Clinical Research Regulation For Canada and South Africa

Last content review/update: June 16, 2023

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; and “therapeutic product authorization” refers to a license that is approved for the import, sale, advertisement, manufacture, preparation, preservation, packaging, labeling, storage, or testing of a therapeutic product. As per the G-CanadaCTApps, HC’s scope of assessment includes clinical trials (Phases I - III) using:

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

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

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

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

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

Clinical Trial Site Information form

What is the Health Products and Food Branch?

1.2, 2.1, 2.3-2.7, and Appendix 1

5.1, 5.2, 5.5, and 5.6

2 and Part II (Section 30 (1.2))

Part C (Division 5 (C.05.001, C.05.002, C.05.005-.008, and C.05.016-.017))

Last content review/update: December 18, 2023

Overview

In accordance with the GRMRSA, the South African Health Products Regulatory Authority (SAHPRA) is responsible for reviewing and approving all clinical trial applications for an unregistered medicine, and for any new indication or dosage regimen of a registered medicine. The scope of the SAHPRA’s assessment includes all clinical trials (Phases I-IV) and bioequivalence/bioavailability studies. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited ethics committee (EC) may be conducted in parallel.

ZAF-36 states that the SAHPRA’s Clinical Trial Unit (CTU) provides the legal framework for the review of clinical trials and bioequivalence studies for human participants and recommends approval of the conduct of clinical trials. The unit also authorizes the importation of unregistered medicines for the purpose of conducting clinical trials. As per G-GenInfo, the CTU is responsible for the evaluation of clinical trial applications, clinical trial amendments, and adverse event reports arising from a clinical trial.

Clinical Trial Review Process

Per ZAF-36, the CTU of SAHPRA receives, processes, and evaluates clinical trial applications and any subsequent amendments for approval to conduct a study within South Africa. Researchers must submit a completed application and the prescribed fee on predetermined dates (ZAF-11). The proof of delivery, proof of payments, and cover page must be sent to SAHPRA via email.

As stated in ZAF-36, the CTU completes a preliminary screening of the application and sends an official letter to the applicant with the outcome and follow-up questions on a screening checklist. As indicated in ZAF-23, incomplete documentation or sub-standard submissions will be rejected. Additionally, applications submitted without clinical trial insurance will be rejected. Applicants will be allowed a maximum of two (2) rounds of queries to respond to, and if the responses are not satisfactory the application will be rejected. Per ZAF-36, if an application is rejected, no response is required; the screening checklist should be used as guidance for resubmission during the next review cycle. Next, the CTU’s Clinical Trial Committee (CTC) (which includes an expert committee of specialists, as needed) reviews the proposed clinical trials pursuant to the schedule on SAHPRA’s website. (See ZAF-11 for 2024 dates). Clinical trial reviews will result in one (1) of the following outcomes:

Category 1A: Approved; no items pending
Category 1B: Approved; ethics approval pending
Category 2A: Not approved; for approval by in-house evaluators, 1-2 or more items outstanding as deemed by the committee
Category 2B: Not approved; for approval by the original evaluator and in-house if a need arises
Category 3: Not approved; items outstanding to be discussed at the next CTC meeting
Category 4: Not approved; for referral for specialist opinion
Category 5: Not approved – technical/scientific deficiencies; applicant to resubmit for the next cycle
Category 6: Rejected due to administrative and technical items outstanding; applicant to resubmit for the next cycle

If an applicant would like to request a meeting with the CTC, the request should be submitted through the SAHPRA Chief Executive Office pursuant to the procedures in the G-ConsultMtg.

Other Considerations

Per the G-Capacity, SAHPRA will also review clinical trial applications for evidence of plans to build capacity at each study site as well as enhancing research activities and skills of professionals from historically disadvantaged groups. See G-Capacity for detailed information on actions that will comply with this requirement.

In addition, see G-Clin for South Africa's use of a “reliance model” to register medicines based on clinical trial data from other regulatory authorities.

Checklist (Note for all applications), 3.1, Annex 3, Annex 5, and Appendix

9.3.2

Part 30 (1)

Regulatory Fees

Last content review/update: June 16, 2023

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

Question 5

Last content review/update: December 18, 2023

South African Health Products Regulatory Authority

Per the MRSA, the South African Health Products Regulatory Authority (SAHPRA) is authorized to make regulations to collect fees for its various medicine regulatory functions. As delineated in the MRSA-Fees and ZAF-37, applicants are responsible for paying several non-refundable fees to submit a clinical trial application. MRSA-Fees delineates the following fees:

For a clinical trial application for the authorization of the use of unregistered medicines:

Clinical trial application (safety and efficacy): South African Rand (R)32 400
Clinical trial application (bioequivalence study): R30 400
Clinical trial application (postgraduate study): R10 800
Any other clinical trial application: R5 000

For amendments to clinical trials:

Technical amendment applications: R7 000
Administrative amendment applications: R4 100
Any other application except for the purpose of performing a clinical trial: R350

For licenses:

