Clinical Research Regulation For Canada
Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Authorizing Body
Clinical Trial Lifecycle
Submission Process
Submission Content
Timeline of Review
Trial Initiation
Safety Reporting
Progress Reporting
Sponsorship
Definition of Sponsor
Trial Authorization
Insurance
Compensation
Quality, Data & Records Management
Site/Investigator Selection
Informed Consent
Documentation Requirements
Required Elements
Compensation Disclosure
Participant Rights
Special Circumstances/Emergencies
Vulnerable Populations
Children/Minors
Pregnant Women, Fetuses & Neonates
Prisoners
Mentally Impaired
Investigational Products
Definition of Investigational Product
Manufacturing & Import
IMP/IND Quality Requirements
Labeling & Packaging
Product Management
Specimens
Definition of Specimen
Specimen Import & Export
Consent for Specimen
Sources
Requirements
Additional Resources
Forms
QUICK FACTS
Clinical trial application language English or French
Regulatory authority & ethics committee review may be conducted at the same time Yes
Clinical trial registration required No
In-country sponsor presence/representation required Yes
Age of minors Under 18 or 19, determined by province or territory
Specimens export allowed Yes
Regulatory Authority > Regulatory Authority
Last content review/update: August 11, 2022
Summary

Health Canada

As per the CanadaFDA, the CanadaFDR, the G-CanadaCTApps, and CAN-29, 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. Per CAN-31, HC assesses clinical trial protocols to evaluate participant protection and safety; reviews drug quality; assures institutional ethics committee review; verifies principal investigator qualifications; and monitors and reviews adverse drug reactions. 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 CAN-16, HPFB’s activities are carried out by nine (9) Directorates and one (1) office, including the Pharmaceutical Drugs Directorate (PDD) and the Biologic and Radiopharmaceutical Drugs Directorate (BRDD). Per CAN-18 and CAN-17, the PDD and the BRDD, respectively, regulate pharmaceutical drugs, and biological drugs and radiopharmaceuticals for human use. 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. 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. If a product does not readily meet one (1) of the statutory definitions, other regulatory areas of HC are asked to participate in the committee's discussion.

As per CAN-41, Health Canada 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.

Contact Information

According to the G-DrugApp and CAN-18, Health Canada PDD contact information is as follows:

Office of Clinical Trials
Drug Clinical Trials
Pharmaceutical Drugs Directorate 
Health Products and Food Branch
Health Canada
Address Locator: 3105A
Ottawa, Ontario

Phone: 613-957-0368
Fax: 613-952-7756
General Inquiries E-mail: pharma_drug_enquiries-renseignements_medicaments_pharma@hc-sc.gc.ca
Office of Clinical Trials Inquiries: oct.enquiries-requetes.bec@hc-sc.gc.ca

Per CAN-17, the following is the contact information for biologic clinical trials:

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Building 6, Address Locator: 0601B
100 Eglantine Driveway
Tunney’s Pasture
Ottawa, Ontario
Canada K1A 0K9

Phone: 613-863-8405
General Enquiries E-mail: hc.brdd.dgo.enquiries.sc@canada.ca

Part II (Section 30 (1.2))
Part C (Division 5 (C.05.001, C.05.002, C.05.005, and C.05.006))
1.2, 1.4, 2.1, and Appendix 1
5
Where to send drug submission applications
What is the Health Products and Food Branch?
Our Regulatory Innovation Agenda
Regulatory Authority > Scope of Assessment
Last content review/update: August 11, 2022
Summary

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 and CAN-19 for background information on HC’s scope of assessment.

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; “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, 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, and
  • Marketed drugs where the proposed use of the drug for one (1) of the following is different: indication(s) and clinical use; target patient populations(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 and CAN-23 indicate 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.

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. As delineated in the G-CanadaCTApps and CAN-23, 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. As specified in the G-CanadaCTApps and CAN-23, 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.

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
2 and Part II (Section 30 (1.2))
Part C (Division 5 (C.05.001, C.05.002, C.05.005, and C.05.006))
1.2, 2.1, 2.3, 2.7, and Appendix 1
5.1, 5.2, 5.5, and 5.6
Clinical Trial Site Information form
What is the Health Products and Food Branch?
Regulatory Authority > Regulatory Fees
Last content review/update: August 11, 2022
Summary

According to CAN-33, there are no fees to submit a clinical trial application in Canada.

Question 5
Ethics Committee > Ethics Committee
Last content review/update: August 11, 2022
Summary

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, institutions specifically funded by 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 CA-ICH-GCPs. This joint EC is the HC-PHAC REB, which must review and approve all human research studies carried out by, performed by, or otherwise under the auspices of HC or PHAC. 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 the CA-ICH-GCPs. See HCNotice-CA-ICH-GCPs for more information on Canada’s implementation of the CA-ICH-GCPs. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (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. The G-TCPS2 is an ethics policy 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). Per the G-TCPS2, the G-TCPS2 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, the G-CanadaCTApps, and the CA-ICH-GCPs, 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. As mentioned earlier, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guidance as a condition of funding.

Terms of Reference, Review Procedures, and Meeting Schedule

According to the CA-ICH-GCPs, institutional ECs must establish written standard operating procedures (SOPs) to cover the entire review process. The SOPs should include EC composition, meeting schedules, notifications, frequency of reviews, protocol deviations, reporting to the EC, and recordkeeping. Further, ECs should make decisions at announced meetings where a quorum is present. Only those members who participate in the EC review and discussion should vote, provide their opinion, or advise. For detailed EC procedures and information on other administrative processes, see the CA-ICH-GCPs. In addition, for examples of EC SOPs, see CAN-13 for the HC-PHAC REB operational policy.

Part C (Division 5 (C.05.001, C.05.002, C.05.005, C.05.006, and C.05.010))
Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11
1.2, 1.4, 2.1, and 2.7
5.1, 5.2, 5.5, 5.6, and 5.10
Introduction and Chapter 6 (Articles 6.4 and 6.10)
2 and 3
About the REB and Policies, Guidelines, and Resources
Ethics Committee > Scope of Review
Last content review/update: August 11, 2022
Summary

Overview

According to the CanadaFDR, the G-CanadaCTApps, the G-TCPS2, and the CA-ICH-GCPs, 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 to protecting the welfare of certain classes of participants deemed vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations.) Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

The CA-ICH-GCPs also state that ECs must ensure an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants, and they must verify the adequacy of confidentiality and privacy safeguards. See the CA-ICH-GCPs for detailed ethical review guidelines.

Role in Clinical Trial Approval Process

As per the CanadaFDR and the CA-ICH-GCPs, 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 he/she submits an institutional EC approval for each participating trial site. The sponsor should use the Clinical Trial Site Information Form (see 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. For HC’s interpretation of the relevant provisions of CanadaFDR, see the G-FDR-0100.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires ECs to 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. In addition, 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.

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.)

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, in the event that 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.

Part C (Division 5 (C.05.001, C.05.005, C.05.006, and C.05.010))
Foreword, 1.27, 2, and 3
1.2, 1.4, 2.1, 2.5, and 2.7
5.1, 5.2, 5.5, 5.6, and 5.10
Introduction, and Chapters 1, 6, and 11
Ethics Committee > Ethics Committee Fees
Last content review/update: August 11, 2022
Summary

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.

Ethics Committee > Authorizing Body
Last content review/update: August 11, 2022
Summary

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

Clinical Trial Lifecycle > Submission Process
Last content review/update: August 11, 2022
Summary

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 he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form (CAN-6)) for each participating trial site. The HCNotice-CTSIForm indicates that the revised CTSI form improves efficiencies and supports the submission of CTAs using the electronic Common Technical Document (eCTD) format. 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 outer label should be clearly identified with "Clinical Trial Application".

