertise, experience, and training to understand the disciplines, methodologies, and approaches of the research that it considers for research ethics review. Institutions should ensure that all EC members receive appropriate education and training in ethics review of research involving humans, to enable them to fulfill their duties. This includes providing training opportunities for all members in core principles and understanding of the G-TCPS2, basic ethics standards, applicable institutional policies, and legal or regulatory requirements. It includes an understanding of the role and mandate of ECs and responsibilities of EC members. Training should be tailored to the types and complexities of the research that the EC reviews.

Per the G-TCPS2, when there is less than full attendance, decisions requiring full review should be made only when the members present have the specific expertise, relevant competence, and knowledge necessary to provide an adequate ethics review. Ad hoc advisors, observers, research ethics administration staff, and other attendees must not be counted toward quorum or permitted to vote; decisions made without quorum are not valid or binding. ECs must hold regular meetings and normally meet face to face to review research not assigned to delegated review. Where members are geographically dispersed or exceptional circumstances prevent attendance, participation by phone, videoconference, or other technology may be acceptable, provided quorum is maintained and the Chair ensures active participation. A schedule of EC meetings should be communicated to researchers, and ECs should establish a process for reaching decisions requiring full review, such as consensus or, where necessary, a vote.

G-TCPS2 indicates that proportionate review means the level of EC review is determined by the level of foreseeable risk to participants: the lower the risk, the lower the level of scrutiny through delegated review; the higher the risk, the higher the level of scrutiny through full-board review. Full EC review should be the default requirement for research involving humans. Where research is determined to involve minimal risk, an EC may authorize delegated review in accordance with its institutional policies and written procedures. Delegated reviewers may refer proposals to the full EC, and any proposed negative decision must be reviewed and endorsed by the full EC before it is communicated to the researcher. Delegated decisions must be well documented and formally reported to the full EC, which remains responsible for the ethics of all research involving humans within its jurisdiction. ECs must function impartially, provide researchers with a fair hearing, and provide reasoned and appropriately documented opinions and decisions. Approvals and refusals must be communicated in writing. Where members disagree, an effort should be made to reach consensus; if disagreement persists, the decision must be made in accordance with the EC’s agreed-upon and documented process. The EC makes the final determination regarding the nature and frequency of continuing research ethics review using a proportionate approach. At minimum, continuing review consists of an annual status report for multi-year projects and an end-of-study report for projects lasting less than one (1) year.

Regarding records, G-TCPS2 indicates that ECs must prepare and maintain comprehensive records, including all documentation related to the projects submitted to the EC for review, attendance at all EC meetings, and accurate minutes reflecting EC decisions. Where the EC denies ethics approval for a research proposal, the minutes must include the reasons for this decision. When deciding the retention period of their files, ECs should be guided by their institutional record-keeping policies and other relevant legal or regulatory requirements. Files, minutes, and other relevant documentation must be accessible to authorized representatives of the institution, researchers, sponsors, and funders when necessary to assist internal and external audits, or research monitoring, and to facilitate reconsideration or appeals. The minutes of EC meetings must clearly document the EC’s decisions, any dissents, and the reasons for them. EC decisions should be supported by clear references (e.g., date of decision, title of project), documentary basis for decision, the plan for continuing ethics review and timelines, reasons for decisions, and any conditions or limitations attached to the approval. Providing reasons for EC decisions is optional when ethics approval is granted. ECs should have written procedures for its management of record keeping and other submitted reports. EC must maintain reports and decisions on unanticipated issues or changes to approved research.

For examples of EC SOPs, see CAN-13 for the HC-PHAC REB operational policy.

Overview

According to the CanadaFDR, the G-CanadaCTApps, and the G-TCPS2, the primary scope of information assessed by institutional ethics committees (ECs) (called Research Ethics Boards (REBs) in Canada) relates to maintaining and protecting the dignity and rights of human research participants and ensuring their safety throughout their participation in a clinical trial. ECs must also pay special attention to reviewing informed consent and protecting the welfare of certain classes of participants deemed vulnerable.

See the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which CAN-50 indicates that Health Canada (HC) has adopted, for additional EC responsibilities and requirements. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Role in Clinical Trial Approval Process

As per the CanadaFDR, HC must approve a clinical trial application (CTA) and an institutional EC(s) must give ethical clearance prior to a sponsor initiating a clinical trial. In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, institutional EC review for each clinical trial site may occur in parallel with HC’s CTA review and approval. Once HC completes its review, the department issues a No Objection Letter (NOL) if the CTA is approved. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until an institutional EC approval for each participating trial site is submitted. The sponsor should use the Clinical Trial Site Information Form (CAN-6) to submit the required information. The CanadaFDR also states that the EC must review and approve any protocol amendments prior to those changes being implemented.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires EC review and approval of research involving living human participants and human biological materials. Further, ECs must have procedures in place to receive and respond to reports of new information, including, but not limited to, safety data, unanticipated issues, and newly discovered risks.

See TCPS2-InterpReview for the Panel on Research Ethics (PRE)’s interpretations of the G-TCPS2, including on the EC’s review of secondary use of non-identifiable information, delegated review of minimal risk studies, and ongoing review.

The G-TCPS2 lays out options, procedures, and considerations for the ethics review of multi-jurisdictional research either entirely within Canada, or in Canada and other countries. An institutional EC may approve alternative review models for research with multiple ECs and/or institutions but remains responsible for the ethics and conduct of research in its jurisdiction or under its auspices regardless of where the research is conducted. The SingleECRev provides guidance on the G-TCPS2’s single EC review model for multi-jurisdictional minimal risk, which seeks to streamline the research ethics review process where additional ethics reviews are not expected to add greater participant protections. In line with a proportionate approach to research ethics review, if research is of minimal risk and spans multiple jurisdictions, institutions that have approved the use of the single EC review model authorize the review of the research by one (1) EC. See the G-TCPS2 for more information about the various review models for multi-jurisdictional research.

Per CAN-8, an attestation must be completed by the EC that reviewed and approved the clinical trial. The completed attestation must be retained by the clinical trial sponsor for a period of 15 years. The attestation should not be submitted to HC unless requested. (See the Submission Process section for detailed submission requirements.)

G-Dcntrl indicates that for clinical trials with decentralized elements a single EC can approve activities at a clinical trial site as well as decentralized trial elements. However, sponsors and qualified investigators may need to obtain their own additional provincial or institutional approvals or permissions, or meet community-specific requirements, to use institutional resources or gain access to specific locations or populations, such as Indigenous communities.

The G-TCPS2 directs the researcher to submit an annual report to enable the EC to evaluate the continued ethical acceptability of the research. Per the G-CanadaCTApps, if an EC terminates or suspends any prior approval or favorable opinion, it must document its views in writing, clearly identifying the trial, the documents reviewed, and the date for the termination or suspension.

Institutional ethics committees (ECs) may independently decide whether to charge fees to conduct protocol reviews. For example, an institutional EC may require industry sponsors or other for-profit organizations to pay a fee. See specific examples of institutional fee requirements in CAN-3 and CAN-1.

There are no applicable regulations or guidance regarding the registration, auditing, and accreditation of institutional ethics committees (ECs).

Overview

In accordance with the CanadaFDR and the G-CanadaCTApps, Canada requires the sponsor to obtain clinical trial authorization from Health Canada (HC) prior to initiating the trial. The sponsor must file a clinical trial application (CTA) to the appropriate Directorate within HC’s Health Products and Food Branch (HPFB). In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, the sponsor may submit a CTA for clinical trial authorization to the HC in parallel with its submission to an institutional ethics committee (EC) (known as a Research Ethics Board (REB) in Canada) for a favorable ethical opinion. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form (CAN-6)) for each participating trial site is submitted. See CAN-30 for instructions on filling out and submitting CAN-6.

CAN-19 provides a full list of HC’s forms for drug-related applications and submissions. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Regulatory Submission

Per the G-CanadaCTApps, CTAs (CAN-4) should be sent directly to the appropriate HPFB Directorate for review—the Pharmaceutical Drugs Directorate (PDD) for pharmaceutical drugs or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) for biological drugs and radiopharmaceuticals.

The G-MDSA and the G-CanadaCTApps indicate that sponsors may request a pre-submission/application meeting with the appropriate directorate within HC if they have any questions or concerns prior to filing a CTA. Additional details on requesting a meeting and meeting procedures are available in the aforementioned guidance documents. According to CAN-4, the submission can be in French or English. For CTAs that use pharmacometric approaches, sponsors should consider the policy statements in G-Pharmacometrics. Pharmacometrics is the science of using quantitative analysis and modelling and simulation approaches to inform and enhance drug development and regulatory review. In addition, see the G-CTACell for guidance on preparing CTAs for use of cell therapy products in humans.

Per the CanadaFDR, an application by a sponsor for authorization to sell or import a drug for the purposes of a clinical trial must be submitted to HC, signed and dated by the sponsor’s senior medical or scientific officer in Canada and senior executive officer. The sponsor’s clinical trial attestation must be submitted with the application (CAN-4). For guidance on completing CAN-4, see the G-DrugApp.

Electronic Common Technical Document (eCTD) Electronic Submission

As indicated in the G-eCTD, clinical trial applications in electronic common technical document (eCTD) format are recommended, not mandatory. However, once a sponsor files a regulatory activity in eCTD format, all additional information and subsequent regulatory activities for the same dossier must be filed in eCTD format. CAN-36 explains that prior to filing the first regulatory transaction for a dossier in eCTD format, the sponsor must request a dossier ID using the online dossier ID request. Per the ElecSubms, CAN-20 is the request form for biological clinical trial dossiers and CAN-21 is for pharmaceutical clinical trial dossiers. A request for a dossier ID should be sent a maximum of eight (8) weeks prior to submitting the CTA. In addition, applicants should review the Rules-eCTD for validation rules before submission. (Note: As per ElecSubms, G-eCTD and CAN-36 are only available upon request at no-reply.ereview.non-reponse@hc-sc.gc.ca. Please ensure the text 'Request for eCTD Guidance Document' is in the subject line of the email.)

Per the G-eCTD and CAN-28, all regulatory transactions in eCTD format must be sent via the Common Electronic Submissions Gateway (CESG) (CAN-25), except for those exceeding 10 gigabytes (GB) in size. The CESG allows users to submit secure regulatory transactions electronically to HC, including CTAs. The G-eCTD and CAN-36 describe how to file CTAs and other clinical trial regulatory transactions (e.g., CTA amendments, responses to requests for information, and other in-scope activities) in eCTD format to CESG. The G-eCTD clarifies that prior to using the CESG for sending transactions, sponsors must register as a trading partner. To access and use CESG, CAN-34 instructs sponsors to follow these steps:

• Register as a trading partner with the U.S. Food & Drug Administration (FDA) at the FDA Electronic Submissions Gateway Next Generation (ESG NextGen) (CAN-51) to be able to send a regulatory transaction (Note: CAN-54 indicates that the new version of the platform, ESG NextGen, continues to support HC submissions.)
• Send regulatory transactions to HC by selecting “HC” as the center on the FDA ESG system; CTAs intended for HC will be automatically redirected.

For detailed information on how to become a trading partner and send regulatory transactions, refer to CAN-54, CAN-51, and CAN-25.