New manufacturing license: R25 200
New import/export license to the holder of certificate of registration: R15 000
Renewal of manufacturing license: R22 000
Renewal of import license to the holder of the certificate of registration: R9 200
Renewal of export license to the holder of the certificate of registration: R9 200
Annual retention of all licenses: R4 200

For inspections to assess the quality, safety, and efficacy of medicines:

Local and international manufacturing sites: R1 600 per hour
Local and international clinical trial sites: R1 600 per hour

Payment Instructions

Per the G-SAHPRAFees, when making payments, applicants should follow these guidelines:

Applicants should submit a cover page that identifies the services requested using the template provided in ZAF-37
Payments should be referenced in accordance with the SAHPRA Fee Categorization Guideline (Annexure A of G-SAHPRAFees)
If the applicable bank limits reference spacing, follow the sequence listed in Annexure A as far as the limitation allows; spacing and dashes (/) may be omitted
Fee payments may be transferred directly into the bank account of SAHPRA via an electronic or manual deposit process
No check payments will be accepted
For administrative control purposes, applicants should make one (1) payment per service
Payment should only be made once the application and required dossiers are ready for submission
Payments do not have to be made upon request of an application number; however, the applications and required dossiers should be submitted within a reasonable time upon receipt of an application number or as specified in the relevant application guidelines

As soon as the fee payment has been made, the proof of payment and cover page should be attached and sent via email to SAHPRA Finance at pop@sahpra.org.za, and the relevant unit(s) processing the application should be copied on the email.

If the proof of payment has not been submitted, or no details to identify the payment reference as per the G-SAHPRAFees have been provided, and any further attempts to clear these payments fail after 12 months, any liability for SAHPRA to refund these payments will be forfeited
If a payment has been received without an application, the applicant will be notified to submit the required application within 14 working days, failing which, the amount will be forfeited
Requests for refunds should be submitted in line with Annex B in the G-SAHPRAFees
Payment and pro forma invoice queries and requests can be directed to finance@sahpra.org.za or 012 501 0323
See the G-SAHPRAFees for details on special requests for extensions to the deadline

Per the G-SAHPRAFees, the bank and account details are as follows:

Account name: South African Health Products Regulatory Authority
Special Name: The Medicines Control Council
Account type: Cheque/Current Account
Account number: 40-5939-2080
Bank: ABSA
Bank Branch Code: 632005
Bank physical address: 240 Vermeulen Street, Pretoria, 0001, South Africa
Swift Code: ABSAZAJJ

Fee payment questions can be directed to finance@sahpra.org.za or 012 501 0323.

Sections 1-3 and Annexure A

35

Fees for Clinical Trials, Fees for New Licenses, and Fees for Inspections

Ethics Committee

Last content review/update: June 16, 2023

Overview

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

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

Institutional ECs are required to comply with the provisions delineated in the CanadaFDR, the G-CanadaCTApps, and 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, 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. Jointly developed by Canada’s three (3) federal research agencies: the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Social Sciences and Humanities Research Council (SSHRC), the G-TCPS2 is a policy that sets the ethical benchmark for all Canadian institutional ECs. However, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guideline as a condition of funding. According to CAN-14, the CIHR, the NSERC, and the SSHRC created the Panel on Research Ethics (PRE) to promote the ethical conduct of research involving human participants. The PRE develops, interprets, and implements the G-TCPS2.

Ethics Committee Composition

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

2 and 3

About the REB and Policies, Guidelines, and Resources

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)

Part C (Division 5 (C.05.001, C.05.002, C.05.005, C.05.006, and C.05.010))

Last content review/update: December 18, 2023

Overview

Per ZAF-51, ethics committees (ECs) in South Africa are governed by the National Health Research Ethics Council (NHREC), which is a statutory body established under the NHA. According to ZAF-52, NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals. As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCPs, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study.

The NHA requires that every institution, health agency, and health establishment at which research is conducted establish an EC or have access to an independent EC. The EC must be registered with the NHREC. The SA-GCPs note that the NHREC accredits and audits the ECs.

Ethics Committee Composition

As delineated in the SA-GCPs and the G-EthicsHR-ZAF, an EC must consist of members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of all proposed research studies.

The G-EthicsHR-ZAF indicates that an EC should comprise:

Members who have documented proof of research ethics training, refreshed at least once within the period of appointment
At least nine (9) members
At least one (1) layperson
At least one (1) member with knowledge of, and current experience in the professional care, counselling, or health-related treatment of people; such a medical practitioner, psychologist, social worker, or nurse
At least one (1) member with professional training and experience in qualitative research methodologies
Members with professional training and experience in quantitative research methodologies
A member with expertise in bio-statistics
A member with expertise in research ethics
At least one (1) member who is legally qualified