The G-MDSA and the G-CanadaCTApps indicate that sponsors may request a pre-submission/application meeting with the appropriate Directorate within HPFB 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.

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.

Per the G-CanadaCTApps, the G-MDSA, and the Non-eCTDformat, HC accepts clinical trial submissions/applications in the eCTD and non-eCTD electronic-only formats. The Non-eCTDformat indicates that the eCTD format is recommended. Per CAN-44, once a submission is filed in eCTD format, all additional information and subsequent regulatory activities for the same dossier (protocol) must be filed in eCTD format, and sponsors must not revert to non-eCTD electronic-only format.

According to the ElecSubms, CTAs in eCTD format are available upon request via email to no-reply.ereview.non-reponse@hc-sc.gc.ca; the text 'Request for Clinical Trial Applications in eCTD Format' should be in the subject line of the email. HC’s guidance documents: “Preparation of Regulatory Activities in eCTD Format” and “Common Electronic Submissions Gateway (CESG) Health Canada Reference Guide” are available upon request via email to no-reply.ereview.non-reponse@hc-sc.gc.ca; the text ‘Request for eCTD Guidance Document’ should be in the subject line of the email. Background information about CESG is available at CAN-25. Applicants must request a dossier ID from HC for eCTD dossiers. The dossier ID request forms for drug and biological product clinical trials are available via ElecSubms. A request for a dossier ID should be sent a maximum of eight (8) weeks prior to filing a clinical trial application in the eCTD format. Per CAN-44, for eCTD format, prior to filing a CTA via the CESG, each company must file a sample transaction to HC in accordance with the applicable guidance documents. Additional questions regarding the CESG and eCTD submissions may be directed to ereview@hc-sc.gc.ca.

For non-eCTD electronic submissions, based on information provided in the G-CanadaNon-eCTD and the G-MDSA, sponsors must submit CTAs on electronic media—a disc or drive. HC recommends PDF and/or MS-Word (where required) for the CTA. The PDF documents must be generated from electronic sources (not scanned material), no larger than 150 MB, properly bookmarked, hyperlinked, and organized in accordance with the CTD specifications in the G-CanadaCTApps and the G-CanadaNon-eCTD. Finally, the sponsor must include a cover letter in both electronic and paper format. (For detailed cover letter requirements, see the G-CanadaNon-eCTD). HC advises sponsors to complete the CTA using the G-CanadaCTApps in conjunction with the G-CanadaNon-eCTD. For validation rules, see the Rules-Non-eCTD. The ElecSubms contains a zip file of the folder structure for clinical trial non-eCTD submissions. The G-Canada-CTD also provides detailed CTD format/structure requirements.

Per the G-CanadaNon-eCTD, sponsors should send CTAs directly to the appropriate Directorate within HC’s HPFB in the following media formats:

  • DVD-RAM UDF standard
  • Single and dual layer Recordable Digital Versatile Discs
  • Single and dual layer Blu-ray discs
  • USB 2.0 or 3.0 drive
  • Portable External Hard Drive with USB 2.0 or 3.0 interfaces

In addition, the G-CanadaNon-eCTD indicates that media should not be password protected, and must be provided on a single disc/drive, scanned using virus-scanning software, and certified as virus free. All discs/drives should be labelled with the following information:

  • Sponsor
  • Brand Name of Drug Master File (DMF) Name
  • Dossier Identifier (if known)
  • Control Number or DMF Number (if known)
  • "Protected B"
  • "This media has been virus-scanned and we certify that it is virus free"
  • Month and year of filing

As per 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 to the addresses listed below.

Office of Clinical Trials
Pharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Address Locator: 3105A
Ottawa, Ontario
Canada K1A 0K9
Phone: 613-957-0368
Fax: 613-952-7756

Office of Clinical Trials Inquiries: oct.enquiries-requetes.bec@hc-sc.gc.ca
General Inquiries E-mail: pharma_drug_enquiries-renseignements_medicaments_pharma@hc-sc.gc.ca

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Building 6, Address Locator: 0601B
100 Eglantine Driveway
Tunney’s Pasture
Ottawa, Ontario
Canada K1A 0K9
Phone: 613-863-8405
General Enquiries E-mail: hc.brdd.dgo.enquiries.sc@canada.ca

Per the HCNotice-CTSIForm, questions related to pharmaceutical CTSI forms should be sent to: oct.enquiries-requetes.bec@hc-sc.gc.ca and questions related to biologic CTSI forms should be sent to brdd.ora@hc-sc.gc.ca.

According to the G-MDSA, HC no longer accepts paper copies of CTAs, CTA amendments, and CTA notifications. See the G-CanadaNon-eCTD, the G-CanadaCTApps, and the G-Canada-CTD for detailed document preparation and submission requirements.

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. 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.

Part C (Division 5 (C.05.002, C.05.004, C.05.005))
Guidance documents, notices, and supporting documents
1.2, 2.2, 2.3, and 2.7
7.1, 8.1, and 8.2
5.2, 5.4, and 5.5
1-3 and Appendix D
2-5, and Appendix D
1.2
Clinical Trial Lifecycle > Submission Content
Last content review/update: August 11, 2022
Summary

Regulatory Authority Requirements

As set forth in the CanadaFDR, the G-CanadaCTApps, and CAN-31, 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, the G-CanadaNon-eCTD, the G-Canada-CTD, 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
  • 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 CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form CAN-6)) for each participating trial site. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Refer to the CanadaFDR, the G-CanadaNon-eCTD, the G-CanadaCTApps, the G-Canada-CTD, the G-DrugApp, 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. However, the following requirements comply with the CA-ICH-GCPs and are basically consistent across all Canadian ECs:

  • Clinical protocol
  • ICFs and participant information
  • Participant recruitment procedures
  • IB
  • Safety information
  • Participant payments and compensation
  • Investigator(s) current curriculum vitaes (CVs)
  • Additional required institutional EC documentation

See section 3.1.2 of CA-ICH-GCPs for additional submission content requirements.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires clinical trial researchers to include a plan for monitoring safety, efficacy/effectiveness (where feasible), and validity in their proposal for EC review. See the G-TCPS2 for additional details on the plan’s required contents.

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

As delineated in the CA-ICH-GCPs, the clinical protocol should include the following elements:

  • General information
  • Background information
  • Trial objectives and purpose
  • Trial design
  • Participation selection/withdrawal
  • Participant treatment
  • Efficacy assessment
  • Safety assessment
  • Statistics
  • Direct access to source data/documents
  • Quality control/quality assurance procedures
  • Ethical considerations
  • Data handling and record keeping
  • Financing and insurance
  • Supplements

For complete protocol requirements, see section 6 of CA-ICH-GCPs.

Part C (Division 5 (C.05.001, C.05.004, and C.05.005))
3.1.2, 6, and 7
2.3 and 2.7
5.1, 5.4, and 5.5
1-3 and Appendix D
2-5, and Appendix D
I, S – Drug Substance, and P – Drug Product
Chapter 11 (Article 11.6)
Apply for Ethics Review
Clinical Trial Lifecycle > Timeline of Review
Last content review/update: August 11, 2022
Summary

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 he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form) for each participating trial site. 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, dialogue with the sponsor, and/or circumstances of the review, including pausing the clock during the scientific review. According to the G-CanadaCTApps and the G-MDSA, if HC authorizes the CTA, then it issues a No Objection Letter (NOL). If HC rejects the CTA, it sends a Not Satisfactory Notice (NSN). HC will issue an NSN if it identifies significant deficiencies, or, if a timely response to requested information has not been provided. The sponsor may resubmit the information and material at a future time, and it will be processed as a new CTA.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. However, according to the CA-ICH-GCPs, the institutional EC should review a proposed clinical trial within a reasonable time. 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 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.