As indicated in the G-eCTD, the following media formats are acceptable for eCTD transactions greater than 10 GB: Universal Serial Bus (USB) 2.0 or 3.0 drive; or portable external hard drive with USB 2.0 or 3.0 interfaces. (Contact HC at hc.ereview.sc@canada.ca for other media formats that may be acceptable at the time of filing.) A paper copy of the cover letter must accompany the media (unless otherwise indicated), and a pre-paid envelope must be provided if the media is to be returned. The complete regulatory transaction must be provided on a single drive, and the label on the drive should contain the following information:

• Stakeholder Name
• Brand Name
• Dossier ID, which is based on the protocol number
• Sequence (regulatory transaction) number

Media must be mailed to HC at the address below:

Health Canada
Finance Building
101 Tunney’s Pasture Driveway
Address Locator: 0201A1
Ottawa, Ontario
K1A 0K9

See the G-eCTD, CAN-54, CAN-34, CAN-36, CAN-25, and CAN-28 for details on registering as a trading partner for CESG transactions, how to use CESG, and submitting CTAs in eCTD format.

Non-eCTD Electronic Submission

For non-eCTD electronic submissions, G-Non-eCTD indicates that the CTA (CAN-4) must be provided in PDF format. Other files submitted should be in PDF format, unless otherwise specified in G-Non-eCTD. PDF documents should be generated from electronic source documents and not from scanned materials, except where access to an electronic source document is unavailable or where a signature is required. Documents that are more than 10 pages should be bookmarked. Sections, subsections, tables, figures, and appendices should be bookmarked, with no more than four (4) levels of bookmarks. Hyperlinks within the same PDF document are acceptable, but hyperlinks between different documents must not be used. Stakeholders are responsible for ensuring that hyperlinks function, and links must also include references to the applicable section or page. Documents that legally require signatures may be signed electronically, or the signature page may be printed, signed, scanned, and saved as a PDF. If only one (1) page of a multi-page document contains a signature, the scanned page should be included in the same location in the PDF. Each document should have only one (1) PDF file. The cover letter does not require a signature but should include the printed name, phone number, and email address of the contact person.

As explained in G-Non-eCTD, all regulatory transactions should be validated before being transmitted to HC. For the applicable requirements, including validation rules, see the Rules-Non-eCTD. Initial CTAs and CTA-As should be submitted on electronic media, accompanied by a paper copy of the cover letter, and sent directly to the Office of Clinical Trials within PDD for pharmaceuticals or the Office of Regulatory Affairs within BRDD for biologics and radiopharmaceuticals. The ElecSubms contains a zip file of the folder structure for clinical trial non-eCTD submissions. (Note: As per ElecSubms, G-Non-eCTD is only available upon request at no-reply.ereview.non-reponse@hc-sc.gc.ca. Please ensure the text 'non eCTD Guidance Document' is in the subject line of the email.)

Per the G-Non-eCTD, CTA submissions to the appropriate Directorate within HC’s HPFB must be in one (1) of these accepted media formats:

• Compact Disc-Recordable (CD-R) conforming to the Joliet specification
• USB 2.0 or 3.0 drive
• Digital Versatile Disc (DVD-RAM and DVD+R/-R) in Universal Disk Format (UDF) standard

All media should be labelled and contain the following information:

• Stakeholder Name
• Brand Name

Subsequent to burning the CD/DVD or transferring data to a drive, applicants should ensure that all files can be opened, files are not corrupted, and that "Thumb.db" files are removed.

As per the G-Non-eCTD, G-MDSA, CAN-18, and CAN-17, non-eCTD CTAs involving pharmaceutical drugs should be sent to PDD, and CTAs involving biologics and/or radiopharmaceuticals should be sent to BRDD at the addresses listed below (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

Office of Clinical Trials
Pharmaceutical Drugs Directorate
Health Canada
5th Floor, Holland Cross, Tower B
1600 Scott Street
Address Locator: 3105A
Ottawa, Ontario, Canada
K1A 0K9
General Inquiries E-mail: oct.enquiries-requetes.bec@hc-sc.gc.ca

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Ground Floor, Health Canada Building 6
100 Eglantine Driveway
Tunney’s Pasture
Address Locator: 0601C
Ottawa, Ontario, Canada
K1A 0K9

Telephone: 613-957-1722
E-mail: brdd.ora@hc-sc.gc.ca

Per the G-Non-eCTD, if an applicant submits a non-eCTD CTA via email, they should meet the following requirements:

• The maximum email size accepted by the corporate mail server is 20 megabytes. If the clinical trial submission is larger than 20 megabytes, the submission may be split and sent as separate emails (e.g., an email for Module 1, and another email for Module 2/3). The subject line of the emails should clearly link to each other (e.g., "Email 1 of 2" in the relevant subject line)
• A duplicate copy must not be provided by mail
• The submission should be organized in folders and the body of the email should only contain the zipped regulatory submission
• Zipped files and documents contained in the email should not be password protected

The G-Non-eCTD provides additional information on emailing other clinical trial submissions, including responses to a clarification request, responses to a no objection letter, notifications, and development safety update reports.

Ethics Review Submission

As indicated in the CanadaFDR and the G-CanadaCTApps, all research involving human participants in Canada must be reviewed by an institutional ethics committee (EC). (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements. Further, Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information. CAN-35 delineates submission requirements to the joint HC-Public Health Agency of Canada (PHAC)’s EC. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers on the premises or in collaboration with external researchers.

Regulatory Authority Requirements

As set forth in the CanadaFDR and the G-CanadaCTApps, Health Canada (HC) requires the sponsor to apply for clinical trial authorization by submitting a clinical trial application (CTA) to HC. As specified in the G-CanadaCTApps and the G-QCM-PharmCTAs, the CTA should be organized into three (3) modules in Common Technical Document (CTD) format:

• Module 1 - Administrative and clinical information about the proposed trial
• Module 2 - Quality (Chemistry and Manufacturing) summaries about the drug product(s) to be used in the proposed trial
• Module 3 - Additional supporting quality information

Per the CanadaFDR, the clinical trial application form (CAN-4) and the following information and documents must be submitted:

• Protocol
• Summary of potential risks/benefits
• Clinical trial attestation that includes drug information (chemistry, names, classifications, dosage, therapeutic purpose, human-sourced excipient, drug identification number or notice of compliance, manufacturing information); sponsor’s contact information; if the drug is to be imported, contact information for the sponsor’s representative in Canada who is responsible for the sale of the drug; and contact information for the qualified investigator at each site, if known at the time of submittal
• Contact information for each institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) that approved the protocol, if known at the time of submitting the application (provided in the required Clinical Trial Site Information (CTSI) form (CAN-6))
• Contact information of any institutional EC that previously refused to approve the protocol, its reasons, and refusal date
• Investigator’s Brochure (IB)
• Informed consent form (ICF)
• Information about use of a human-sourced excipient
• Chemistry and manufacturing information
• Proposed date for trial commencement at each site, if known

Per the Mdrn-CTFrmwrk, for multi-site trials operating within a streamlined multi-site ethics review process, sponsors sometimes identify the same EC for all clinical trial sites. When providing information on a new site through CAN-6, sponsors only need to include the contact information for an EC once, as long as:

• The same EC has previously been identified as having approved other sites in that trial
• The EC's contact information has already been provided to HC in the context of the clinical trial, and continues to be up to date

Accordingly, as indicated in the Mdrn-CTFrmwrk, the form's section on EC approval may only contain the name of the approving board and the date of its approval.

Refer to the CanadaFDR, the G-FDR-0100, the G-CanadaCTApps, the G-DrugApp, the G-QltyBioCTs, and the G-QCM-PharmCTAs for detailed submission information.

Ethics Committee Requirements

Each institutional EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies to be supplied and application format requirements.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires clinical trial researchers to submit their research proposals for EC review and approval of their ethical acceptability prior to the start of recruitment of participants, data collection, access to data or collection of human biological materials. Researchers must submit sufficient details to enable the EC to make an informed review of the ethical acceptability of the research. In addition, they should include a plan for monitoring safety, efficacy/effectiveness (where feasible), and validity in their proposal for EC review. This plan must describe:

• How participant safety will be monitored and what actions will be taken in the event of a threat to participant safety
• How intervention efficacy will be monitored (where feasible) and what actions will be taken if efficacy is found to be greater than expected
• The criteria by which participants may be removed from a study for safety reasons
• The study-wide stopping rules (if any) by which studies may be stopped or amended due to evidence of inferior safety, superior efficacy or futility
• The reporting procedure that will be followed to ensure any information relevant to participant welfare or consent is reported clearly and in a timely fashion to the EC

See CAN-35 for submission requirements to the joint HC-Public Health Agency of Canada (PHAC)'s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

Clinical Protocol

The CanadaFDR requires submission of a clinical trial protocol. Per G-FDR-0100, a protocol should describe the objectives, design, methodology, statistical considerations and organization of a clinical trial, and it should be consistent with the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52). The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence. CAN-50 indicates that HC adopted CAN-52.

Overview

As delineated in the CanadaFDR and the G-CanadaCTApps, the review and approval of a clinical trial application (CTA) by Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) may be conducted in parallel. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form) for each participating trial site is submitted. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Regulatory Authority Approval

According to the CanadaFDR and the G-CanadaCTApps, an authorized clinical trial is one that has been filed with HC and has not received an objection within 30 days. All CTAs are subject to the 30-day default period from the date of receipt of the completed application at the appropriate Directorate within HC’s Health Products and Food Branch (HPFB). While the Directorates can establish shorter administrative targets of seven (7) days for the review of bioequivalence trials, the 30-day default system remains the regulatory requirement. Applications to conduct Phase I clinical trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines, or reproductive and genetic technologies are not included in the seven-day target system. Please see the G-CanadaCTApps for special requirements regarding reviews of comparative bioavailability studies and joint reviews of clinical trials covering a combination of devices, biologics, and pharmaceuticals.

As specified in the G-CanadaCTApps and the G-MDSA, during the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. The G-MDSA clarifies that, where warranted, HC can adjust the timelines to be longer or shorter based on the complexity of the request, communications with the sponsor, and/or circumstances of the review, including pausing the clock during the scientific review. The G-CanadaCTApps also states that HC will issue a Not Satisfactory Notice (NSN) if a timely response to requested information has not been provided. The G-MDSA indicates that the review of the submission will stop on the date the NSN is sent.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, recommends a proportionate approach to ethics review—the lower the level of risk, the lower the level of scrutiny (delegated review); the higher the level of risk, the higher the level of scrutiny (full board review). In either case, pursuant to the G-TCPS2, the institutional EC should make its decisions in an efficient and timely manner.