Terms of Reference, Review Procedures, and Meeting Schedule

Per the G-EthicsHR-ZAF, an institution or organization must select EC members according to prescribed recruitment and appointment procedures. Members must receive a formal notice of appointment and assurance that they will be legally protected with respect to any liabilities that may arise during their term. EC quorum should be a simple majority, and where the number of members is more than 15, the quorum may be 33%. An EC must also establish and record written procedures to address several administrative issues including meetings, agenda/minutes preparation, research protocol presentations, application registration, protocol submission requirements, review and decision notification process, adverse event reporting, protocol amendment reporting, and end-of-trials review. A reasonable term of office is between two (2) and four (4) years, renewable twice, after which the person should stand down for at least one (1) term. Further, EC members and researchers are expected to familiarize themselves with the institutional documentation as well as national and international research ethics guidelines and should have documented proof of such familiarity. Training of all EC members is critical, especially for ECs that review high-risk research. Training and refresher courses should be available, and EC members should produce, at least once during a term of appointment, evidence of recent training. This ensures that both expertise and responsibility are distributed and encouraged in a range of members, and that institutional memory is accumulated. The SA-GCPs stipulate that EC members who review clinical trial proposals should have research ethics training and good clinical practice training, evidenced by certificates issued in the last three (3) years.

Per the SA-GCPs, the EC should retain all relevant records for a period of at least three (3) years or as per institutional requirement, whichever period is longer, after completion of the trial and make them available upon request from the applicable regulatory authority. The G-EthicsHR-ZAF indicates that ECs should keep written records of all research protocols received for review in the form in which they were approved. Electronic records are acceptable if the signatures are properly documented and included in the record. EC records must provide a reliable and authoritative record of the EC’s business that will stand up to scrutiny in the event of queries, conflicts, and audits.

4.2-4.5, 5.1, and 5.2-5.4

4.3 and 12

Chapter 9 (72 and 73)

Scope of Review

Last content review/update: June 16, 2023

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 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 an institutional EC approval for each participating trial site is submitted. The sponsor should use the Clinical Trial Site Information Form (CAN-6) to submit the required information. The CanadaFDR also states that the EC must review and approve any protocol amendments prior to those changes being implemented. 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 EC review and approval of research involving living human participants and human biological materials. Further, ECs must have procedures in place to receive and respond to reports of new information, including, but not limited to, safety data, unanticipated issues, and newly discovered risks. 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.

The G-TCPS2 lays out options, procedures, and considerations for the ethics review of multi-jurisdictional research either entirely within Canada, or in Canada and other countries. An institutional EC may approve alternative review models for research with multiple ECs and/or institutions but remains responsible for the ethics and conduct of research in its jurisdiction or under its auspices regardless of where the research is conducted. See the G-TCPS2 for more information about the various review models for multi-jurisdictional research.

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

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.

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 1-2, 6, 8, and 11

Part C (Division 5 (C.05.001, C.05.005, C.05.006, and C.05.010))

Last content review/update: December 18, 2023

Overview

Per the SA-GCPs, clinical trials should be conducted in accordance with all ethical principles outlined in the Declaration of Helsinki (ZAF-44) and consistent with good clinical practice and other applicable regulatory requirements. In accordance with the NHA, the SA-GCPs, and the G-EthicsHR-ZAF, ethics committees (ECs) must evaluate the ethical and scientific rigor of all research studies to be conducted in the country. An EC’s primary responsibilities are to (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

Review protocols to ensure that research involving human participants has scientific merit and will promote health, and prevent or cure disability and disease; in addition, ensure the research has social merit in light of South Africa’s research priorities or is otherwise justified
Ensure clinical trials are governed by the ethical principles of beneficence and non-maleficence, distributive justice (equity), and respect for persons (dignity and autonomy)
Grant approval for research where the protocols meet the ethical standards of the institution, agency, or establishment
Determine whether and why randomization is relevant, and how this is addressed
Evaluate the appropriateness of the inclusion/exclusion criteria and the recruitment process in the South African context
Ensure the feasibility of obtaining meaningful results with the lowest possible risk of harm for participants and whether the risk of harm is appropriately weighed against anticipated benefits for participants or the class of persons from which they are drawn; high risk of harm may be justifiable where the anticipated benefit is of high importance to increase relevant knowledge and appropriate mitigating measures are in place to minimize harm to participants; and attention must be given to harms and benefits beyond the life of the trial itself, especially in respect to early phase studies and (pharmacovigilance) surveillance for chronic and life-threatening conditions

An EC must also pay special attention to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Informed Consent topic for additional information about these populations).

Role in Clinical Trial Approval Process

Per the G-EthicsHR-ZAF, the SA-GCPs, and the NHAParticipants, the principal investigator (PI) or the sponsor must submit a clinical trial application to both the South African Health Products Regulatory Authority (SAHPRA) and a registered EC for review and approval before a study may commence. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited EC may be conducted in parallel.