Part C (Division 5 (C.05.005 and C.05.006))
3.1.2
2.1, 2.3.3, 2.5, and 2.7
11.1, 12.1 and 13.3-13.4
5.5 and 5.6
Chapter 2 (Articles 2.8 and 2.9) and Chapter 6 (Article 6.13)
Apply for Ethics Review
Clinical Trial Lifecycle > Trial Initiation
Last content review/update: August 11, 2022
Summary

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 form, the date of commencement of the trial 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)) 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, if a sponsor (Canadian or foreign) wants to import a drug into Canada to conduct a clinical trial, he/she must include a copy of HC’s clinical trial authorization (i.e., the NOL) 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 the trial, as delineated in the G-FDR-0100 and the CA-ICH-GCPs, the sponsor must sign an agreement between all involved parties, including ECs, Qualified Investigators (QIs), contract research organizations, and others, to ensure full compliance with the regulatory requirements. Further, the sponsor should obtain the investigator’s/institution's agreement:

  • To conduct the trial in compliance with good clinical practice, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC
  • To comply with procedures for data recording and reporting
  • To permit monitoring, auditing, and inspection
  • To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

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 practices 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.

See CAN-6, CAN-8, and CAN-19 for additional clinical trial forms.

Clinical Trial Registration

As per the G-CanadaCTApps, sponsors should register their clinical trials on one (1) of two (2) publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization (WHO), ClinicalTrials.gov (CAN-45), and the International Standardized Randomized Controlled Trial Number (ISRCTN) Registry (CAN-46). According to HCNotice-CTRegDisc, clinical trial registration is not a mandatory requirement at this time. However, per the G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, clinical trials must be registered before recruitment of the first trial participant in a publicly accessible registry that is acceptable to the WHO or the International Committee of Medical Journal Editors (ICMJE). In addition, following registration, researchers are responsible for ensuring that the registry is updated in a timely manner with: new information; safety and, where feasible, efficacy reports; reasons for stopping a trial early; and the location of findings.

Part C (Division 5 (C.05.006 and C.05.012))
1.17, 5.1.2, 5.6.3, and 8.2.6
1.2 and 2.7
5.6 and 5.12
Chapter 11 (Articles 11.10, 11.11, and 11.17)
Clinical Trial Lifecycle > Safety Reporting
Last content review/update: August 11, 2022
Summary

Safety Reporting Definitions

According to the CanadaFDR and G-CanadaCTApps, and the CA-ICH-GCPs, the following definitions provide a basis for a common understanding of Canada’s safety reporting requirements:

  • Adverse Event (AE) – Any adverse occurrence in the health of a clinical trial subject who is administered a drug that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.
  • Adverse Drug Reaction (ADR) – Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.
  • Serious Adverse Drug Reaction (SADR) or Serious Adverse Event (SAE) – Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or causes a congenital anomaly/birth defect.
  • Serious, Unexpected ADR – A serious ADR that is not identified in nature, severity, or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.

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.

Safety Reporting Requirements

Investigator Responsibilities

Per the CA-ICH-GCPs, all SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify participants by unique code numbers assigned to the trial subjects rather than by their names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious adverse drug reactions to the regulatory authority(ies) and the EC. AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. For reported deaths, the investigator should supply the sponsor and the EC with any additional requested information (e.g., autopsy reports and terminal medical reports).

Sponsor Responsibilities

As delineated in the CanadaFDR, the G-CanadaCTApps, the HCNotice-E2A, and CAN-22, 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. Further detail and clarifications on AE/ADR reporting criteria can be found in the HCNotice-E2A and CAN-22. As specified in the G-CanadaCTApps and the HCNotice-E2A, when evaluating whether an AE is serious and unexpected, the Qualified Investigator’s (QI) and sponsor’s determination of causality is important. Only serious and unexpected ADRs found to have a reasonable suspected causal relationship to 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, upon request, directly to the Office of Submissions and Intellectual Property (OSIP). HC recommends that DSURs in electronic Common Technical Document (eCTD) format be sent via the Common Electronic Submission Gateway (CESG) and DSURs in "non-eCTD electronic-only" format be sent to OSIP via CD/DVD. Sponsors may provide DSURs when important new safety information on a drug needs to be conveyed as long as a strong rationale for the filing of the DSUR is 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, the HCNotice-E2A, and CAN-22, all serious and unexpected ADRs should be reported individually to HC. According to HC-ICH-E2A (which Canada adopted pursuant to the HCNotice-E2A), 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.

Part C (Division 5 (C.05.001 and C.05.014))
Attachment 1
1.1, 1.2, 1.50, 1.60, and 4.11
Notice, 1.2, and 2.4
2.1 and 2.8
5.14
Chapter 11 (Article 11.8)
Clinical Trial Lifecycle > Progress Reporting
Last content review/update: August 11, 2022
Summary

Interim and Annual Progress Reports

Pursuant to the CanadaFDR, the G-CanadaCTApps, CAN-22, and the CA-ICH-GCPs, 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. Note that per HCNotice-CA-ICH-GCPs, HC-implemented International Council for Harmonisation (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.

As per the CA-ICH-GCPs, the investigator should promptly provide written reports to the sponsor and the institutional EC on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

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

Pursuant to the CA-ICH-GCPs, the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested.

Final Report

Upon completion of the trial, as delineated in CA-ICH-GCPs, the investigator is required to submit a final report to the institutional EC summarizing the trial’s outcome. The CanadaFDR does not require submission of a final study report to HC.

Part C (Division 5 (C.05.012 and C.05.013))
4.10 and 4.13
2.8
5.12 and 5.13
Chapter 11 (Article 11.8)
Sponsorship > Definition of Sponsor
Last content review/update: August 11, 2022
Summary

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. The CA-ICH-GCPs expands on this definition to include individuals, companies, institutions, or organizations that take responsibility for the initiation, management and/or financing of a clinical trial.

In accordance with the CA-ICH-GCPs, Canada also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

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.

Part C (Division 5 (C.05.001, C.05.005, C.05.015)
1.53, 5.1, and 5.2
2.1
5.1 and 5.5
Sponsorship > Trial Authorization
Last content review/update: August 11, 2022
Summary

In accordance with the CanadaFDR, the G-CanadaCTApps, and CAN-31, the sponsor submits a clinical trial application (CTA) or amendment to a previously approved clinical trial application (CTA-A) to Health Canada (HC) to obtain authorization to conduct a clinical trial, or pursue the clinical trial amendment. In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, the sponsor may submit a CTA for clinical trial authorization to HC in parallel with his/her submission to an institutional ethics committee (EC) (known as 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 he/she submits an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form) for each participating trial site. The HCNotice-CTSIForm indicates that completed CTSI forms must be provided to HC prior to commencement of a clinical trial. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

According to the G-CanadaCTApps, if HC authorizes the CTA, then it issues a No Objection Letter (NOL). If HC rejects the CTA, it sends a Not Satisfactory Notice (NSN). HC will issue an NSN if it identifies significant deficiencies, or, if a timely response to information requested has not been provided. The sponsor may resubmit the information and material at a future time, and it will be processed as a new CTA.

For details on the submission process and review, see the Clinical Trial Lifecycle section.