See CAN-35 for ethics review timelines with the joint HC-Public Health Agency of Canada (PHAC)'s EC. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

Overview

In accordance with the CanadaFDR and the G-CanadaCTApps, a clinical trial can only commence after the sponsor receives authorization from both Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada). No waiting period is required following the applicant’s receipt of these approvals. CAN-30 specifies that for purposes of the Clinical Trial Site Information (CTSI) Form (CAN-6), the trial commencement date is the date when the clinical trial site is ready to enroll participants. The commencement date is a date after which the sponsor has both the HC authorization from the appropriate Directorate (date on the No Objection Letter (NOL) or the date of the Notice of Authorization) and approval from the relevant EC. Further, the commencement date would be the date when the sponsor implements the protocol, which includes the screening period that occurs prior to the check-in date. See the Scope of Review section for detailed institutional EC requirements, and the Submission Content section for additional HC approval information. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

In addition, per the G-CanadaCTApps, if a sponsor (Canadian or foreign) wants to import a drug into Canada to conduct a clinical trial, a copy of HC’s clinical trial authorization (i.e., the NOL) must be included with the drug shipment. According to the G-CanadaCTApps and CAN-32, if a sponsor plans to import investigational drugs directly to each trial site, then the sponsor must also authorize the importer (i.e., the clinical trial site) when submitting the clinical trial application using Appendix I of HC’s Drug Submission Application Form (CAN-4). See the Manufacturing & Import section for detailed import requirements.

Clinical Trial Agreement

Prior to initiating trial activities, as delineated in the G-FDR-0100, agreements made by the sponsor with the qualified investigator, institution, service providers, and any other parties (e.g., independent data monitoring committee or adjudication committee) involved with the clinical trial should be documented. The sponsor is also responsible for obtaining agreements from all involved parties to permit monitoring and auditing by sponsors, inspections by regulatory authorities (domestic and foreign) and review by ECs, including providing direct access to source records and facilities, including those of service providers. Any of the sponsor's trial-related activities that are transferred to and assumed by a service provider should be documented in an agreement. The sponsor's trial-related activities that are not specifically transferred to and assumed by a service provider are retained by the sponsor.

In accordance with the G-CanadaCTApps, prior to initiating a clinical trial, the sponsor must ensure that a Qualified Investigator Undertaking (QIU) form (CAN-37 or similar documentation that meets the CanadaFDR requirements) has been completed and is kept on file by the sponsor. Per the CanadaFDR, the form certifies that the QI will conduct the clinical trial in accordance with good clinical practice and will immediately inform trial participants and the institutional EC of trial discontinuance and the reason for this discontinuance. If there is a change in the QI at a site, a new CTSI Form must be submitted to HC, and a new QIU form must be maintained by the sponsor.

G-Dcntrl indicates that sponsors and QIs are responsible for ensuring that all agreements supporting decentralized trial activities clearly define roles, responsibilities, and oversight expectations. Trial-related activities delegated to service providers should be documented in written agreements that establish how tasks will be performed, supervised, and documented; investigational products and data will be managed; and compliance with regulations and good clinical practice will be maintained.

See CAN-6, CAN-8, and CAN-19 for additional clinical trial forms. Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Clinical Trial Registration

As per the CT-Rgstrn, sponsors should register their clinical trial before it has opened for enrollment in Canada but no later than 21 calendar days after the date of enrollment of the first participant. HC considers the registration date as the date when the clinical trial registration materials are first submitted to a registry. For a multi-national clinical trial with one (1) or more Canadian sites, sponsors should add the Canadian site(s) to their existing registry record. Ideally, this should be done before opening for enrollment, but no later than 21 calendar days after the date of enrollment of the first participant at the Canadian site(s). Sponsors should register their clinical trial with an international clinical trial registry that complies with World Health Organization (WHO) international standards, including the International Clinical Trials Registry Platform (ICTRP) (CAN-60). Two (2) widely used registries that are publicly accessible and part of the WHO network are ClinicalTrials.gov (CAN-45), and the International Standardized Randomized Controlled Trial Number (ISRCTN) Registry (CAN-46). Sponsors should include the protocol code/number in their registry record.

Also see HC’s Clinical Trial Search Portal (CAN-59), which is a search tool to find information about Canadian clinical trials. It is not a registry, but some of the information is collected directly from international registries.

Safety Reporting Definitions

According to the CanadaFDR and G-CanadaCTApps, 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 participant 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.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs), requires researchers to promptly report new information revealed during the conduct of the trial that might affect the welfare or consent of participants to the EC, 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 ECs to determine which participants must be informed, and how the information should be conveyed.

For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Safety Reporting Requirements

Investigator Responsibilities

Per the G-FDR-0100, the collection, assessment, and reporting of AEs is a critical component of the conduct of any clinical trial. The assessment of the site AEs should be done by the qualified investigator (QI) or the delegated sub-investigator(s) for seriousness, expectedness, and causality determination, when they become aware. All SAEs should be reported immediately (after the QI reasonably becomes aware of the event) to the sponsor. The QI should also include an assessment of causality. In accordance with applicable regulatory requirements, the protocol may identify SAEs not requiring immediate reporting; for example, deaths or other events that are endpoints. Subsequent information should be submitted as a follow-up report, as necessary.

Sponsor Responsibilities

As delineated in the CanadaFDR and the G-CanadaCTApps, the sponsor is required to expedite reports of ADRs to HC that meet these three (3) criteria: serious, unexpected, and having a suspected causal relationship. ADR reports that are expected or unexpected, but not serious, should not be reported to HC, but rather monitored and tracked by the sponsor. As specified in the G-CanadaCTApps, when evaluating whether an AE is serious and unexpected, the QI’s and sponsor’s determination of causality is important. Only serious and unexpected ADRs found to have a reasonable suspected causal relationship with the drug should be reported by the sponsor to HC.

Per the CanadaFDR and the G-CanadaCTApps, during a clinical trial, the sponsor is required to inform HC of any serious, unexpected ADR that has occurred inside or outside Canada. An ADR report must be filed in the following specified timelines:

• When the ADR is neither fatal nor life-threatening, within 15 days after becoming aware of the information
• When it is fatal or life-threatening, immediately when possible and, in any event, within seven (7) days after becoming aware of the information
• Within eight (8) days after having informed HC of the ADR, submit a report that includes an assessment of the importance and implication of any findings

Other Safety Reports

The G-DSUR delineates that the development safety update report (DSUR) and the DSUR Checklist (CAN-38) should be provided when requested by HC. A DSUR may be submitted voluntarily to HC when important new safety information on a drug needs to be conveyed by a clinical trial sponsor. In these cases, a rationale/justification for the filing of the DSUR should be included in the cover letter. For additional details, see the G-DSUR.

The G-DSUR-CanUK describes the region-specific requirements for DSURs submitted to the regulatory authorities of Canada and the United Kingdom. This guidance applies to both marketed and non-marketed drugs that are used in clinical trials and applies to DSURs prepared by the manufacturer and/or marketing authorization holder of the investigational drug.

Form Completion & Delivery Requirements

As per the G-CanadaCTApps, all serious and unexpected ADRs should be reported individually to HC. According to CAN-48 (which Canada adopted pursuant to CAN-50), at a minimum, the report should include an identifiable patient, the name of a suspect medicinal product, an identifiable reporting source, and an event or outcome that can be identified as serious and unexpected and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. The G-CanadaCTApps requires the sponsor to complete the expedited reporting form (CAN-5) and the CIOMS Form I (CAN-7) and fax them to the appropriate HC Directorate: BRDD Fax: 613-957-0364; PDD Fax: 613-941-2121.

Additionally, the G-DSUR indicates that HC recommends that DSURs in electronic Common Technical Document (eCTD) format be submitted via the Common Electronic Submissions Gateway (CESG) (CAN-25). For information on eCTD format, refer to the ElecSubms. For technical questions on eCTD filings, contact ereview@hc-sc.gc.ca as instructed in the G-DSUR.

Interim and Annual Progress Reports

Pursuant to the CanadaFDR and the G-CanadaCTApps, 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 institutional ethics committee (EC) and submit interim progress reports to the EC and Health Canada (HC) if there are any significant changes affecting the trial or risk to participants. The sponsor is required to submit annual reports (in the form of an updated Investigator’s Brochure (IB)) to HC. Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

According to the G-TCPS2, investigators must report new information that may affect the welfare or consent of participants to the institutional EC, HC, 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 ECs 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 (1) 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

Final Report

While the CanadaFDR does not require submission of a final study report to HC, the CT-Rgstrn states that HC’s policy for reporting summary results aligns with international initiatives, including the Declaration of Helsinki (CAN-58). Sponsors should submit the summary results of their clinical trial within 12 months following primary study completion, which is the final study visit for collection of data on the primary outcome for the last participant in a global study, whether the clinical trial concluded according to the pre-specified protocol or stopped early. For clinical trials with more than one (1) primary outcome measure with different completion dates, the primary study completion is the date when data collection is completed for all primary outcome measures. In cases where submission of summary results within one (1) year of primary study completion will jeopardize the scientific integrity of the clinical trial, summary results may be submitted within one (1) year of study completion, which is the final study visit for collection of data on any remaining secondary outcome measures and adverse event information for the last participant in the global study, whether the clinical trial concluded according to the pre-specified protocol or stopped early. If a sponsor intends to apply for market authorization for the product studied or a new condition of use, the sponsor may defer submitting summary results until 30 calendar days after HC renders a decision on the application or the sponsor cancels or withdraws it, or up to 36 months following primary study completion, whichever is earlier. HC does not support deferral for products or new conditions of use that the sponsor does not intend to market or for which product development has stopped. Sponsors should submit the summary results of their clinical trial to the same registry where their trial is registered. (See Initiation, Agreements & Registration section for information on clinical trial registration.)

Per the G-CanadaCTApps, the sponsor should notify the HC Directorate when a clinical trial is completed or a clinical trial site is closed. A study is considered to be completed after the last participant globally completes the "end of study" visit as defined in the protocol. The "end of study visit" is the final visit for study-related tests and procedures, including the capture of any final potential study-related adverse events, and usually occurs after the participant has completed/discontinued study drug administration. The "end of study visit" is normally an in-person visit, but for some studies it can also be carried out over the telephone. There may be certain scenarios (e.g., gene therapies, drugs with very long half-lives) where a study may be ongoing well beyond the period of study treatment, i.e., where long-term safety monitoring and reporting would be required. The reporting requirements with regard to such long-term follow-up of safety are normally specified in the study protocol and agreed to between the sponsor and HC prior to the authorization of the clinical trial in Canada.

As per the CanadaFDR and the G-CanadaCTApps, a sponsor is defined as an individual, corporate body, institution, or organization that conducts a clinical trial. In accordance with the G-FDR-0100, a sponsor may transfer any or all of the sponsor's trial-related activities to a service provider in accordance with applicable regulatory requirements. However, the ultimate responsibility for the sponsor's trial-related activities, including protection of participants' rights, safety, and well-being and reliability of the trial data, resides with the sponsor.