The G-EthicsHR-ZAF indicates that after the deliberative review process, the EC should approve, require amendment to, or reject a research protocol. In considering a research protocol, the EC may seek assistance from experts. EC decisions should be recorded in writing. A decision to approve should include the conditions (e.g., the duration of the approval, the reporting requirements, etc.). Reasons for a decision to require an amendment or to reject a research protocol should be recorded. Outright rejection should be avoided if a researcher can be advised to improve the protocol. Researchers should be encouraged to address the concerns and improve their protocols. ECs should require researchers to report immediately if a project is terminated or suspended before the anticipated date of completion. ECs should require researchers to report immediately anything that might warrant reconsideration of ethical approval of the protocol, including but not limited to:

Serious or unexpected adverse effects on participants
Proposed changes in the protocol
Unforeseen events that might affect continued ethical acceptability of the project

Per the G-EthicsHR-ZAF, ECs may, at their own discretion, recognize prior review and approval of a research protocol by another registered EC to avoid duplication of effort. Reciprocal recognition means that two (2) or more registered ECs decide to recognize each other’s prior review. ECs that recognize prior review in this manner must determine the nature of the documents to be filed locally, which must, at minimum, include a copy of the approval letter from the other ECs. In addition, ECs may establish procedures for expedited review for research that poses no more than minimal risk of harm to participants.

The SA-GCPs requires the EC’s approval of the following before the clinical trial may begin: protocol and any amendments; case report form, if applicable; informed consent form(s); any other written information to be provided to the participants; advertisement for participant recruitment (if used); participant compensation; and any other documents given approval/favorable opinion.

The SA-GCPs mandate that the sponsor receive confirmation of EC review from the investigator(s) or institution(s). The sponsor must receive the following information prior to the trial’s commencement:

The name and address of the relevant EC registered with National Health Research Ethics Council (NHREC), with its documented approval
If EC approval is conditional on required modifications, a copy of the modification(s) made and the date the final approval was granted by the EC
Documentation and dates of any EC re-approvals/re-evaluations

As delineated in the G-EthicsHR-ZAF, ECs have the right to monitor the research it approves, and researchers should provide appropriate information to the EC to facilitate monitoring, including alerts and investigator brochures. The frequency and type of monitoring should reflect the degree and extent of risk of harm to participants or animals. ECs may recommend and adopt any additional appropriate mechanism for monitoring.

Per ZAF-20, if there is an amendment to the protocol, the sponsor must notify the EC and get its approval. This approval should be sent to the SAHPRA using the Application for Protocol Amendment to an Approved Trial (ZAF-20).

3 (Part 4)

3.1 and Appendix

2, 4, 5, and Appendix 1

2.1, 2.6, 4.3, and 9.2

3

Chapter 9, Sections 72 and 73

Ethics Committee Fees

Last content review/update: June 16, 2023

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.

REB Review Fees

Last content review/update: December 18, 2023

Based on the G-EthicsHR-ZAF, ethics committees (ECs) may independently decide whether to charge fees for a protocol review. The G-EthicsHR-ZAF states that an EC should establish and record working procedures concerning fees charged, if any. Researchers without affiliation to an institution or organization with an EC should approach a registered EC to request it to review their health research protocols. If the EC is willing to review external applications, a fee for service may be levied.

4.2 and 4.3.1

Oversight of Ethics Committees

Last content review/update: June 16, 2023

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

Last content review/update: December 18, 2023

Overview

Per ZAF-51, ethics committees (ECs) in South Africa are governed by the National Health Research Ethics Council (NHREC), which is a statutory body established under the NHA. As delineated in the NHA, the NHREC was created by the Minister of Health to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. According to ZAF-52, NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals. Further, NHREC upholds the principle that research involving human participants is based on a moral commitment to advancing human welfare, knowledge, and understanding, and to exploring cultural dynamics, especially in large-scale trials conducted in developing countries. Of fundamental importance is the duty to conduct scientifically sound research while acting in the participant’s best interests and respecting and protecting the participant’s autonomy.

As delineated in the NHA, the SA-GCPs, and the G-EthicsHR-ZAF, the NHREC’s core responsibilities center on promoting, ensuring, and monitoring compliance by ECs. According to ZAF-52, the functions of the NHREC include:

Determine guidelines for the functioning of ECs
Register and audit ECs
Set norms and standards for conducting research on humans and animals including clinical trials
Adjudicate complaints about the functioning of ECs
Refer to the relevant statutory health professional council matters involving the violation or potential violation of an ethical or professional rule by a health care provider
Institute such disciplinary action as prescribed
Advise the national department and provincial departments on any ethical issues concerning research

Registration, Auditing, and Accreditation

As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCPs, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study. The application to register an EC is available at ZAF-53. ZAF-54 states that the EC registration is recorded and publicly listed by the NHREC. The annual report form that ECs must submit to NHREC is available at ZAF-54. Per the SA-GCPs, the NHREC accredits and audits the ECs.

4.6, 5.2, and 5.4

4.1 and 12.0 (National Health Research Ethics Council)

Chapter 9, Sections 72 and 73

Submission Process

Last content review/update: June 16, 2023

Overview

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

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." Per ElecSubms, applicants must submit CTAs electronically in either eCTD format or non-eCTD format. According to the G-MDSA, HC does not accept paper copies of CTAs, CTA amendments, and CTA notifications.