Part C (Division 5 (C.05.005, C.05.006, C.05.008)
2.3, 2.4, 2.5, and 2.7
5.5, 5.6, and 5.8
Food and Drugs Act and Regulations
Sponsorship > Insurance
Last content review/update: August 11, 2022
Summary

The CanadaFDR does not require the sponsor to provide insurance coverage to investigators, institutions, or trial participants. However, the CA-ICH-GCPs guides sponsors on providing insurance. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

5.8
Sponsorship > Compensation
Last content review/update: August 11, 2022
Summary

The Canadian regulations do not require compensation for trial participants in the event of trial-related injuries or death. However, the CA-ICH-GCPs indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries. (See the Compensation Disclosure section for more information on participant compensation rights). Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

4.8 and 5.8
Sponsorship > Quality, Data & Records Management
Last content review/update: August 11, 2022
Summary

Quality Assurance/Quality Control

Per the CA-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. Per CAN-48, Canada implements the International Council for Harmonisation (ICH) of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance E8(R1): General Considerations for Clinical Studies (CAN-49), which provides guidance on conduct during the clinical trial. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

The quality management system should use a risk-based approach that includes:

  • During protocol development, identifying processes and data that are critical to ensure participant protection and the reliability of trial results
  • Identifying risks to critical trial processes and data
  • Evaluating the identified risks, against existing risk controls
  • Deciding which risks to reduce and/or which risks to accept
  • Documenting quality management activities and communicate to those involved in or affected by these activities
  • Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
  • In the clinical study report, describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken

As stated in the CanadaFDR and the CA-ICH-GCPs, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the CA-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that both parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per the HCNotice-ICH-E9, HC adopted and implements the ICH guidance on statistical principles for clinical trials (HC-ICH-E9), as well as the ICH addendum on estimands and sensitivity analysis (CAN-39), which presents a framework for defining an appropriate estimand for a clinical trial and conducting sensitivity analyses.

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

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 PIPEDA covers the personal information-handling practices of federal government departments and agencies in Canada, and the PrivAct regulates private businesses’ data protection practices. Both statutes protect health data and require consent for its use except under prescribed conditions, such as for research or during emergencies. In addition, some provinces and territories have laws that deal specifically with protection of personal health information. See CAN-43 for a list of provincial and territorial privacy laws and webpages.

Electronic Data Processing System

When using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain SOPs that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the CA-ICH-GCPs for additional information.

The G-FDR-0100 provides that if electronic records are generated during a clinical trial, then the electronic system must be validated to confirm that the system’s specifications meet the goals and requirements for the clinical trial. This evidence of validation should be kept for the required record retention period and available for inspection by HC inspectors. See the G-FDR-0100 for additional details.

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. 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 ethics committee 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.

In addition, the CA-ICH-GCPs states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Audit Requirements

As part of its QA system, the CA-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the CA-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditors’ qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or, where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Premature Study Termination/Suspension

The CanadaFDR states 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.

According to the CA-ICH-GCPs, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the ethics committee (EC) should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

3, 7, and 8
Part I (2, 6.1, and 7)
Part C (Division 5 (C.05.007-008, C.05.010, C.05.012, and C.05.015))
Regulatory Impact Analysis Statement
1.65, 5.0, 5.1, 5.2, 5.5, 5.18, 5.19, 5.21, 5.23, 6.10, and 8
5.10, 5.12, and 5.15
Purpose and Scope, and Glossary
Sponsorship > Site/Investigator Selection
Last content review/update: August 11, 2022
Summary

Overview

As set forth in the CA-ICH-GCPs, the sponsor should select the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by training and experience. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s). Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

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. Per the CanadaFDR, the form certifies that the qualified investigator will conduct the clinical trial in accordance with good clinical practices, and will immediately inform trial participants and the institutional ethics committee (EC) (known as Research Ethics Boards in Canada) of trial discontinuance, and the reason for this discontinuance. (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 CAN-27, the Canadian Clinical Trials Asset Map (CCTAM) (CAN-26) is an interactive 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 represent the sponsor, and sign and date the application and the clinical trial attestation form.

Data Safety and Monitoring Board

Although not specified as a sponsor requirement, the CA-ICH-GCPs states that a Data and Safety Monitoring Board (DSMB) (known as an Independent Data-Monitoring Committee in Canada) may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

The G-TCPS2 provides the following considerations to help researchers and ECs determine whether a DSMB 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

Multicenter Studies

Per the CA-ICH-GCPs, if a multicenter trial will be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. In addition, the sponsor must ensure that:

  • All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and, if required, by HC
  • The EC has given approval to the protocol
  • The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
  • The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
  • All investigators are given instructions on following the protocol, on complying with a uniform set of standards to assess clinical and laboratory findings, and on completing the CRFs
  • Communication between investigators is facilitated

The CanadaFDR, the G-CanadaCTApps, and the G-CanadaNon-eCTD, 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 the Clinical Trial Site Information form (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 HCNotice-ICH-E17, HC announced the implementation of 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.

Part C (Division 5 (C.05.005))
1.25, 5.5, and 5.6
2.1 and 2.7.2
5.5
1-3 and 3-3
Chapter 11 (Article 11.7)
Informed Consent > Documentation Requirements
Last content review/update: August 11, 2022
Summary

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, the G-TCPS2, the CA-ICH-GCPs, and CAN-35. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (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.

As per the CanadaFDR, the G-TCPS2, and the CA-ICH-GCPs, 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 and the CA-ICH-GCPs state that the qualified investigator (QI) must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). As delineated in the G-TCPS2, CAN-35, and the CA-ICH-GCPs, 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 his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate. CAN-35 notes that the person obtaining consent may also need to explain the consent form verbally to ensure that the participant fully understands the information. See CAN-35 for informed consent and assent templates and sample forms.

Re-Consent

According to the CA-ICH-GCPs, any change in the ICF that is relevant to the participant’s consent should be approved by the institutional EC prior to implementing any changes. The participant and/or his/her legal representative(s) or guardian(s) should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented.

Per the G-TCPS2, consent must be maintained throughout the research project. Researchers have an ongoing duty to provide participants with all information relevant to their ongoing consent to participate in the research. Further, 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.

Language Requirements

CAN-35 further specifies that consent forms should be provided in the language that participants are most comfortable with. The G-TCPS2 and the CA-ICH-GCPs require the ICF to be presented in plain language that the participant is able to understand. Per CAN-35, ICFs should be translated where it is relevant to particular communities. If there is a language barrier, the G-TCPS2 indicates that the qualified investigator should select an intermediary who has the necessary language skills to ensure effective communication. Further, per CAN-35, the level of language used should be appropriate to the age and comprehension/reading level of the participant population, generally at approximately a grade 6-8 reading level.

Documenting Consent

As per the CA-ICH-GCPs and CAN-35, the participant and/or his/her legal representative(s) or guardian(s), as well as the qualified investigator, must sign and date the ICF. The CA-ICH-GCPs and the G-FDR-0100 state that the QI should retain the signed ICF. CAN-35 indicates that information letters and ICFs must be presented on institutional/department letterhead.

According to the CA-ICH-GCPs, where the participant is illiterate and/or his/her legal representative(s) and/or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:

  • The written ICF and any other written information to be provided to the participant is read and explained to the participant and his/her legal representative(s) and/or guardian(s)
  • The participant and his/her legal representative(s) and/or guardian(s), have orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so

Before participating in the study, the participant or his/her legal representative(s) and/or guardian(s) should receive a copy of the signed and dated ICF.

As per the G-TCPS2 and the CA-ICH-GCPs, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) and/or guardian(s) to waive or appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representative(s) from their liabilities for any negligence.

Per CAN-35, in some situations, written consent is not be feasible or desirable, for example due to logistical issues or because of the preferences of the participants. In addition, some individuals may perceive written consent as an attempt to legalize the consent process, thereby creating mistrust. It is also important to recognize that in some cultures written consent is not consistent with community traditions. In these cases, it may be more appropriate to use a handshake, a verbal agreement, or oral consent. Article 10.2 of the G-TCPS2 further indicates that researchers use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (a consent log, audio or video recordings, or other electronic means). Evidence of consent may also be documented via completed questionnaires (in person, by mail, or by email or other electronic means). 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.