According to the CanadaFDR and G-CanadaCTApps, a sponsor may be domestic or foreign. 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.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Overview

Per the CanadaFDR and the G-FDR-0100, every sponsor must ensure that a clinical trial is conducted in accordance with good clinical practice (GCP) and must also ensure that:

• At each clinical trial site, there is no more than one (1) qualified investigator (QI)
• At each clinical trial site, medical care and medical decisions, in respect of the clinical trial, are under the supervision of the QI
• Each individual involved in the conduct of the clinical trial is qualified by education, training, and experience to perform the tasks

The G-FDR-0100 explains that the sponsor’s selection and oversight of QIs and service providers are fundamental features of the oversight process. As stated in Mdrn-CTFrmwrk, a "qualified investigator" may be:

• A physician or dentist who is authorized under CanadaFDR to act as a qualified investigator
• An individual who has the education, training, and experience required to conduct the clinical trial in accordance with regulatory requirements, despite not meeting the regulatory requirement to be a physician or dentist in CanadaFDR

Mdrn-CTFrmwrk further specifies that in clinical trials where the investigator is not a physician or dentist, medical decisions with respect to the trial that are outside the licensed scope of practice of the investigator must be made by a qualified physician or dentist on the clinical trial team who is:

• Licensed to practice in the province or territory where the site is located
• Responsible for medical oversight and participant care, including medical decisions with respect to the trial

In accordance with the G-CanadaCTApps, prior to initiating a clinical trial, the sponsor must ensure that a Qualified Investigator Undertaking (QIU) form (CAN-37) (or similar documentation that meets the CanadaFDR requirements) has been completed and kept on file by the sponsor; it should be retained by the sponsor for 15 years. Per the CanadaFDR, the form certifies that the QI will conduct the clinical trial in accordance with GCP, and, if the trial is discontinued, will immediately inform trial participants and the institutional ethics committee (EC) (known as Research Ethics Boards in Canada) of the discontinuance, and the reason for it. (See the Submission Content section for additional information on clinical trial application requirements). For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Per G-Dcntrl, for clinical trials with decentralized elements, sponsors and QIs should assess whether decentralized locations have sufficient funding, time, equipment, and staff to support trial conduct that complies with GCP. Considerations include local care and institutional practices, provincial or territorial requirements, training needs, and coordination and communication across locations. The main location and remote locations supervised by one (1) QI constitute a single clinical trial site. The main location must be identified on the Clinical Trial Site Information (CTSI) form (CAN-6) and receive EC approval before trial initiation.

For additional guidance on investigator selection, qualifications, and training, see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Per CAN-11, the Canadian Clinical Trials Asset Map (CCTAM) (CAN-26) is a pan-Canadian research inventory of investigators, clinical research sites, and other resources across the country. Sponsors can use CCTAM to identify potential sites and investigators, which may expedite study feasibility and start-up timelines. To view the CCTAM, the user must register and create an account.

Foreign Sponsor Responsibilities

According to the CanadaFDR and the G-CanadaCTApps, a sponsor may be domestic or foreign. A foreign sponsor is required to have a senior medical or scientific officer residing in Canada to represent the sponsor, and sign and date the application and the clinical trial attestation form.

Data and Safety Monitoring Board

The G-TCPS2 provides the following considerations to help researchers and ECs determine whether a Data and Safety Monitoring Board (DSMB) (known as an Independent Data-Monitoring Committee in Canada) is needed:

• The magnitude of foreseeable research-attributable harms to participants
• Whether the circumstances of the participants make them vulnerable in the context of research
• The feasibility of interim data analysis
• The complexity of the study
• Conflicts of interest

Also see CAN-52 for ICH guidance on DSMBs.

Multicenter Studies

The CanadaFDR and the G-CanadaCTApps, require the sponsor to complete and retain the Research Ethics Board (REB) Attestation (CAN-8) and Qualified Investigator Undertaking (QIU) (CAN-37) forms at each trial site, while submitting in electronic format CAN-6 to the appropriate HC Directorate for each trial site.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, provides that in multi-site clinical trials, a lead principal investigator (PI) is a designated PI who is responsible for the ethical conduct of the study for all sites. The lead PI is responsible for communicating any changes to the study, new information, and/or unanticipated events to the EC, to the sponsor, and to local site PIs.

Per CAN-50, Canada has implemented the ICH Guidance E17: Multi-Regional Clinical Trials (CAN-40), which describes general principles for the planning and design of multi-regional clinical trials with the aim of increasing the acceptability of these trials in global regulatory submissions. HC recognizes that the scope and subject matter of current HC guidance may not be entirely consistent with ICH guidance. In such circumstances, HC-implemented ICH guidance takes precedence.

Insurance

The CanadaFDR does not require the sponsor to provide insurance coverage to investigators, institutions, or trial participants. However, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50, guides sponsors on providing insurance. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Compensation

Injury or Death

The Canadian regulations do not require compensation for trial participants in the event of trial-related injuries or death. However, the G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs) (known as Research Ethics Boards in Canada), provides that, during informed consent, participants should be given information about any payments, including compensation for injury.

Trial Participation

The Canadian regulations do not require compensation for trial participation. However, as per the G-TCPS2, the informed consent form (ICF) should contain a statement with a description of the anticipated prorated payment to the participant(s) that is reasonably expected for participation in the trial. Any compensation or incentive to participants must not be so excessive that it may unfairly influence participants or cause them to overlook important facts and risks.

Also see CAN-52, which guides sponsors on providing compensation.

Quality Assurance/Quality Control

As stated in the CanadaFDR, the sponsor must ensure that a clinical trial is conducted in accordance with good clinical practice and must ensure, among other things, that the trial is scientifically sound and clearly described in a protocol; the trial and use of the drug comply with the protocol and the CanadaFDR; and systems and procedures that assure the quality of every aspect of the trial are implemented. Regarding quality, the G-FDR-0100 explains that the sponsor is responsible for the establishment of a quality management system consisting of documented procedures (standard operating procedures (SOPs), protocol procedures, etc.) to assure the quality of every aspect of a clinical trial. The range and extent of oversight measures should fit the purpose and be tailored to the complexity of and risks associated with the trial. Quality management includes the design and implementation of efficient clinical trial protocols, including tools and procedures for trial conduct (including data collection and management), to ensure the protection of participants' rights, safety, and well-being, and the reliability of trial results. The sponsor should adopt a proportionate and risk-based approach to quality management, which involves incorporating quality into the design of the clinical trial (i.e., quality by design) and identifying those factors that are likely to have a meaningful impact on participants' rights, safety, and well-being, and the reliability of the results. The sponsor should describe the quality management approach in the clinical trial report.

In addition, G-FDR-0100 states that risks to critical-to-quality factors should be managed proactively and adjusted when new or unanticipated issues arise once the trial has begun. Risk review is a key component to risk-based quality management systems, and Health Canada (HC) expects that sponsors will be able to demonstrate that risk control measures are periodically reviewed and remain effective and relevant, considering emerging knowledge and experience throughout the trial.

Per G-Dcntrl, for trials with decentralized elements, sponsors and qualified investigators (QIs) should collaborate with trial sites and service providers to implement a quality management system covering decentralized activities and supporting compliance with HC regulations and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. Processes should identify, evaluate, control, communicate, and review risks affecting participant safety or the reliability of results, including risks arising from decentralized elements. Additional training, continuing quality checks, and competency assessments may be needed beyond SOPs. See G-Dcntrl for additional details.

Further, CAN-50, Canada implements the ICH Guidance E8(R1): General Considerations for Clinical Studies (CAN-49), which provides guidance on conduct during the clinical trial. Other relevant ICH guidance adopted per CAN-50 are the guidance on statistical principles for clinical trials (CAN-53) and the addendum on estimands and sensitivity analysis (CAN-39). The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Monitoring Requirements

As indicated in the G-FDR-0100, the sponsor should determine the appropriate extent and nature of monitoring based on identified risks. Factors to consider include the objective, purpose, design, complexity, blinding, number of trial participants, investigational product, current knowledge of the safety profile, and endpoints of the trial. Monitoring may include site monitoring (performed onsite and/or remotely) and centralized monitoring. The frequency of monitoring activities should also be determined based on identified risks. Monitoring activities and their frequency should be modified as appropriate using knowledge gained. Centralized monitoring processes provide additional monitoring capabilities that can complement and reduce the extent and/or frequency of site monitoring or be used on its own. Use of centralized data analytics can help identify systemic or site-specific issues, including protocol noncompliance and potential unreliable data. In addition to monitoring, a sponsor should perform audits in a manner that is proportionate to the risk associated with the conduct of the trial. See CAN-52 for additional guidance on sponsor responsibilities involving monitoring and auditing.

Further, per the G-FDR-0100, it is critical to include processes that will be followed to address situations of non-compliance, as well as to identify events that would require either a review or revision of the monitoring plan. HC expects these components to be clearly documented in risk-based monitoring plans. The sponsor should describe the requirements of monitoring reports (including their content and frequency) in the standard procedures. Reports of site and/or centralized monitoring should be provided to the sponsor in a timely manner for review and follow up. When needed, the report should describe findings requiring escalation for action and resolution. The sponsor should decide on the appropriate action to be taken, and these decisions and the resolution of the actions involved, where needed, should be recorded. For additional information on monitoring reports, refer to the U.S. Food & Drug Administration (FDA)’s Guidance for Industry: A Risk-Based Approach to Monitoring of Clinical Investigations Questions and Answers.

Next, per the G-FDR-0100, if it is discovered that noncompliance significantly affects or has the potential to significantly affect human participant protection or reliability of trial results, the sponsor should perform a root cause analysis, implement appropriate corrective and preventive actions, and confirm their adequacy, unless otherwise justified. Where the sponsor identifies issues that are likely to significantly impact the rights, safety, or well-being of the trial participant(s) or the reliability of trial results (i.e., serious noncompliance), the sponsor should notify the HC and the institutional ethics committee (known as Research Ethics Boards in Canada).

Per the HCNotice-ICH-E19, HC adopted and implemented ICH guidance on selective safety data collection in specific late stage pre-approval or post-approval clinical trials (CAN-15). Selective safety data collection refers to the recording of certain data by investigators in case report forms. It does not affect the monitoring and clinical care of individual trial participants or documentation of their adverse events in medical records. See the HCNotice-ICH-E19 and the CAN-15 for more information.

Per G-Inspections, regulated parties (sponsors, qualified investigators, contract research organizations, and any other party involved in the conduct of clinical trials) have mandatory responsibilities under the CanadaFDA and can be inspected. Foreign entities that conduct regulated activities in Canada, or in relation to a product imported in Canada, are also subject to Canadian law. During an inspection or a compliance verification, a regulated party is required to provide all reasonable assistance and information necessary for the HC inspector to perform their duties, including providing evidence that its facility, equipment, and practices and procedures meet the applicable requirements. As indicated in G-Dcntrl, sponsors should oversee decentralized elements in clinical trials across all locations, including remote locations, with monitoring directed toward potential safety concerns, data quality, and reliable results. See the Risk-Insp for HC’s risk classification guide for observations related to inspections of clinical trials of human drugs.

Premature Study Termination/Suspension

The CanadaFDR and the G-CanadaCTApps state that if a trial is prematurely terminated or suspended, the sponsor should inform HC no later than 15 days after the termination or suspension. In addition, the sponsor should provide HC with the reason(s) for the termination or suspension and its impact on the proposed or ongoing clinical trials related to the drug in Canada by the sponsor. The sponsor should also promptly notify the qualified investigators of the termination or suspension and advise them in writing of any potential risks to the participants’ health. Further, the G-CanadaCTApps states that the sponsor’s notification to HC should include confirmation that the sale or importation of the drug to the discontinued sites has been stopped and that reasonable measures to ensure the return of all unused quantities of the drug will be taken. This notification must also be submitted for premature discontinuation of a clinical trial or clinical trial site outside Canada where there are ongoing trials with the drug in Canada. See G-FDR-0100 for additional information and interpretation of discontinuation, suspension, and cancellation. CAN-52 also provides guidance on premature termination or suspension.