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

eCTD Electronic Submission

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.

Non-eCTD Electronic Submission

For non-eCTD electronic submissions, Non-eCTDformat indicates that HC requires both PDF and MS-Word formats for the CTA (CAN-4). The PDF documents must be generated from electronic sources (not scanned material), except when access to an electronic source document is unavailable or where a signature is required. It is important that PDF files be properly bookmarked and hyperlinked. Documents that legally require signatures may be signed with an electronic signature, or the signature page can be printed, signed, scanned, and saved as a PDF file. The cover letter does not require a signature, but should include a printed name, phone number, and email address. All regulatory submissions should be validated prior to transmitting to HC. For validation rules, see the Rules-Non-eCTD. The ElecSubms contains a zip file of the folder structure for clinical trial non-eCTD submissions.

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

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

All media should be labelled and contain the following information:

Sponsor Name
Brand Name
Dossier ID (if known)

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

As per the Non-eCTDformat, 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 Canada
5th Floor, Holland Cross, Tower B
1600 Scott Street, Address Locator: 3105A
Ottawa, Ontario, Canada
K1A 0K9
General Inquiries E-mail: oct.enquiries-requetes.bec@hc-sc.gc.ca

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
Ground Floor, Health Canada Building 6
100 Eglantine Driveway
Address Locator: 0601C
Ottawa, Ontario, Canada
K1A 0K9
General Enquiries E-mail: brdd.ora@hc-sc.gc.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.

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

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

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

Ethics Review Submission

As indicated in the CanadaFDR and the G-CanadaCTApps, all research involving human participants in Canada must be reviewed by an institutional ethics committee (EC). (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements. Further, Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information. 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.

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

2-5, and Appendix D

1.2, 3, and Appendix B

Part C (Division 5 (C.05.002, C.05.004, C.05.005))

Last content review/update: December 18, 2023

Overview

As delineated in the SA-GCPs, the sponsor and the investigator must obtain approval from the South African Health Products Regulatory Authority (SAHPRA) and a registered ethics committee (EC) to begin a clinical trial in South Africa. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited EC may be conducted in parallel. Per ZAF-20, the same process applies to the review and approval of an amendment to the protocol.

Regulatory Submission

Per ZAF-36, researchers must submit a completed application (ZAF-23) and the prescribed fee on predetermined dates (ZAF-11) and obtain proof of delivery. The proof of delivery, proof of payments, and cover page must be sent to SAHPRA via email. The G-CTA-Electronic delineates the electronic submission and communication process in SAHPRA’s Clinical Trial Unit (CTU). For new clinical trial applications (excluding bioequivalence studies), upon submission at SAHPRA Reception, applicants are requested to alert the CTU via e-mail at ctcresponses@sahpra.org.za and include a copy of the proof of delivery, proof of payment, and proof of insurance. In the subject of the e-mail, provide type of application, protocol number, SAHPRA predetermined cycle (see ZAF-11), and email number in case of multiple emails (e.g., “email 1 of 5”). Note that the submission email must include organized zipped folders for various sections of the clinical trial application. Individual site documents for each staff member must be uploaded into one (1) document and labelled with the staff name and arranged in folders according to the site which they belong to.

Per G-CTA-Electronic, to respond to SAHPRA’s screening checklist or to CTU’s expert committee review, the applicant must submit all responses by e-mail to ctcresponses@sahpra.org.za and include labelled attachments to the required documents. In the subject of the email, the applicant should provide the type of application, protocol number, and SAHPRA database tracking number. Responses to the CTU’s expert committee recommendations can be in MSWord or PDF formats. All other accompanying documents should be in PDF format v1.4, 1.5, 1.6, or 1.7 and legible with the Acrobat Reader search plugin or any other freeware viewer. PDF files should be saved as “Optimized” to reduce the size and allow faster opening when viewed online. The use of additional software to navigate and work with the files is not acceptable. If PDF files are not produced from an electronic source document but from scanned paper, readability and file size should be balanced; the following is recommended: resolution 300 dpi (photographs up to 600 dpi), avoid grayscale or color where possible, use only lossless compression techniques. The file must be searchable (OCR scanned). In addition, the maximum size of documents allowed per e-mail is 5 MB. As per arrangement with CTU, in case of a big file of documents and documents that need to be couriered, the waybill should indicate the type of application, protocol number, and SAHPRA database tracking number.

Per G-CTA-Electronic, for bioequivalence studies, the application and accompanying documents should be emailed to ctcbeprotocols@sahpra.org.za. The clinical trial application form should be in MS Word format and all other accompanying documents in PDF, as described above. As per arrangement with CTU, in case of a big file of documents and documents need to be couriered, the waybill should indicate the type of application, protocol number and SAHPRA database tracking number. The email subject should include the type of application, protocol number, and SAHPRA database tracking number. See the G-CTA-Electronic for specific examples of labeling the emails.