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 alteration 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 precise nature and extent of any proposed alteration is defined
  • There is a plan to provide a debriefing (if any) that may also offer participants the possibility of refusing consent and/or withdrawing data and/or human biological materials

Consent for Processing Personal Data

Personal data, including health data, is protected and requires consent for its use in accordance with the provisions in the PIPEDA and the PrivAct, as well as provincial and territorial privacy laws (CAN-43). See the Quality, Data & Records Management section for more information.

3, 7, and 8
Part I (2, 6.1, and 7)
Part C (Division 5 (C.05.005, C.05.006, C.05.008, and C.05.010))
4.8, 8.2, and 8.3
5.5, 5.6, 5.8, 5.10, 5.12
Chapters 3 and 10
Policies, Guidelines, and Resources; Consent Process (Key Considerations)
Informed Consent > Required Elements
Last content review/update: August 11, 2022
Summary

Based on the G-TCPS2, the CA-ICH-GCPs, and CAN-35, the informed consent form (ICF) should include the following statements or descriptions in plain language, as applicable (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

  • The study involves research and an explanation of its purpose and duration
  • The trial treatment(s) and the probability for random assignment to each treatment
  • The procedures to be followed, including all invasive procedures
  • The participant’s responsibilities
  • Those aspects of the trial that are experimental
  • Any reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
  • Any reasonably expected benefits; if no benefit is expected, the participant should be made aware of this
  • The disclosure of specific alternative procedure(s) or therapies available to the participant, and their important potential benefits and risks
  • Compensation and/or treatment available to the participant in the event of a trial-related injury
  • The anticipated prorated payment, if any, to the participant for participating in the trial
  • Any expenses the participant needs to pay to participate in the trial
  • That participation is voluntary, and that the participant can refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the participant is otherwise entitled
  • 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
  • Confidentiality of records identifying the participant will be maintained, and permission given to monitors, the auditors, the ethics committee (EC), and Health Canada (HC) to access the participant’s medical records to verify the procedures and/or data, without violating the confidentiality of the participant, insofar as the applicable laws and regulations permit, and that, by signing a written ICF, the participant or the participant’s legal representative(s) or guardian(s) is authorizing such access
  • That records identifying the participant will not be made publicly available, insofar as the applicable laws and/or regulations permit; if the results of the trial are published, the participant’s identity will remain confidential
  • The participant and/or his/her legal representative(s) or guardian(s) will be notified in a timely manner if information becomes available that may affect the participant’s willingness to continue
  • The qualified investigator’s contact information for further information regarding the trial and the rights of participants, and whom to contact in the event of a trial-related injury
  • The identity and contact information of a qualified designated representative who can explain scientific or scholarly aspects of the research to participants
  • Information on stopping rules, foreseeable circumstances, and/or reasons under which the participant’s involvement in the trial may be terminated
  • The approximate number of participants in the trial

Per CAN-35, if blood is taken, indicate total volume (e.g., teaspoons and milliliter equivalent) and note the possibility of bruising or swelling while giving blood, or other possible discomforts at the site where blood is drawn. Further, state that there may be minimal chance of infection and that discomforts experienced will be brief and transient.

CAN-35 also indicates that participants should not be told if an EC has approved the study, since this may appear to offer a guarantee of safety. Further, no clause or language should be used to excuse or appear to excuse investigators or other persons or institutions involved from liability for their negligence or other faults. Sample consent forms are available from the Research Ethics Board Secretariat upon request: hc.reb-cer.sc@canada.ca.

See the Compensation Disclosure, Vulnerable Populations, and Consent for Specimen sections for further information.

4.8
Chapter 3
Policies, Guidelines, and Resources
Informed Consent > Compensation Disclosure
Last content review/update: August 11, 2022
Summary

Overview

In accordance with the G-TCPS2, the CA-ICH-GCPs, and CAN-35, the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

Compensation for Participation in Research

As per the G-TCPS2 and the CA-ICH-GCPs, the 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. CAN-35 furthers states that the ICF should describe any compensation, incentives, or reimbursements to be paid or given to participants and how participant withdrawal will affect the offered compensation (e.g., prorated remuneration). If no compensation will be provided, this should be stated.

Compensation for Injury

As per the G-TCPS2 and the CA-ICH-GCPs, the ICF should include a statement advising the participant about whether compensation and medical treatment is available in the event of any trial-related injury. (See the Required Elements section for additional details on what should be included in the ICF.)

3.1, 3.2, and 4.8
Chapter 3 (Article 3.2)
Policies, Guidelines, and Resources, Consent Process (Consent Form Template)
Informed Consent > Participant Rights
Last content review/update: August 11, 2022
Summary

Overview

In accordance with the CanadaFDR, the G-TCPS2, and the CA-ICH-GCPs, Canada’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-TCPS2 and the CA-ICH-GCPs state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (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.

The informed consent template in CAN-35 provides that if a participant has any questions about their rights, they should contact:

Health Canada-PHAC Research Ethics Board Secretariat
70 Colombine Driveway, Room 941C, PL: 0909C
Brooke Claxton Building, Tunney's Pasture
Ottawa, ON K1A 0K9
Telephone: 613-941-5199
Fax: 613-941-9093
hc.reb-cer.sc@canada.ca

The Right to Participate, Abstain, or Withdraw

As stated in the G-TCPS2 and the CA-ICH-GCPs, the participant and/or his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she 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.

Per CAN-35, the participant should be assured that their participation is completely voluntary, and that they are under no obligation to participate and are free to withdraw at any time without consequence. It should be made clear that their decision to withdraw will not influence their relationship with the researcher in any way. The researcher should explain what will happen to participant samples or data if they choose to withdraw. If applicable, clearly state the point in the study at which removal of samples or data becomes difficult or impossible.

The Right to Information

As per the G-TCPS2 and the CA-ICH-GCPs, a potential research participant and/or his/her legal representative(s) or guardian(s) 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 and the CA-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

Per CAN-35, the ICF should explain what information will be collected about participants and for what purpose, including the type of information that will be collected (e.g., will it be coded or de-identified?) and how it will be stored. Further, the ICF should state who will have access to the collected information, and describe the efforts that will be made to prevent the risk of participant re-identification. Limits to confidentiality and additional requirements for projects led by HC or the Public Health Agency of Canada (PHAC) are provided in CAN-35.

The Right of Inquiry/Appeal

The G-TCPS2 and the CA-ICH-GCPs state that the research participant and/or his/her legal representative(s) or guardian(s) should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or his/her rights.

The Right to Safety and Welfare

The CA-ICH-GCPs, which upholds the Declaration of Helsinki, clearly state that a research participant’s right to safety and the protection of his/her health and welfare must take precedence over the interests of science and society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

Part C (Division 5 (C.05.001 and C.05.005))
1.27, 3.1, and 4.8
5.1 and 5.5
Chapter 1 (Article 1.1), Chapter 2, and Chapter 3 (Articles 3.1 and 3.2)
Consent Process (Consent Form Template)
Informed Consent > Special Circumstances/Emergencies
Last content review/update: August 11, 2022
Summary

The G-TCPS2 and the CA-ICH-GCPs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. As per the CA-ICH-GCPs, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or his/her legal representative(s) or guardian(s), or, if an effective treatment is lacking but the investigational product could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the ethics committee (EC) (known as Research Ethics Board in Canada) must approve the protocol in advance. The participant and/or his/her legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

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 of his/her legal representative(s) or guardian(s), 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 for 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 his/her legal representative(s) or guardian(s) 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
4.8
Chapter 3 (Articles 3.7-3.9)
Informed Consent > Vulnerable Populations
Last content review/update: August 11, 2022
Summary

Overview

As per the G-TCPS2, 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. The CA-ICH-GCPs characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from not participating. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students, subordinate hospital and laboratory personnel, employees of the pharmaceutical industry, members of the armed forces, and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

The CA-ICH-GCPs specify that ethics committees (ECs) (known as Research Ethics Boards in Canada) must pay special attention to protecting participants who are from vulnerable populations. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

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

1.61, 3.1, and 4.8
Chapter 3 (Article 3.9) and Chapter 4 (Article 4.7)
Informed Consent > Children/Minors
Last content review/update: August 11, 2022
Summary

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.