Electronic Data Processing System

The G-FDR-0100 states that systems and processes that aid in data capture, management, and analyses, as well as those that help ensure the quality of the information generated from the clinical trial, should fit the purpose of the trial, capture the data required by the protocol, and be implemented in a way that is proportionate to the risks to participants and the importance of acquired data. Quality should be addressed in the design or adaptation of electronic systems for clinical trial purposes to ensure the integrity of relevant trial data. Any electronic system used to capture, process, manage, and/or archive clinical trial information should be adequately validated, and evidence of validation should be retained and readily available for inspection by Health Canada (HC) inspectors. The approach for validation should be based on a risk assessment that considers the intended use of the system; the purpose and importance of the data/record that are collected/generated, maintained, and retained in the system; and the potential of the system to affect the well-being, rights, and safety of trial participants and reliability of trial results. The responsibilities of the sponsor, qualified investigator (QI), and other parties with respect to the use of these computerized systems should be clear, and the users should be provided with training in their use. The sponsor should periodically review the risk control measures to ascertain whether the implemented systems remain effective and relevant, considering experience and emerging knowledge.

Per the G-FDR-0100, any modifications or additions made to the electronic system (for example software upgrades or migration of data) can impact its intended functions by altering the quality of validated applications and the system itself. This may affect the integrity of electronic information and the reliability of the system. Therefore, adequate documented assessment and approval of changes to hardware or software during the clinical trial are required. The impact of such a change should be evaluated and documented, and partial validation of some components of the electronic system may be required.

G-Dcntrl states that computerized systems and digital health technologies used in decentralized activities should be suitable for their intended use and validated through a risk-based approach consistent with the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. Sponsors should address data transfer integrity, security, interoperability, audit trails, and cybersecurity, with documented procedures and training supporting system development, maintenance, and use. See G-Dcntrl for additional details.

For additional information on computerized system validation and electronic records, see CAN-52. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Records Management

As set forth in the CanadaFDR and the CanadaFDR1024, the sponsor must record, handle, and store all trial-related information to allow complete and accurate reporting, interpretation, and verification. The CanadaFDR requires the sponsor to maintain all trial-related records for a period of 15 years. Per the G-FDR-0100, the electronic system should allow for the retrieval of records and the generation of complete and accurate paper copies of the electronic source data. The system should provide audit trails for the entire 15-year record retention period. Records created, maintained, and processed by outsourced systems are subject to the same requirements as the data/records generated by company-owned systems.

Pursuant to CanadaFDR1024, the sponsor must submit requested records to HC within 48 hours if safety concerns arise. Additionally, to facilitate inspection of a site, the sponsor must submit information to HC within seven (7) days of a request. Per CAN-8, an attestation must be completed by the institutional ethics committee (EC) (known as Research Ethics Boards in Canada) that reviewed and approved the clinical trial. The completed attestation must be retained by the clinical trial sponsor for a period of 15 years. The attestation should not be submitted to HC unless requested.

G-Dcntrl states that records of agreements and contracts (paper or electronic) must be available or accessible from the main location of the clinical trial site. Per the Mdrn-CTFrmwrk, the sponsor is responsible for obtaining and retaining records for all EC approvals that may be required for participating sites, in accordance with applicable local requirements. The sponsor must retain records of all approvals for verification during clinical trial inspections. To meet this requirement, the sponsor must maintain complete and accurate records demonstrating EC approval for research undertaken at a clinical trial site.

Also see CAN-52 for additional guidance.

Responsible Parties

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs), states that where researchers seek to collect, use, share, and access different types of information or data about participants, they should determine whether the information or data proposed in research may reasonably be expected to identify an individual. Researchers and ECs must consider whether information is identifiable or non-identifiable. Researchers, ECs, and institutions share the responsibility for protecting participant confidentiality.

Data Protection

Per CAN-42, the Office of the Privacy Commissioner of Canada provides advice and information for individuals about protecting personal information, and enforces the two (2) federal privacy laws that set out the rules for how federal government institutions and certain businesses must handle personal information, including health data. The PrivAct covers the personal information-handling practices of federal government departments and agencies in Canada, and the PIPEDA regulates private businesses’ data protection practices. In addition, some provinces and territories have laws that deal specifically with the protection of personal health information. See CAN-43 for a list of provincial and territorial privacy laws and webpages.

Per the G-TCPS2, in the research context, the most simplified method to protect participants is through the collection and use of anonymous or anonymized data. When anonymized data is not possible or desirable, a next best alternative is to use de-identified data, which is provided to the researcher in de-identified form and the existing key code is accessible only to a custodian or trusted third party who is independent of the researcher. Where it is not feasible to use anonymous or anonymized data for research, the ethical duty of confidentiality and the use of appropriate measures to safeguard information become paramount. Researchers should consult their ECs if they are uncertain about whether information proposed for use in research is identifiable (e.g., when proposing to link anonymized or coded data sets).

G-Dcntrl states that for decentralized data collection through wearables, digital platforms, or remote monitoring, sponsors should consider where data is stored, who may access it, and how to prevent unauthorized sharing or reuse.

Consent for Processing Personal Data

Both PIPEDA and the PrivAct require consent for the use of personal data, including health data, except under prescribed conditions, such as for research or during emergencies. Also see CAN-43 for provincial and territorial privacy laws.

The G-TCPS2 states that to seek broad consent for the storage and future unspecified use of data, researchers must provide prospective participants, or authorized third parties, with applicable information as set out in the informed consent requirements. See the Informed Consent topic, as well as the following details:

• The type, identifiability, and amount of data being collected and stored for re-use, and for what potential purpose
• The voluntariness of the participant’s consent, including any limitations on the feasibility of withdrawal
• A general description of the nature and types of future research that may be conducted, including whether the research might be conducted outside of Canada (if known)
• The risks and potential benefits of data storage and use in future unspecified research, including areas of uncertainty where risks cannot be estimated
• Access to a general description of the repository and its governance
• A statement regarding participants’ preference to being contacted for additional future research
• Whether the data could be shared with researchers who are not subject to the G-TCPS2
• Whether the research will (if known) or might include whole genome sequencing or similar technologies that may pose a substantial risk of re-identification of the participant or identification of material incidental findings (when appropriate)
• Whether linkage of data gathered in the research with other data about participants – either contained in public or personal records – is anticipated
• Separate options for consenting to participate in a specific research project and for consenting to the storage of data for future unspecified research

See Brd-Cnst for additional clarifications on broad consent for the storage and future unspecified use of data.

Per G-Dcntrl, when using digital tools for decentralized activities, there may be concerns about data storage, access, and reuse or sharing without consent. Sponsors and qualified investigators can work collaboratively with participants to ensure informed consent is maintained.

Obtaining Consent

In all Canadian clinical trials, a freely given informed consent is required from each participant in accordance with the requirements set forth in the CanadaFDR and the G-TCPS2. Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence. For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

As per the CanadaFDR and the G-TCPS2, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a Research Ethics Board (REB) in Canada) and provided to HC with the clinical trial application (CTA). (See the Required Elements section for details on what should be included in the form.)

The G-TCPS2 states that the qualified investigator (QI) must provide detailed research study information to the participant or legal representative/guardian. The ICF content should be in plain language (i.e., non-technical and easy to understand) and provided in a format that facilitates understanding. For example, written documentation may be supplemented with audio and/or visual aids. The participant and legal representative/guardian should also be given adequate time to consider whether to participate.

As stated in Mdrn-CTFrmwrk, HC is moving from “written” to “documented” informed consent to allow new approaches for obtaining consent (e.g., remote or electronic platforms, electronic signatures, and documentation of consent where it is provided orally). Informed consent requirements will be considered met by HC where processes:

• Are appropriately documented
• Comply with good clinical practice and CAN-52 principles
• Ensure that consent is informed and given in accordance with the applicable laws governing consent

Per G-Dcntrl, sponsors must inform participants of the potential risks and anticipated benefits of any decentralized elements in a clinical trial. In designing and implementing consent processes across locations, sponsors should consider whether the approach may introduce additional cognitive or emotional demands for participants. Reasonable steps should be taken to minimize unnecessary burden while supporting informed and voluntary decision-making. Virtual meeting platforms and electronic signatures may make the informed consent process more efficient for those who live in remote areas. However, participants may face additional challenges in providing informed consent remotely. Sponsors and QIs should be careful not to create a disadvantage for those who face barriers such as reliable private internet access, digital literacy, or comfort with virtual tools, or prefer not to use virtual platforms. Trial-related documentation should support any proposed delegation of duties related to the informed consent process to trial personnel or other third party, any proposed virtual meeting to obtain informed consent, and the proposed medium of the documented record of participants providing their consent (for example, written, video, audio). The following should also be considered:

• Providing different methods of informed consent to those who request them, including in-person consent meetings and physical copies of the ICF
• Using virtual meeting platforms that include both audio and video features so that QIs (or delegated persons) and participants can take part in the informed consent process and discussion in real time, and interact virtually with a real person

Further, the G-FDR-0100 indicates that a clinical trial participant cannot be involved in any aspect of a clinical trial until they have gone through the informed consent process, with a trial staff member (doctor, study nurse, clinical trial coordinator, etc.) and signed the document indicating that they understand the information and have agreed to participate in the trial. Neither the QI, nor the QI site staff, should coerce or unduly influence a participant to participate or to continue their participation in a trial. A qualified physician should be available to answer any medical questions that the participant may have regarding their participation in the trial. Information should be as clear and concise as possible, use simple language, and avoid unnecessary volume and complexity. See CAN-52 for additional information.

For guidance from Canadian researchers on the core elements for obtaining consent to ensure transparency and improve participants’ understanding of their involvement in research studies, see CAN-57.

Re-Consent

Per the G-TCPS2, consent must be maintained throughout the research project. Researchers have a continuous duty to provide participants with all information relevant to their ongoing consent to participate in the research. Consent begins with the initial contact (e.g., recruitment) and carries through to the end of participation in the study. Throughout the clinical trial, researchers have a continuous responsibility to provide participants and ECs with all information relevant to participants’ ongoing consent to participate in the research. The researcher must also notify participants of any changes to the research project that may affect them. These changes may have ethical implications, may be relevant to their decision to continue in the study, or may be unique to the particular circumstances of individual participants. Specifically, researchers must disclose changes to the risks or potential benefits of the research.

The G-TCPS2 indicates that rather than an age-based approach to consent, researchers should use an approach based on decision-making capacity in compliance with any laws governing research participation. This includes those whose decision-making capacity is in the process of development, those whose decision-making capacity is diminishing or fluctuating, and those whose decision-making capacity remains only partially developed. Mechanisms should be in place from the outset to identify and address any changes that could affect consent. A change in participant capacity is an important element of ongoing consent.