Per the G-CTAPHEmerg, during a public health emergency, applicants should use the modified clinical trial application form in G-CTAPHEmerg. This form recognizes the constraints on the availability of information posed by the emergency. SAHPRA may accept clinical trial applications with reduced information together with a commitment to update and complete the required information as soon as possible. However, all documents submitted must be organized with zipped folders according to the checklist in G-CTAPHEmerg and correctly labelled to ensure easy validation by SAHPRA (See the Submission Content and Emergencies sections for more details).

The G-CTA-Electronic provides instructions on submitting protocol amendments during the conduct of clinical trials, for additional investigators and sites during the conduct of clinical trials, bioequivalence studies, notifications and notification studies, and individual serious adverse events. The applicant must submit to SAHPRA the application for amendment to an approved trial (ZAF-20), as well as notify and get EC approval. (Also see Site/Investigator Selection and Safety Reporting sections for information about these submittal processes.)

The G-CTA-Electronic and ZAF-23 state that the clinical trial application must be sent to SAHPRA in a submission email (per directions above). However, ZAF-1 provides the following address for delivery of clinical trial applications to SAHPRA Reception:

South African Health Products Regulatory Authority
SAHPRA reception – 2nd floor
Loftus Park, Building A
402 Kirkness St, Arcadia
Pretoria, 0007
South Africa

Per ZAF-1, upon receipt of the clinical trial application at SAHPRA Reception, an acknowledgement of receipt in the form of a stamp and signature will be issued. The waybill from a courier company does not suffice as proof of delivery. SAHPRA’s CTU requires a document, referred to as the ‘stamp page,’ which includes the SAHPRA trial reference number, protocol number, and study title. This document will then be date-stamped and signed by SAHPRA’s Administrative Department and returned as proof.

As per the GRMRSA, all applications and supporting data submitted to the SAHPRA should be presented in English. Original documents that are not in English must be accompanied by an English translation.

Ethics Review Submission

Each EC has its own required submission procedures, which can differ significantly regarding the number of copies to be supplied and application format requirements. Refer to each EC’s website for specific submission procedures (Note: ECs are referred to as health research ethics committees (HRECs) in South Africa).

3-7

Where Do I Submit a New Clinical Trials Application?, How Do I Make Sure My Hard Copy Application Gets to the Right Place?, and What Should an Acceptable Proof of Delivery Look Like?

2.6 and 6.2

Application for the Registration of a Medicine – Part 16 (4)

Submission Content

Last content review/update: June 16, 2023

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-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

Refer to the CanadaFDR, 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.

Apply for Ethics Review

3.1.2, 6, and 7

2.3 and 2.7

2-5, and Appendix D

I, S Drug Substance, and P Drug Product

Chapter 11 (Article 11.6)

Part C (Division 5 (C.05.001, C.05.004, and C.05.005))

Last content review/update: December 18, 2023

Regulatory Authority Requirements

As per ZAF-23, the following documentation must be submitted to the South African Health Products Regulatory Authority (SAHPRA):

The clinical trial application form (ZAF-23)
Two (2) cover letters (one (1) signed in PDF and one (1) in MS-Word format)
Two (2) completed copies of the clinical trial application (one (1) signed in PDF and one (1) in MS-Word format) (ZAF-23 and ZAF-20 (for amendments))
Checklist
Protocol
Patient information leaflets (PILs) and informed consent forms (ICFs); include standardized SAHPRA contact details (Annex 1 of ZAF-23)
Copy(ies) of recruitment advertisement(s) (if applicable) and questionnaires
Investigator’s Brochure (IB)/SAHPRA and other regulatory authorities’ approved professional information (Package insert(s))
Summary of previous trials with the investigational product(s) (IP(s)), if applicable
Certificate of analysis of the product
Signed investigator(s) Curriculum Vitae(s) (CV) in SAHPRA format (Annex 2 of ZAF-23)
Signed declaration(s) by all investigator(s) (Annex 3 of ZAF-23)
Signed joint financial declaration by sponsor and principal investigator (PI) or national PI (Annex 4 of ZAF-23)
Signed declaration by applicant and national PI
Signed declaration by national PI (See page 4 and Annex 3 (ZAF-23)
Signed declaration by sub-investigators (Annex 5 of ZAF-23)
CV(s) and signed declaration by regional monitor(s) (Annexes 2 and 6 of ZAF-23)
Proof of application to register the trial on the South African National Clinical Trials Register (SANCTR) (ZAF-48)
Active insurance certificate for clinical trial
Proof of sponsor indemnity for investigators and trial site(s) (Annex 7 of ZAF-23)
Active Good Clinical Practice (GCP) Certificates
Workload forms for investigators (Annex 8 of ZAF-23)
Proof of registration with professional statutory bodies
Proof of professional indemnity (malpractice insurance) of trialist(s)
Ethics committee (EC) approval letter or copy of letter submitted to EC
Study budget
Electronic copies of key peer reviewed publications following International Committee of Medical Journal Editors (ICMJE) recommendations to support the application (if applicable)
Proof of payment (bank validated)
Certificate of good manufacturing practice (GMP) for manufacture of the IP(s) (including placebo and comparator)
Evidence of accreditation/certifications of the designated laboratories
Data Safety Monitoring Board charter and composition (where applicable)

See ZAF-36 for additional information on submissions. For phase IV trials of approved products, the applicant must notify SAHPRA following the instructions provided in ZAF-17.