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 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 and the CA-ICH-GCPs, when the research participant is a child, the informed consent form (ICF) must be signed by the child’s legal representative(s) and/or guardian(s). 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. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

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 his/her welfare.

Assent Requirements

Per G-TCPS2 and TCPS2-InterpCnsnt, 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 legal representative(s) and/or guardian(s), their expression of dissent must be respected.

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, his/her affirmative assent is required to participate in a study according to his/her 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.

CAN-35 provides sample assent forms and templates. For more detail and guidance about best practices for research involving pediatric participants, CAN-12.

4.8
1
Chapter 3 (Article 3.10) and Chapter 4 (Article 4.4)
Guidelines III and IV
Consent Process (Key Considerations)
Informed Consent > Pregnant Women, Fetuses & Neonates
Last content review/update: August 11, 2022
Summary

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.

In accordance with the CA-ICH-GCPs, informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

4.8
Chapter 4 (Article 4.3)
Informed Consent > Prisoners
Last content review/update: August 11, 2022
Summary

According to the G-TCPS2 and the CA-ICH-GCPs, 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. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

1.61
Chapter 3 (Article 3.1) and Chapter 4 (Article 4.7)
Informed Consent > Mentally Impaired
Last content review/update: August 11, 2022
Summary

According to the G-TCPS2 and the CA-ICH-GCPs, 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.

Per CAN-35, adults with diminished decision-making capacity include:

  • Individuals whose decision-making capacity remains only partially developed, such as those living with permanent cognitive impairment, and
  • Individuals who once were capable of making an autonomous decision regarding consent but whose decision-making capacity is diminishing or fluctuating (e.g., due to cognitive impairment resulting from an injury or disease).

As is the case for any vulnerable population, care must be taken to ensure that adults with diminished decision-making capacity are not inappropriately included in research because of their situation, and neither should they be excluded from participating in research that may benefit them.

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, as 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(s) or guardian(s) in accordance with the best interests of the persons concerned
  • The legal representative(s) or guardian(s) 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 shall 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(s) or guardian(s), 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

In general, many of the same principles for obtaining consent for children apply to adults with diminished decision-making capacity. Per CAN-35 and the G-TCPS2, the participant’s legal representative(s) or guardian(s) 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(s) or guardian(s) 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.

Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent.

1.61 and 3.1
Chapter 3 (Article 3.7-3.10)
Consent Process (Key Considerations)
Investigational Products > Definition of Investigational Product
Last content review/update: August 11, 2022
Summary

As delineated in the CanadaFDR, the G-GMP-Annex13, and the CA-ICH-GCPs, 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. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (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.

Part C (Division 5 (C.05.001))
3.0
1.33
5.1
Investigational Products > Manufacturing & Import
Last content review/update: August 11, 2022
Summary

Manufacturing

As specified in the CanadaFDR, the G-CanadaCTApps, and the CA-ICH-GCPs, 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. Note that per HCNotice-CA-ICH-GCPs, HC-implemented International Council for Harmonisation (ICH) guidance takes precedence over other HC guidance when they are not consistent. 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.

Import

Per the CanadaFDR and the G-FDR-0100, HC can authorize 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 applicable section of 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 Appendix 1 should be provided to HC.

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, he/she must include a copy of HC’s authorization (i.e., the No Objection Letter (NOL)) issued by either the Pharmaceutical Drugs Directorate (PDD) or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) 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: hc.hpbcp-pcpsf.sc@canada.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 the G-FDR-0100, if a sponsor plans to send the clinical trial IP(s) directly to each trial site, then the sponsor must also meet the following conditions:

  • Each party, including individual Canadian clinical trial sites, importing drugs directly (i.e., receiving drug shipment directly from outside of Canada) is identified on Appendix 1 of the Drug Submission Application Form (HC/SC 3011 form) (CAN-4) for Phase I-III trials (submitted with the application if known at the time or prior to importation at the site). Appendix 1 may be replicated as many times as necessary to capture all importing parties.
  • 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 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 Good Manufacturing Practice (GMP) requirements (e.g., certificates of manufacture, certificates of analysis, and/or evidence of approved lot release by a qualified individual).

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 subject

Other changes must follow the amendment requirements delineated in the CanadaFDR.

See the G-FDR-0100 for additional HC interpretation of the relevant provisions of the CanadaFDR.

Part C (Divisions 2-5)
1.0
2.12 and 5.13
2.3 and 2.7
5.2-5.3 and 5.6
I, S – Drug Substance, and P – Drug Product
Section # Block D and Appendix 1 Guidance
Importer’s Role, Table 1, and Human Drugs
Appendix 1
Drug Importation
Investigational Products > IMP/IND Quality Requirements
Last content review/update: August 11, 2022
Summary

Investigator’s Brochure

In accordance with the CanadaFDR and the CA-ICH-GCPs, the sponsor is responsible for providing the investigators with an Investigator’s Brochure (IB). The CanadaFDR and the CA-ICH-GCPs specify that the IB must contain all of 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. Note that per HCNotice-CA-ICH-GCPs, Health Canada (HC)-implemented International Council for Harmonisation (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.

The CanadaFDR and the CA-ICH-GCPs require 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)

See Section 7.3 of the CA-ICH-GCPs for detailed content guidelines.

In accordance with the G-CanadaCTApps and CAN-22, 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. As required in G-CanadaNon-eCTD, the annual updated IB should be submitted electronically as a clinical trial application (CTA)-Notification, and include a statement confirming that the protocol and/or informed consent form do not require changes as a result of the updated IB. In all cases, the updated IB should be accompanied by a list of changes that clearly describe the sections that have changed, including a rationale for each change.

Quality Documentation

Pursuant to the CA-ICH-GCPs, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial. As specified in the CA-ICH-GCPs, G-GMP, and G-GMP-Annex13, the sponsor must ensure that the products are manufactured in accordance with Good Manufacturing Practices (GMPs). The G-GMP requires a quality management system, incorporating GMPs, 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.

Part C (Division 5 (C.05.001, C.05.005, and C.05.012))
4
2.12, 5.13, 7.3, and 8.2
4
2.8
5.1, 5.5, and 5.12
Investigational Products > Labeling & Packaging
Last content review/update: August 11, 2022
Summary

Investigational product (IP) labeling in Canada must comply with the requirements set forth in the CanadaFDR, the G-CanadaCTApps, the G-GMP-Annex13, and the CA-ICH-GCPs. 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.

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 investigational drug 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

With regard to the expiration date, the G-GMP-Annex13 further 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, specific and standard operating procedures and under contract, if applicable, and should be checked by a second person. This additional labelling should be properly documented in both the trial documentation and in the packaging records.

For 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.

In addition, the CA-ICH-GCPs state that the IP must be coded and labeled in a manner that protects the blinding, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Part C (Divisions 2 (C.02.006, C.02.011, C.02.015-016) and 5 (C.05.011))
8.6 and 8.7
5.13
2.8.7
5.11
Investigational Products > Product Management
Last content review/update: August 11, 2022
Summary

Supply, Storage, and Handling Requirements

Per CanadaFDR, drugs must be manufactured, handled, and stored in accordance with good manufacturing practices (GMPs). As defined in the CA-ICH-GCPs, the sponsor must supply the investigator(s) with the IP(s), including the comparator and placebo, if applicable. The sponsor should not supply the IP(s) until he/she obtains approvals from Health Canada (HC) and the institutional EC. The CA-ICH-GCPs specify that the sponsor must ensure the following:

  • Timely delivery of the IP(s)
  • Records maintained for IP document shipment, receipt, disposition, return, and destruction
  • Written procedures including instructions for IP handling and storage, adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
  • IP product quality and stability over the period of use
  • IP manufactured according to any application of GMPs
  • Proper coding, packaging, and labeling of the IP(s)
  • Acceptable IP handling and storage conditions and shelf-life

Refer to the CA-ICH-GCPs for detailed sponsor-related IP requirements.