Further, the G-TCPS2 states that within the limits of consent provided by the participant, researchers should disclose to the participant any material incidental findings discovered in the course of research. Incidental findings are considered to be material incidental findings if they are reasonably determined to have significant welfare implications for the participant or prospective participant. Where material incidental findings are foreseeable, researchers should inform participants during the initial consent process. In addition, researchers should develop a management plan for review by the EC. For more information on how to address material incidental findings, see G-ConsentMatIncFindings.

See CAN-52 for additional information.

Language Requirements

Per the G-FDR-0100, the ICF must be made available for each participant in either official language (French or English) or other language as appropriate. The G-TCPS2 requires the ICF to be presented in plain language that the participant is able to understand. If there is a language barrier, the QI should select an intermediary who has the necessary language skills to ensure effective communication.

Documenting Consent

As per the G-TCPS2, the participant or legal representative/guardian, as well as the QI, must sign and date the ICF. The G-FDR-0100 states that the QI should retain the signed ICF.

The G-TCPS2 further indicates that researchers can use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (e.g., 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, by email, or other electronic means). ECs should consider the power relationship that might exist between researchers and participants, and whether a waiver of the requirement for signed written consent may affect the welfare of the participants. If researchers plan to obtain non-written consent, they must explain their strategy to the EC.

See CAN-52 for additional information.

Waiver of Consent

As explained in the G-TCPS2, there are research situations that call for alterations of consent. The EC may approve research that involves an alteration to the consent requirements if the EC is satisfied, and documents that all of the following apply:

• The research involves no more than minimal risk to the participants
• The change to consent requirements is unlikely to adversely affect the welfare of participants
• It is impossible or impracticable to carry out the research and to address the research question properly, given the research design, if the prior consent of participants is required
• In the case of a proposed alteration, the exact nature and extent of any proposed alteration is defined
• There is a plan to brief participants and offer the option of refusing consent and/or withdrawing data and/or human biological materials

Based on the CanadaFDR and the G-TCPS2, the informed consent form (ICF) should generally include the following statements or descriptions in plain language, as applicable (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Information that the individual is being invited to participate in a research project
• The study involves research and an explanation of its purpose and duration
• The identity of the researcher and the funder/sponsor
• The procedures to be followed
• The participant’s responsibilities
• Any reasonably foreseeable risks or anticipated benefits to the participant and in general
• Information about any payments, including incentives for participants, reimbursement for participation-related expenses, and compensation for injury
• An assurance that prospective participants are under no obligation to participate and are free to withdraw at any time without prejudice to pre-existing entitlements
• An assurance that prospective participants will be given, in a timely manner throughout the course of the research project, information that is relevant to their decision to continue or withdraw from participation
• An assurance that prospective participants will be given information on their right to request the withdrawal of data or human biological materials, including any limitations on the feasibility of that withdrawal
• Information concerning the possibility of commercialization of research findings, and the presence of any real, potential, or perceived conflicts of interest on the part of the researchers, their institutions, or the research sponsors
• The measures to be undertaken for dissemination of research results and whether participants will be identified directly or indirectly
• The identity and contact information of a qualified designated representative who can explain scientific or scholarly aspects of the research to participants
• The identity and contact information of the appropriate individual(s) outside the research team whom participants may contact regarding possible ethical issues in the research
• An indication of what information will be collected about participants and for what purposes
• An indication of who will have access to information collected about the identity of participants
• A description of how confidentiality will be protected
• A description of the anticipated uses of data
• Information indicating who may have a duty to disclose information collected, and to whom such disclosures could be made
• A statement to the effect that, by consenting, participants have not waived any rights to legal recourse in the event of research-related harm
• Information on stopping rules and when researchers may remove participants from trial
• All other aspects of the clinical trial that are necessary for a person to make the decision to participate in the clinical trial

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Overview

In accordance with the CanadaFDR and the G-TCPS2, Canada’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-TCPS2 states that a participant’s rights must be clearly addressed in the informed consent form (ICF) and during the informed consent process. For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

The Right to Participate, Abstain, or Withdraw

As stated in the G-TCPS2, the participant or legal representative/guardian should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As per the G-TCPS2, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to the G-TCPS2, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

The Right of Inquiry/Appeal

The G-TCPS2 states that the research participant or legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or the participant’s rights.

The Right to Safety and Welfare

The G-FDR-0100 upholds the Declaration of Helsinki (CAN-58), which states that a research participant’s right to safety and the protection of their health and welfare must take precedence over the interests of science and society.

G-FDR-0100 states that in emergency situations, when prior consent of the participant is not possible, the consent of the participant's legal representative/guardian (as defined by provincial requirements), if present, should be requested. When prior consent of the participant is not possible, and the participant's legal representative/guardian is not available, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval by the ethics committee (EC) (known as a research ethics board in Canada), to protect the participant's rights, safety, and well-being, and to ensure compliance with applicable regulatory requirements. The participant or the participant's legal representative/guardian should be informed about the trial as soon as possible, and consent should be requested as appropriate.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which Canada has implemented per CAN-50. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Per G-TCPS2, research involving medical emergencies must be conducted only if it addresses the emergency needs of the individuals involved, and then only in accordance with criteria established in advance of such research by the EC. The EC may allow research that involves medical emergencies to be carried out without the consent of participants, or legal representatives/guardians, if all of the following apply:

• A serious threat to the prospective participant requires immediate intervention
• Either no standard efficacious care exists, or the research offers a realistic possibility of direct benefit to the participant in comparison with standard care
• Either the risk is not greater than that involved in standard efficacious care, or it is clearly justified by the prospect of direct benefits to the participant
• The prospective participant is unconscious or lacks capacity to understand the risks, methods, and purposes of the research project
• Authorization from the legal representative/guardian cannot be secured in sufficient time, despite diligent and documented efforts to do so
• No relevant prior directive by the participant is known to exist

The G-TCPS2 states that consent will not apply to public health activities undertaken by federal, provincial, and territorial public health officials operating under statutory powers during publicly declared health emergencies. The Ethcs-Emrgcy is an educational resource that provides ethical considerations, including for consent, to help institutions, ECs, and researchers protect participants and uphold public trust in the ethics review and conduct of research during publicly declared emergencies. It includes examples of practical applications from various publicly declared emergency contexts.

Overview

Per the G-FDR-0100, the responsibility of an institutional ethics committee (EC) (known as a research ethics board in Canada) is to protect the rights, safety, and well-being of all human participants. An EC should pay special attention to trials that may include vulnerable human participants (elderly, children, mentally ill, prisoners, etc.). The G-TCPS2 states that in all Canadian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations.

Per CAN-35, because the G-TCPS2 does not specify an age of consent for children, the decision on whether to seek consent from children is based on whether they have the capacity to understand the research and the risks and benefits of their participation. Youth who have not reached the age of majority (either 18 or 19 depending on the province or territory) may still be old enough to provide their own consent. For children who are not sufficiently mature to provide consent but are able to understand the nature of study participation, researchers must obtain the child’s assent in addition to the consent of an authorized third party. The decision of a child not to assent must be respected regardless of whether third-party consent was obtained. (Note: CAN-35 offers practical guidance that is consistent with the G-TCPS2, but it is only required for research reviewed by the joint Health Canada (HC)-Public Health Agency of Canada (PHAC) Research Ethics Board (REB).)

CAN-35 provides the following criteria for determining whether participants can provide their own consent, or whether an authorized third party should be involved:

• The risk level associated with the research project
• The legal requirements for age of consent in that jurisdiction
• The characteristics of the research participant (e.g., maturity level)
• In certain cases, the topic of the research itself

CAN-35 states that it is generally accepted that youth can consent to minimal risk studies at 16 years of age, and that assent should be sought from children beginning at approximately seven (7) years of age. However, it is ultimately up to the researcher to determine whether to obtain assent or consent from children, and to provide the rationale for this decision to the ethics committee (EC) (known as a Research Ethics Board in Canada). Researchers should also consider that within a single research project, some minors may be capable of consenting while others may not. See CAN-35 for additional details regarding obtaining consent from minors.

As per the G-TCPS2, when the research participant is a child, the informed consent form (ICF) must be signed by the child’s parent/legal guardian. All pediatric participants, however, should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the ICF.

As stated in G-TCPS2, children should only participate in clinical studies when the research objective cannot be achieved with adult participants only. When considering the inclusion of children in research, the investigators and ECs must consider a child’s stage of physical, physiological, psychological, and social development to ensure adequate protections for the child’s welfare.

Assent Requirements

G-FDR-0100 states that if minors are to be included in a trial, the EC should review the assent information considering the age, maturity, and psychological state of the minor population intended to be enrolled, as well as applicable regulatory requirements. Where a minor is to be included as a participant, age-appropriate assent information should be provided and discussed with the minor as part of the consent process, and assent from the minor to enroll in the trial should be obtained as appropriate. A process for consent should be considered if, during the trial, the minor reaches the age of legal consent, in accordance with applicable regulatory requirements.

Per G-TCPS2, where a child has some ability to understand the significance of the research, the researcher must ascertain the wishes of that individual with respect to participation. Children—whose decision-making capacity is in the process of development—may be capable of verbally or physically assenting to, or dissenting from, participation in research. While their assent would not be sufficient to permit them to participate in the absence of consent by the child’s parent/legal guardian, their expression of dissent must be respected. See TCPS2-InterpCnsnt for additional information.

Further, according to CAN-12, which offers best practices and guidance to researchers and ECs in pediatric research and complements the G-TCPS2, provincial laws in Canada vary as to when a child is presumed to be legally competent to provide informed consent. Some provinces use age while others use a competence-based evaluation.

As per CAN-12, if the pediatric participant has the capacity for assent, then affirmative assent is required to participate in a study according to the participant’s level of development and capacities. When the child develops the legal capacity to provide informed consent or attains the legal age of majority (which depends on the province), researchers should obtain an informed consent. Regarding dissent, CAN-12 states that the researchers must respect the dissent of a child who is capable of understanding.

For more details and guidance about best practices for research involving pediatric participants, see CAN-12.

As per the G-TCPS2, studies involving women of childbearing age, or who are pregnant, require additional safeguards to ensure that the research assesses the risks to the women and the fetuses. The following guidance applies to research involving materials related to human reproduction:

• Research using materials related to human reproduction in the context of an anticipated or ongoing pregnancy must not be undertaken if the information can reasonably be obtained by alternative methods
• Materials related to human reproduction for research use must not be obtained through commercial transaction, including exchange for services

Per the G-TCPS2, research on in vitro embryos already created and intended for implantation to achieve pregnancy is acceptable if:

• The research is intended to benefit the embryo
• Research interventions will not compromise the care of the woman, or the subsequent fetus
• Researchers closely monitor the safety and comfort of the woman and the safety of the embryo
• Consent was provided by the gamete donors

According to the G-TCPS2, research involving embryos that have been created for reproductive or other purposes permitted by law, but are no longer required for these purposes, may be ethically acceptable if:

• The ova and sperm from which they are formed were obtained in accordance with the G-TCPS2
• Consent was provided by the gamete donors
• Embryos exposed to manipulations not directed specifically to their ongoing normal development will not be transferred for continuing pregnancy
• Research involving embryos will take place only during the first 14 days after their formation by combination of the gametes, excluding any time during which embryonic development has been suspended

Per the G-TCPS2, research involving a fetus or fetal tissue:

• Requires the consent of the woman
• Must not compromise the woman’s ability to make decisions regarding continuation of her pregnancy

According to the G-TCPS2, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority.