ZAF-20 delineates the contents and requirements for submitting an application for protocol amendment to an approved clinical trial.

Per the G-CTAPHEmerg, SAHPRA states that during a public health emergency, new and experimental treatments may become necessary and clinical trials are essential to provide the evidence to develop appropriate policies for patient treatments. Under these circumstances, there may be limited information available. However, applications need to contain a certain minimum of information to enable a meaningful evaluation and regulatory decisions. To address this, SAHPRA provides an information grading system in the G-CTAPHEmerg wherein required information is labelled. Applicants must attempt to provide the information listed below and justify when this is not available. The required information is graded as follows:

Essential – Application will not be considered without this
Important – Necessary information that must be provided later and must be justified if not available
Not essential – May be omitted from this preliminary application

All incomplete information must be explained, justified, and provided to SAHPRA as a complete application (ZAF-23), when available. This means that repeat evaluations of an application may be necessary.

Ethics Committee Requirements

Each 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 requirements list provided below is basically consistent across all South African ECs.

The following list was compiled from ZAF-24, ZAF-22, ZAF-45, ZAF-42, and ZAF-49, to exemplify the common elements shared by the various application forms:

Cover letter
Completed EC-specific application form
Protocol
Protocol synopsis
PIL(s) and ICF(s) and process for obtaining informed consent
Separate assent form required for adolescents/children under the age of 18 (See Children/Minors section for additional information)
IB and package insert(s) (if applicable)
SAHPRA approval letter or letter of application and notification
Approval letter from institution’s scientific committee (if applicable)
Copy of completed clinical trial application signed by all participating investigators
All questionnaires and diaries to be used in the study
Advertisement(s) (if applicable)
Trial site information (address, telephone numbers, PI names, etc.)
Trial payment schedule and budget schedule per site/draft financial contract and additional funding details
Proof of submission fees payment
Current investigator(s) CVs
GCP training certificates for PIs and subinvestigators
Information on registration with SANCTR (ZAF-48)
Declaration of trialists (PI and sub-investigators) in SAHPRA format
Insurance certificate

Further, per the MTA-Human, all the providers and recipients of human biological material for use in research or clinical trials under the auspices of ECs must use the “Material Transfer Agreement of Human Biological Materials” in MTA-Human. The agreement must be signed by the research institution’s authorized representative and the EC. (For additional details, see Specimens topic.)

Clinical Protocol

As delineated in ZAF-23 and the SA-GCPs, the clinical protocol should contain the following information (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

General information
Background information
Study rationale and motivation
Trial objectives, purpose, and endpoints (with justifications)
Trial design and methodology
IP information
Participant eligibility, selection, and withdrawal
Participant treatment
Efficacy assessment
Safety assessment
Statistics
Direct access to source data/documents
Quality control/quality assurance
Data and safety monitoring plan
Data handling/recordkeeping
Statistical measures
Financing/insurance
Publication policy

Per the SA-GCPs, the protocol must also provide details on ethical and administrative issues, including how the following matters are addressed:

Compliance of multi-center/national trials with all South African regulatory requirements
The trial design must be customized appropriately for the local setting to ensure that local realities are considered and appropriately integrated into the design
For multi-national trials, whether a reasonable proportion of significant project team members, including scientists and health care professionals, are South African researchers, including those from previously disadvantaged backgrounds
If South Africa is selected as a clinical trial site but the country of origin or other high-income countries are not, an explanation and reason for this with a clear ethical justification

For detailed information on protocol elements, please refer to ZAF-23 and the SA-GCPs.

Submission Documents

2.6, 6.2, 7.1-7.16

Cover page, 3, and Annexure A

Timeline of Review

Last content review/update: June 16, 2023

Overview

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

Regulatory Authority Approval

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

As specified in the G-CanadaCTApps and the G-MDSA, during the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. The G-MDSA clarifies that, where warranted, HC can adjust the timelines to be longer or shorter based on the complexity of the request, 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.

Apply for Ethics Review

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)

Part C (Division 5 (C.05.005 and C.05.006))

Last content review/update: December 18, 2023

Overview

Based on ZAF-23 and the SA-GCPs, the review and approval of clinical trial applications by the South African Health Products Regulatory Authority (SAHPRA) and an accredited ethics committee (EC) may be conducted in parallel. The applicant must notify each regulatory body of the other’s approval once it has been received.

Regulatory Authority Approval

In general, per ZAF-36, SAHPRA’s Clinical Trial Unit (CTU) aims to process new applications and issue a screening checklist within three (3) weeks of receipt. After that, the expert Clinical Trials Committee (CTC) recommendations will be sent within 10 weeks of the submission due date. There are cases where this turnaround time might be prolonged, such as an unfamiliar investigational product which may be referred to external reviewers or other SAHPRA committees for input.