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

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 HC within seven (7) days of a request.

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.

Part C (Division 5 (C.05.001, C.05.005, C.05.010, and C.05.012))
Regulatory Impact Analysis Statement
5.5, 5.12, 5.13, 5.14, and 7
5.1, 5.5, 5.10, and 5.12
Specimens > Definition of Specimen
Last content review/update: August 11, 2022
Summary

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).

Chapter 12 and Glossary
Glossary
Specimens > Specimen Import & Export
Last content review/update: August 11, 2022
Summary

Overview

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 are considered to be potential carriers of human or animal pathogens, and are regulated by the Public Health Agency of Canada (PHAC) and the Canadian Food Inspection Agency (CFIA). Per CAN-24, CAN-2, and CAN-9, 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.

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.

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. See CAN-2 and CAN-9 for detailed information and instructions on how to obtain a license for activities associated with Risk Groups 2 through 4.

Purpose of the Act, Interpretation and Application, Obligation, Prohibitions, and Licenses
Licenses
Blood and blood components for transfusion
Chapter 21
Chapters 1 and 2
Specimens > Consent for Specimen
Last content review/update: August 11, 2022
Summary

In accordance with the G-TCPS2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or his/her legal representative(s).

Per the G-TCPS2, prior to the collection of research participant biological materials, the investigator(s) must obtain institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) review and approval, and consent 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 in order to seek participant consent to use his/her biological materials in research, the investigator (s) must provide prospective participants or authorized third parties 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

Per CAN-35, if there is a possibility of secondary future use of biological materials, researchers should consider describing this possibility in the consent form and obtaining permission from participants to retain their data or biological materials for future use. If consent for future use is not obtained initially then researchers may be required to obtain re-consent from individuals in the future. Researchers should be as specific as possible when describing the potential future uses. For example, if future uses include possible genetic or genomic studies, this must be stated. The EC may not approve future uses that are too open-ended or too dissimilar from the initial use. It is generally preferable to give participants the opportunity to opt out of future use. If this option is not provided, researchers should be prepared to explain their decision to the EC. When seeking consent, researchers may wish to give participants different options for how their samples or data can be used, to accommodate differences in comfort levels among participants.

In rare cases, it may be possible to use identifiable information for secondary use without the consent of the participants who provided that information. While the possibility of an exception may exist, the EC generally expects that researchers will make every reasonable effort to seek the consent of participants. Thus, the best practice is for researchers to always obtain consent for future use at the time of initial recruitment if there is any possibility of secondary use of data or biological materials. Also see Chapter 5 of the G-TCPS2 for additional details on confidentiality and future use of information.

 See Chapters 3 and 12 of the G-TCPS2 for detailed consent requirements for human biological materials.