According to the G-TCPS2, the ethics committee (EC) (known as Research Ethics Board in Canada) must approve the participation of research participants who are mentally or physically incapable of giving consent.

The G-TCPS2 indicates that for research involving individuals who lack the capacity, either permanently or temporarily, to decide for themselves whether to participate, the EC must ensure that, at a minimum, the following conditions are met:

• The researcher involves participants who lack the capacity to decide on their own behalf to the greatest extent possible in the decision-making process
• The researcher seeks and maintains consent from the participant’s legal representative/guardian in accordance with the best interests of the persons concerned
• The legal representative/guardian is not the researcher or any other member of the research team
• The researcher demonstrates that the research is being carried out for the participant’s direct benefit, or for the benefit of other persons in the same category; if the research does not have the potential for direct benefit to the participant but only for the benefit of the other persons in the same category, the researcher must demonstrate that the research will expose the participant to only a minimal risk and minimal burden, and demonstrate how the participant’s welfare will be protected throughout the participation in research
• When authorization for participation was granted by a legal representative/guardian, and a participant acquires or regains decision-making capacity during the course of the research, the researcher must promptly seek the participant’s consent as a condition of continuing participation

The G-TCPS2, the participant’s legal representative/guardian can provide consent for adults who lack the capacity to decide on their own behalf in accordance with the best interests of the persons concerned. In such cases, participants should still be involved to the greatest extent possible in the decision-making process, and their assent to participate must be obtained if they are capable of expressing their wishes in a meaningful way (whether verbally or physically). Importantly, when authorization for participation was granted by the participant’s legal representative/guardian and a participant acquires or regains decision-making capacity during the course of the research, the researcher must promptly seek the participant’s consent as a condition of continuing participation.

As delineated in the CanadaFDR and the G-GMP-Annex13, an investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form.

For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Manufacturing

As specified in the CanadaFDR and the G-CanadaCTApps, Health Canada (HC) authorizes the manufacture of investigational products (IPs) in Canada. HC approves the manufacture of IPs as part of the clinical trial application (CTA) approval. The G-QCM-PharmCTAs provides guidance and templates to assist sponsors in completing the quality portion of the CTA, which in turn, enables HC to assess IP characteristics adequately. The G-GMP-Annex13 requires the sponsor to ensure that IPs for clinical trials are manufactured and imported in accordance with its provisions and with CanadaFDR requirements. Per the G-CanadaCTApps, sponsors must file amendments or notifications to a previously authorized CTA when manufacturing changes are proposed that may affect the quality or safety of the clinical trial drug or biologic supplies.

Per G-GMP-Annex13, during development, critical parameters and in-process controls should be identified, adapted based on production experience, and justified by the knowledge available at the time. Although the manufacturing process need not be validated to the extent necessary for routine production, premises and equipment are expected to be validated in accordance with applicable good manufacturing practice (GMP) principles. Manufacturers must identify process steps that ensure participant safety and the reliability and robustness of clinical trial data and maintain written cleaning procedures and analytical methods to prevent cross-contamination. For sterile products, controls and processes related to sterility should meet the same standards as those for marketed products; where required, virus inactivation/removal and removal of other biological impurities should be demonstrated, with enhanced attention to aseptic-process validation and operator training. If a drug is modified, data such as stability, comparative dissolution, or bioavailability should demonstrate that the changes do not significantly alter its original quality characteristics; the sponsor should justify an appropriate retest date, and a reference sample of the comparator product should be retained following repackaging or over-encapsulation. For blinded products, systems should maintain the blind while permitting rapid product identification when necessary; where the manufacturer generates randomization codes, unblinding information should be available to the person in charge of quality control before the drugs are supplied, and the expiry assigned to all products should correspond to that of the shortest-dated product. See the G-GMP-Annex13 for additional details.

Per CAN-55, HC is a member of the Pharmaceutical Inspection Co-operation Scheme (PIC/S) and meets international GMP standards.

Per CAN-50, Canada has implemented the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which provides additional guidelines on manufacturing IPs. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Import

Per the CanadaFDR and the G-FDR-0100, HC authorizes the sponsor to import an IP. A sponsor who is not based in Canada must have a Canadian representative who is responsible for the import of the IP and demonstrates compliance with the applicable regulatory requirements. This representative should be the sponsor’s senior medical or scientific officer residing in Canada and is responsible for providing an attestation with respect to the CTA at the time of filing. Per the G-CanadaCTApps, the G-DrugApp, and CAN-4, if clinical trial drugs are to be imported into Canada, the authorization template (Appendix 1) in CAN-4 should be completed and submitted for each importer in Canada. The G-DrugApp states that Canadian importer(s) must be located within Canada. As additional importers are identified, additional copies of the authorization template in CAN-4 should be provided to HC.

The G-FDR-0100 provides additional guidance on requirements if a sponsor plans to send the clinical trial IP(s) directly to each trial site:

• A No Objection Letter (NOL) has been issued by HC authorizing the importation of the clinical trial material in Phase I-III trials; no clinical trial drugs should be imported prior to the NOL issuance and the NOL should accompany the package at the time of the importation
• Each party, including individual Canadian clinical trial sites, importing drugs directly (i.e., receiving drug shipments directly from outside of Canada) is identified on Appendix 1 of the Drug Submission Application Form (HC/SC 3011 form) (CAN-4)
• Clinical Trial Site Information (CTSI) forms (CAN-6) for each Canadian site conducting the clinical trial are submitted to HC for Phase I-III trials, prior to the start of the study
• Systems are in place, when appropriate, to monitor the transportation and storage conditions from the foreign source to the various clinical trial sites across Canada
• There is documented accountability of the imported drugs used in clinical trials and distributed to various clinical trial sites located in Canada, including the disposition of drugs returned from the clinical trial sites
• A written agreement is in place between the sponsor and the qualified investigator (QI) describing their specific responsibilities, and this agreement is available at the clinical trial site
• There is evidence that the drugs used in clinical trials conducted in Canada meet GMP requirements (e.g., certificates of manufacture, certificates of analysis, and/or evidence of approved lot release by a QI)

The G-CanadaCTApps, the G-HlthProdImprtExptReqs, the G-FDR-0100, and CAN-32 state that if a sponsor wants to import a drug into Canada for a clinical trial, a copy of HC’s authorization (i.e., the NOL) issued by either the Pharmaceutical Drugs Directorate (PDD) or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) must be included for the applicable trial with the shipment. A copy of this authorization must be provided at the port of entry. The G-HlthProdImprtExptReqs states that drugs without a Drug Identification Number may be imported where authorized for a Canadian clinical trial and a NOL was issued. The G-FDR-0100 further states that if 30 days have passed and the NOL was not issued, specific requests to import IPs should be directed to the Health Product Border Compliance Program at the following email account: hpbcp-pcpsf@hc-sc.gc.ca. Note that a sponsor does not have to submit a CTA for authorization to import an IP used in a Phase IV clinical trial.

Per CanadaFDR, the sponsor can make the following changes to the authorized use or importation of drugs if the sponsor notifies HC in writing within 15 days after the date of the change:

• A change to the chemistry and manufacturing information that does not affect the quality or safety of the drug
• A change to the protocol that does not alter the risk to the health of a clinical trial participant

Other changes must follow the amendment requirements delineated in the CanadaFDR. See the G-FDR-0100 for additional HC interpretations of the relevant provisions of the CanadaFDR.

Investigator’s Brochure

In accordance with the CanadaFDR, the sponsor is responsible for providing the investigators with an Investigator’s Brochure (IB). The IB must contain all the relevant information on the investigational product(s) (IPs), including significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information. The sponsor must ensure that an up-to-date IB is made available to the investigator(s), and the investigator(s) must provide an up-to-date IB to the ethics committee. Per CAN-50, Canada has implemented the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which provides additional guidance on IB development and contents. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence. For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

The CanadaFDR requires the IB to provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and post-marketing experiences)
• Summary of data and guidance for the investigator(s)

In accordance with the G-CanadaCTApps, the sponsor must submit annually to HC an updated IB, which serves as the annual report, including all safety information and global status. Revisions that are more frequent may be appropriate depending on the stage of development and the generation of relevant new information.

Quality Management

As specified in the G-GMP-CAN and G-GMP-Annex13, the sponsor must ensure that the products are manufactured in accordance with good manufacturing practice (GMP). The G-GMP-CAN requires a quality management system, incorporating GMP, to ensure that IPs are of the quality required for their intended use.

Per the G-GMP-Annex13, the manufacturer’s quality system should be described in written procedures and available to the sponsor, taking into account GMP principles and guidelines. The manufacturer should establish and maintain a quality control system placed under the authority of a person who has the requisite qualifications and is independent of production. Quality control of the clinical trial drug, including that of the comparator product or placebo, should be performed in accordance with the information submitted in the application for the clinical trial, as authorized by the relevant country. Verification of the effectiveness of blinding should be performed and recorded.

Per the G-FDR-0100, if a sponsor plans to send the clinical trial IP(s) directly to each trial site, there should be evidence that the drugs used in clinical trials conducted in Canada meet GMP requirements (e.g., certificates of manufacture, certificates of analysis, and/or evidence of approved lot release by a qualified individual).

Investigational product (IP) labeling in Canada must comply with the requirements set forth in the CanadaFDR, the G-CanadaCTApps, and the G-GMP-Annex13. The CanadaFDR and the G-CanadaCTApps state that for an IP to be used in a clinical trial, it must be properly labeled in both official languages: English and French. The CanadaFDR requires that IPs be packaged and labelled under the supervision of personnel who have had satisfactory technical, academic, and other training. The packager and/or labeler must have written procedures and ensure that the IP is packaged, labelled, and tested in compliance with those procedures. For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. Per CAN-50, Canada has implemented the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which provides additional guidelines on labeling IPs. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

As delineated in the CanadaFDR and the G-GMP-Annex13, the following information must be included on the IP label:

• A statement indicating that the drug is an IP to be used only by a qualified investigator
• Name, number, or identifying mark
• Expiration date
• Recommended storage conditions
• Lot number
• Sponsor’s name and address
• Protocol code or identification
• Radiopharmaceutical information, if applicable

Per the G-FDR-0100, a label includes any legend, word, or mark attached to, included in, belonging to, or accompanying any drug or package. The sponsor is responsible for ensuring that the labeling of a clinical trial drug meets the requirements of the CanadaFDR, and that the system in place is validated, traceable, and does not compromise participant safety or product quality. The required information must be attached to, included with, or accompany each container of the drug product. If a label provides all the required information in both official languages (English and French), it is considered to have met the requirements of the CanadaFDR. However, traceability to the manufacturing lot should be maintained on the label immediately attached to the IP (i.e., primary container) such that its identity can be determined, and, if necessary, which unit was dispensed to each participant. For blinded clinical trials the sponsor must ensure that labeling information does not compromise the blinding. Labeling of a clinical trial drug with a manufacturer's lot number may compromise a blinded clinical trial. Identifiers other than a "lot" or "(L)" number (for example a batch number, a kit number, or a bar code) may be considered compliant, provided traceability is maintained. Where a bar code is included as the identifier on the label, the code on the drug label should readily link to information (for example, lot number and expiration date) through a validated computerized system. During an inspection, HC may verify that there is a system of traceability in place to ensure participant safety and that the computerized system, if applicable, is fully validated. It is acceptable for a marketed drug used in a clinical trial as a comparator, to be labelled in accordance with its marketing authorization, provided that the label on the marketed drug is appropriate for the trial. However, a marketed comparator drug used off-label must comply with the IP labeling requirements.