Chapters 3, 5, and 12
Consent Process (Key Considerations)
Sources > Requirements
(Legislation) Privacy Act (R.S.C., 1985, P-21) (PrivAct) (Last Amended June 23, 2022)
Parliament of Canada
(Legislation) Food and Drugs Act (R.S.C., 1985, c. F-27) (CanadaFDA – English and French) (Last Amended May 6, 2021)
Parliament of Canada
(Legislation) Human Pathogens and Toxins Act (S.C. 2009, c. 24) (HPTA) (Last Amended June 21, 2019)
Parliament of Canada
(Legislation) Personal Information Protection and Electronic Documents Act (S.C. 2000, c.5) (PIPEDA) (Last Amended June 21, 2019)
Parliament of Canada
(Regulation) Food and Drug Regulations, (CRC, c. 870) (CanadaFDR – English and French) (Last Amended June 21, 2022)
Parliament of Canada
(Regulation) Human Pathogens and Toxins Regulations (SOR/2015-44) (HPTR) (Last Amended December 1, 2015)
Parliament of Canada
(Regulation) Regulations Amending the Food and Drug Regulations (1024 - Clinical Trials) (CanadaFDR1024 – English and French) (Effective September 1, 2001)
Parliament of Canada
(Guidance) Annex 13 to the Current Edition of the Good Manufacturing Practices Guidelines - Drugs Used In Clinical Trials (GUI 0036) (G-GMP-Annex13) (Effective December 1, 2009)
Health Canada
(Guidance) Clinical Safety Data Management Definitions and Standards for Expedited Reporting ICH Topic E2A: Guidance for Industry (HC-ICH-E2A) (June 1995)
Health Canada
(Guidance) Filing Submissions Electronically (ElecSubms) (Last Updated August 26, 2022)
Health Products and Food Branch, Health Canada
(Guidance) Good Clinical Practice: Integrated Addendum to E6(R1) ICH Topic E6(R2) (CA-ICH-GCPs) (Effective May 25, 2017)
Health Products and Food Branch, Health Canada
(Guidance) Good Manufacturing Practices Guide for Drug Products (GUI 0001) (G-GMP) (Effective July 1, 2020)
Health Canada
(Guidance) Guidance Document - Development Safety Update Report (DSUR) - International Conference on Harmonisation (ICH) Topic E2F (G-DSUR) (Effective December 4, 2015)
Health Canada
(Guidance) Guidance Document for Clinical Trial Sponsors: Clinical Trial Applications (G-CanadaCTApps) (Last Revised March 17, 2016)
Health Products and Food Branch, Health Canada
(Guidance) Guidance Document: Management of Drug Submissions and Applications (G-MDSA) (Last Updated August 2, 2022)
Health Canada
(Guidance) Guidance Document: Part C, Division 5 of the Food and Drug Regulations “Drugs for Clinical Trials Involving Human Subjects” (G-FDR-0100) (August 20, 2019)
Health Canada
(Guidance) Guidance Document: Preparation of Drug Regulatory Activities in the "Non-eCTD Electronic-Only" Format (G-CanadaNon-eCTD) (Last Revised February 3, 2016)
Health Canada
(Guidance) Guidance Document: Preparation of Drug Regulatory Activities in the Common Technical Document (CTD) Format (G-Canada-CTD) (June 22, 2012)
Health Canada
(Guidance) Guidance Document: Preparation of Regulatory Activities in Non-eCTD Format (Non-eCTDformat) (Effective September 7, 2022)
Health Canada
(Guidance) Guidance Document: Quality (Chemistry and Manufacturing) Guidance: Clinical Trial Applications (CTAs) for Pharmaceuticals (G-QCM-PharmCTAs) (Effective June 1, 2009)
Health Products and Food Branch, Health Canada
(Guidance) Guidance for Completing the Drug Submission Application Form (G-DrugApp) (Last Updated March 31, 2021)
Health Canada
(Guidance) Guideline: Increasing Transparency when Presenting Safety Information in the Development Safety Update Report (DSUR): Region-Specific Requirements for Canada and the United Kingdom (G-DSUR-CanUK) (July 6, 2021)
Health Canada
(Guidance) Guidelines for Environmental Control of Drugs During Storage and Transportation (GUI-0069) (G-Storage) (August 24, 2020)
Health Canada
(Guidance) How to Address Material Incidental Findings – Guidance in Applying TCPS2 (2018) Article 3.4 (G-ConsentMatIncFindings) (2019)
Panel on Research Ethics, Government of Canada
(Guidance) Importing and Exporting Health Products for Commercial Use (GUI-0117) (G-HlthProdImprtExptReqs) (Effective December 21, 2020)
Health Products and Food Branch, Health Canada
(Guidance) Policy Statement: Use of Pharmacometrics in Drug Submissions and Clinical Trial Applications (G-Pharmacometrics) (Last Updated March 31, 2021)
Health Canada
(Guidance) Statistical Principles for Clinical Trials ICH Topic E9: Guidance for industry (HC-ICH-E9) (February 10, 2003)
Health Canada
(Guidance) TCPS 2 Interpretations – Consent (TCPS2-InterpCnsnt) (Last Updated August 7, 2018)
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada
(Guidance) TCPS 2 Interpretations – REB Review (TCPS2-InterpReview) (Last Updated May 17, 2021)
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada
(Guidance) Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (G-TCPS2) (December 2018)
Canadian Institutes of Health Research, Natural Sciences and Engineering Research Council of Canada, and Social Sciences and Humanities Research Council of Canada
(Guidance) Validation Rules for Regulatory Transactions Provided to Health Canada in the Non-eCTD Format (Rules-Non-eCTD) (Version 5.1) (Effective August 1, 2022)
Health Canada
(Notice) E2A: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting – Reminder for Sponsors (HCNotice-E2A) (August 21, 2012)
Health Products and Food Branch, Health Canada
(Notice) Release of ICH E17: Multi-Regional Clinical Trials (HCNotice-ICH-E17) (Last Updated May 9, 2019)
Health Products and Food Branch, Health Canada
(Notice) Release of ICH E6(R2): Good Clinical Practice (HCNotice-CA-ICH-GCPs) (Last Updated November 15, 2019)
Health Canada
(Notice) Release of ICH E9(R1): Defining the Appropriate Estimand for a Clinical Trial/ Sensitivity Analyses (HCNotice-ICH-E9) (Last Updated July 22, 2020)
Health Canada
(Notice) Update to Clinical Trial Site Information Form (HCNotice-CTSIForm) (Last Updated February 23, 2022)
Health Canada
(Notice) Update: Registration and Disclosure of Clinical Trial Information (HCNotice-CTRegDisc) (October 19, 2012)
Health Canada
Sources > Additional Resources
(Document) Best Practices for Health Research Involving Children and Adolescents: Genetic, Pharmaceutical and Longitudinal Studies (CAN-12) (2012)
Canadian Institutes of Health Research, Government of Canada; Centre of Genomics and Policy, McGill University; and Maternal Infant Child and Youth Research Network
(Document) Canadian Biosafety Handbook (CAN-9) (Second Edition) (May 26, 2016)
Government of Canada
(Document) Canadian Biosafety Standard (CBS) (CAN-2) (Second Edition) (March 11, 2015)
Government of Canada
(Document) Research Ethics Board’s Operational Policy Framework: Ethics Review of Research Involving Human Subjects (CAN-13) (April 1, 2010)
Health Canada
(Document) University of Calgary CHREB Administration Fee for Industry Sponsored Protocols (CAN-3) (January 1, 2021)
University of Calgary, Research Services, Calgary, Canada
(International Guidance) Addendum on Estimands and Sensitivity Analysis in Clinical Trials to the Guideline on Statistical Principles for Clinical Trials, E9 (R1) (CAN-39) (Step 4 Version) (November 20, 2019)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) General Considerations for Clinical Studies E8(R1) (CAN-49) (October 6, 2021)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) General Principles for Planning and Design of Multi-Regional Clinical Trials, E17 (CAN-40) (Step 4 Version) (November 16, 2017)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) ICH E8(R1): General Considerations for Clinical Studies (CAN-48) (October 6, 2021)
Health Canada
(Not Available Online) NIAID Communication with Health Canada (June 2022) (CAN-44)
(Webpage) Biologic and Radiopharmaceutical Drugs Directorate (CAN-17) (Last Updated June 23, 2021)
Health Products and Food Branch, Health Canada
(Webpage) Canadian Clinical Trials Asset Map (CCTAM) (CAN-26) (Current as of August 11, 2022)
Canadian Clinical Trials Coordinating Centre
(Webpage) Clinical Trials - Background (CAN-31) (Last Updated July 11, 2006)
Health Canada
(Webpage) Clinical Trials Drug Importation Frequently Asked Questions (CAN-32) (Last Updated July 11, 2006)
Health Products and Food Branch, Health Canada
(Webpage) ClinicalTrials.gov (CAN-45) (Current as of August 11, 2022)
US National Library of Medicine
(Webpage) Common Electronic Submissions Gateway (CAN-25) (Last Updated May 23, 2014)
Health Canada
(Webpage) Filing of Clinical Trials Frequently Asked Questions (CAN-33) (Last Updated February 21, 2008)
Health Canada
(Webpage) Forms: Applications and Submissions for Drug Products (CAN-19) (Last Updated July 28, 2022)
Health Canada
(Webpage) Health Portfolio (CAN-29) (Last Updated August 8, 2017)
Government of Canada
(Webpage) Health Products and Food Branch (CAN-16) (Last Updated June 24, 2022)
Health Products and Food Branch, Health Canada
(Webpage) How Drugs are Reviewed in Canada (CAN-23) (Last Updated February 12, 2015)
Health Canada
(Webpage) Instructions for Completing the Clinical Trial Site Information Form (CAN-30) (Last Updated June 15, 2022)
Health Canada
(Webpage) ISRCTN Registry (CAN-46) (Current as of August 11, 2022)
ISRCTN Registry
(Webpage) Office of the Privacy Commissioner of Canada (CAN-42) (Last Updated July 5, 2022)
Office of Privacy Commissioner of Canada
(Webpage) Panel on Research Ethics – Navigating the Ethics of Human Research (CAN-14) (Last Updated February 10, 2022)
Panel on Research Ethics, Government of Canada
(Webpage) Pharmaceutical Drugs Directorate (CAN-18) (Last Updated May 2, 2022)
Health Products and Food Branch, Health Canada
(Webpage) Post-Authorization Requirements (CAN-22) (Last Updated February 5, 2009)
Health Canada
(Webpage) Provincial and Territorial Privacy Laws and Oversight (CAN-43) (Last Updated June 11, 2020)
Office of Privacy Commissioner of Canada
(Webpage) Public Health Agency of Canada – Licensing Program (CAN-24) (Last Updated April 28, 2020)
Public Health Agency of Canada
(Webpage) REB Review Fees (CAN-1) (Effective January 1, 2022)
University of Alberta
(Webpage) Regulatory Innovation for Health Products: Overview (CAN-41) (Last Updated February 23, 2022)
Health Canada
(Webpage) Research Ethics Board: Overview of the Health Canada and Public Health Agency of Canada REB (CAN-35) (Last Updated March 28, 2022)
Health Canada
(Webpage) What is the Canadian Clinical Trials Asset Map? (CAN-27) (Current as of August 11, 2022)
Canadian Clinical Trials Coordinating Centre
Sources > Forms
(Form) Adverse Drug Reactions (ADRs) for Clinical Trials – Expedited Reporting Summary Form (CAN-5) (Date Unavailable)
Health Canada
(Form) Check list for Submitting Requested Development Safety Update Reports (DSUR) in Electronic Format (CAN-38) (Date Unavailable)
Health Canada
(Form) CIOMS Form I (CAN-7) (Date Unavailable)
Council for International Organizations of Medical Sciences
(Form) Clinical Trial Site Information Form (CAN-6) (Ver.21.12.21) (Effective January 2, 2020)
Health Canada
(Form) Health Canada 3011: Drug Submission Application Form for Human, Veterinary or Disinfectant Drugs and Clinical Trial Application/Attestation (CAN-4) (Version 5.03) (Last Updated March 2, 2022)
Health Canada
(Form) Qualified Investigator Undertaking (CAN-37) (March 23, 2022)
Health Canada
(Form) Research Ethics Board Attestation (CAN-8) (Last Updated March 2, 2022)
Health Products and Food Branch, Health Canada
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