With regard to the expiration date, the G-GMP-Annex13 states that if it becomes necessary to change the expiration date, an additional label should be affixed to the IP. This additional label should state the new expiration date and repeat the batch number. It may be superimposed on the previous expiration date, but for quality control reasons, not on the original batch number. This operation should be performed at an appropriately authorized manufacturing site. However, when justified, it may be performed at the investigational site by or under the supervision of the clinical trial site pharmacist or other health care professional in accordance with national regulations and with the sponsor’s requirements. Where this is not possible, it may be performed by the clinical trial monitor(s) who should be appropriately trained. The operation should be performed in accordance with good manufacturing practice (GMP) principles, operating procedures, and applicable contractual provisions, and should be checked by a second person. This additional labeling should be properly documented in both the trial documentation and in the packaging records.

As indicated in the G-FDR-0100, HC may verify that a clinical trial drug has a valid expiration date during an inspection. If stability studies to support the expiration date for an IP are still ongoing at the time of labeling, the following may be considered acceptable in lieu of an expiration date:

• A re-test date on the label if the sponsor has data to support the extended shelf-life of the drug, and
• A manufacturing date is listed on the label, as long as the clinical trial site where the drug is dispensed has a document from the sponsor documenting the shelf-life of the drug

The above process should be documented, and procedures and quality control systems should be in place and in accordance with the approved clinical trial application. This additional labeling information should be properly documented in both the trial documentation and in the packaging records.

Supply, Storage, and Handling Requirements

Per CanadaFDR, drugs must be manufactured, handled, and stored in accordance with good manufacturing practice (GMP). For investigational product (IP) packaging, the G-GMP-Annex13 provides the following guidance:

• The risk of product mix up must be minimized by using appropriate procedures, specialized equipment, and relevant staff training.
• To prevent errors, particularly when IPs are blinded, use heightened precautions, such as label reconciliation, line clearance, and in-process control checks by appropriately trained staff.
• The packaging must ensure that the IP remains in good condition during transport and storage at intermediate destinations; any opening or tampering of the outer packaging during transport should be readily discernible.

The G-Storage provides principles and interpretations on the environmental control of clinical trial drugs during storage and transportation, including packaging. See G-Storage for information regarding compliance with the CanadaFDA and the CanadaFDR, as it relates to packaging clinical trial drugs for human use, such as the role of environmental controls, quality risk management, and special considerations for active pharmaceutical ingredients.

G-Dcntrl states that for decentralized activities, sponsors and qualified investigators (QIs) must ensure GMP- and protocol-compliant transport, storage, and handling of IPs. Sponsors are responsible for preserving product integrity during transport and storage and addressing controlled-substance diversion risks. QI oversight may include maintaining accountability for the IP at decentralized locations. Sponsors should ensure that direct-to-home shipment and dispensing comply with applicable provincial and territorial requirements.

Per CAN-50, Canada has implemented the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3) (CAN-52), which provides additional guidance on IP management. The G-FDR-0100 explains the relationship between the CanadaFDR and CAN-52, including additional guidance where needed or where CAN-52 does not apply. At all times, where the CanadaFDR exceeds the guidance set out in CAN-52, the CanadaFDR takes precedence.

Record Requirements

As set forth in the CanadaFDR, the G-FDR-0100, and the CanadaFDR1024, the sponsor must record, handle, and store all trial-related information to allow complete and accurate reporting, interpretation, and verification. The CanadaFDR states that the sponsor should maintain all trial-related records for a period of 15 years. Pursuant to CanadaFDR1024, the sponsor must submit requested records to HC within 48 hours if safety concerns arise. Additionally, to facilitate inspection of a site, the sponsor must submit information to Health Canada (HC) within seven (7) days of a request.

Per the G-FDR-0100, drug accountability records should include the following information:

• Date of arrival on site
• Quantity received
• Identification (batch/lot number)
• Expiration date
• Quantity and date dispensed and to whom
• Quantity and date returned by participants
• Quantity and date of destruction or return to sponsor

As explained in the G-FDR-0100, to ensure that participants receive the IP according to their randomization, qualified investigators (QIs) should maintain records. The QI and/or a pharmacist or other appropriate individual should maintain records of the product's delivery, the inventory, the use by each participant (including documenting that the participants were provided the doses specified by the protocol), and the return to the sponsor and destruction or alternative disposition of unused product(s). Drug accountability records are required for:

• Drugs that are the subject of the clinical trial, and do not have market authorization
• Drugs that are the subject of the clinical trial, have market authorization, but are used off-label
• Comparator drug, if it does not have market authorization
• Comparator drug, if it has market authorization, but its labeling was changed (for example for blinding purposes)
• Comparator drug, if it has market authorization, but is used off-label (unless it was not considered to be investigational in the context of the particular clinical trial, based on the assessment of the application)

Further, per in the G-FDR-0100, drug accountability records are not required for:

• Drugs that are the subject of a Phase IV clinical trial
• Comparator drug, if it has market authorization, is used on-label, and has not been altered in any manner
• Rescue or concomitant medications, authorized for sale in Canada, that may be used on or off-label but are not the subject of the clinical trial (for example, they are used as supportive medications for known clinical applications)

The G-Storage provides that when contracted parties, such as warehouses or commercial carriers, store or transport drugs, there should be a written agreement that outlines all relevant conditions.

See CAN-52 for additional guidance on IP record keeping.

In Canada, a specimen is referred to as “human biological material” or “biological material.” According to the G-TCPS2, human biological materials include tissues, organs, blood, plasma, skin, serum, DNA, RNA, proteins, cells, hair, nail clippings, urine, saliva, and other body fluids. The term also comprises materials related to human reproduction, including embryos, fetuses, fetal tissues, and human reproductive materials. The G-TCPS2 breaks down human biological material further into the following categories: anonymized, anonymous, coded, and identified human biological materials. Refer to the G-TCPS2 for more detailed information on these categories.

In addition, CAN-2 defines biological material as pathogenic and non-pathogenic microorganisms, proteins, and nucleic acids, as well as any biological matter that may contain microorganisms, proteins, nucleic acids, or parts thereof. Examples include, but are not limited to, bacteria, viruses, fungi, prions, toxins, genetically modified organisms, nucleic acids, tissue samples, diagnostic specimens, live vaccines, and isolates of a pathogen (e.g., pure culture, suspension, purified spores).

Import/Export

According to the G-HlthProdImprtExptReqs, Health Canada (HC) does not have jurisdiction over human biological materials to be imported for testing or research purposes. The G-HlthProdImprtExptReqs further states that all blood samples as well as cultures, diagnostic specimens, or research tissue may 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). Per CAN-24 and CAN-2, the PHAC’s Centre for Biosecurity oversees the licensing process under the authority of the HPTA and the 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 specified in the HPTA, the HPTR, and CAN-2, 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. Per CAN-2, because all human biological materials are potential carriers of human pathogens, the PHAC has categorized these materials 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 the HPTR 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 the HPTR licensing requirements. See CAN-2 for detailed information and instructions on how to obtain a license for activities associated with Risk Groups 2 through 4.

Other Considerations

Per the G-TCPS2, institutions and researchers that maintain biobanks must ensure that they have or use appropriate facilities, equipment, policies, and procedures to store human biological materials safely, and in accordance with applicable standards. They must also establish appropriate physical, administrative, and technical safeguards to protect human biological materials and any information about participants from unauthorized handling. Procedures for storage and record keeping must include effective measures to ensure that participants’ identities are protected, including the security of facilities and effective procedures for data handling, record keeping, and regulating access to human biological materials and information. Appropriate governance of biobanks is also important for managing access to and use of stored biological materials. The appropriate governance structure and management of a biobank will vary depending on its size and usage. Organizations that maintain biobanks may have their own policies on privacy of, confidentiality of, and access to materials. Researchers should be aware of requirements for compliance with such policies. Identifiable data derived from human biological materials may be linked to other research or public databases. Researchers who propose to engage in data linkage must obtain ethics committee (EC) approval prior to carrying out the data linkage. Where data linkage involves or is likely to produce identifiable information, researchers must show that the data linkage is essential to the research, and appropriate security measures will be implemented to safeguard information.

In accordance with the G-TCPS2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent from the participant and/or the legal representative(s) and review/approval from the institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) must be obtained. Specifically, consent is required from the following:

• The participant who will be donating biological materials, or an authorized third party on behalf of a participant who lacks capacity, taking into account any research directive that applies to the participant, or
• A deceased participant through a donation decision made prior to death, or by an authorized third party

In addition, the G-TCPS2 states that to seek participant consent to use the participant’s biological materials in research, the investigator(s) must provide the prospective participant or authorized third party with the following information:

• The type and amount of biological materials to be taken
• The manner in which biological materials will be taken, and the safety and invasiveness of the procedures
• The intended uses of the biological materials, including any commercial use
• The measures employed to protect the privacy of and minimize risks to participants
• The length of time the biological materials will be kept, how they will be preserved, location of storage (e.g., in Canada or outside Canada), and process for disposal, if applicable
• Any anticipated linkage of biological materials with information about the participant
• The plan for handling results and findings, including clinically relevant information and incidental findings
• The participant’s right to request the withdrawal of data or human biological materials, including any limitations on the feasibility of that withdrawal

The G-TCPS2 states that to seek broad consent for the storage and future unspecified use of human biological materials, researchers must provide prospective participants, or authorized third parties, with applicable information as set out in the informed consent requirements, as well as the following details:

• The type, identifiability, and amount of human biological materials being collected and stored for re-use, and for what potential purpose
• The voluntariness of the participant’s consent, including any limitations on the feasibility of withdrawal
• A general description of the nature and types of future research that may be conducted, including whether the research might be conducted outside of Canada (if known)
• The risks and potential benefits of storage of human biological materials and of their use in future unspecified research, including areas of uncertainty where risks cannot be estimated
• Access to a general description of the repository and its governance
• A statement regarding participants’ preference to being contacted for additional future research
• Whether the human biological materials could be shared with researchers who are not subject to the G-TCPS2
• Whether the research will (if known) or might include whole genome sequencing or similar technologies that may pose a substantial risk of re-identification of the participant or identification of material incidental findings (when appropriate)
• Separate options for consenting to participate in a specific research project and for consenting to the storage of human biological materials for future unspecified research

See Brd-Cnst for additional clarifications on broad consent for the storage and future unspecified use of data.

See the G-Dcntrl for considerations on collecting specimens during home visits in decentralized clinical trials. Also see the G-TCPS2 for additional details on confidentiality, future use of information, broad consent for the storage of data and human biological materials for future unspecified research, biobanks, and stem cell consent.