Per ZAF-1, during the preliminary screening, the CTU screens the application and sends an official letter to the applicant with the outcome and follow-up questions on a screening checklist. The applicant receives the screening checklist within 15 working days after application submission. The applicant must respond within seven (7) working days after receipt of the screening review.

Next, the CTC reviews the proposed clinical trials. ZAF-11 provides the dates of the 2024 CTC meetings and the SAHPRA submission due dates. It is advisable to submit clinical trial applications before these due dates. Once the reviewer approves the application, the CTC presents the committee’s/reviewer’s recommendations to the SAHPRA. ZAF-1 states that applicants receive a response within 10 working days from the CTC meeting, and they must send an answer within seven (7) working days after receipt of comments. If an applicant would like to request a meeting with the CTC, the request should be submitted through the SAHPRA Chief Executive Office pursuant to the procedures in the G-ConsultMtg.

Ethics Committee Approval

As earlier stated, an applicant must also submit the clinical trial application for review and approval by an accredited local EC. Review timelines vary per an individual EC’s procedures.

Governance

In addition, as described in the G-EthicsHR-ZAF and ZAF-6, all clinical trials must obtain site-specific provincial and/or hospital approval to assess the impact the clinical trial will have on the resources of the establishment hosting the trial.

Chapter 4 – South Africa (MCC, HREC, Provincial/Hospital) (full ebook only available for purchase)

How Will I Know If My Application has been Received and Reviewed?, What is the Timeline for Receipt of Screening Checklist?, What is the Timeline for Response of Screening Checklist?, What is the Expected Timeline for Response from Clinical Trial Committee Review?, and What is the Timeline for Submitting Responses from Expert Committee Review?

5.5

4.4

Initiation, Agreements & Registration

Last content review/update: June 16, 2023

Overview

In accordance with the CanadaFDR and the G-CanadaCTApps, a clinical trial can only commence after the sponsor receives authorization from both Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada). No waiting period is required following the applicant’s receipt of these approvals. CAN-30 specifies that for purposes of the Clinical Trial Site Information (CTSI) Form (CAN-6), the trial commencement date is the date when the clinical trial site is ready to enroll participants. The commencement date is a date after which the sponsor has both the HC authorization from the appropriate Directorate (date on the No Objection Letter (NOL)) 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, a copy of HC’s clinical trial authorization (i.e., the NOL) must be included with the drug shipment. According to the G-CanadaCTApps and CAN-32, if a sponsor plans to import investigational drugs directly to each trial site, then the sponsor must also authorize the importer (i.e., the clinical trial site) when submitting the clinical trial application using Appendix I of HC’s Drug Submission Application Form (CAN-4). See the Manufacturing & Import section for detailed import requirements.

Clinical Trial Agreement

Prior to initiating 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.

1.17, 5.1.2, 5.6.3, and 8.2.6

1.2 and 2.7

5.6

Chapter 11 (Articles 11.10-11.11)

Part C (Division 5 (C.05.006))

Last content review/update: December 18, 2023

Overview

In accordance with the GRMRSA, the SA-GCPs, the G-EthicsHR-ZAF, and the NHAParticipants, a clinical trial can only commence in South Africa once an applicant receives approval from the South African Health Products Regulatory Authority (SAHPRA) and from an accredited local ethics committee (EC). There is no waiting period required following the applicant’s receipt of these approvals.

In addition, the principal investigator (PI) for each study site must be a South African-based scientist (resident of South Africa), and should have the appropriate qualifications, training, and experience to assume responsibility for the proper conduct of a trial. The trial must be conducted in compliance with the SA-GCPs, the G-EthicsHR-ZAF, and the GRMRSA. Also, per the SA-GCPs, all clinical trials must be conducted in a laboratory complying with Good Laboratory Practices (GLP). See ZAF-46 for the World Health Organization (WHO)’s handbook on GLPs.

Per the SA-GPPs, pharmacists must be involved in clinical trials, including for example, assisting in the development of protocols, overseeing medicine supplies, monitoring administration protocols, and maintaining registries.

Clinical Trial Agreement

According to the SA-GCPs, all parties involved in the conduct of a trial should be familiar with guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. Before the trial begins, a sponsor must prepare a written agreement. The agreement must be signed by the sponsor and the PI, and any other parties involved (e.g., institutions and contract research organizations) with the trial to confirm the contract terms. Both the sponsor and the PI must commit to providing safety information between each other. The sponsor should also obtain the investigator's agreement to:

Conduct the trial in compliance with the SA-GCPs, the SAHPRA requirements, ZAF-27, and the EC approved protocol

Comply with data recording/reporting procedures

Permit monitoring, auditing, and inspection

Retain the trial-related essential documents until the sponsor informs the investigator(s) and institution(s) that these documents are no longer needed

In addition, per the SA-GCPs, the financial aspects of the trial should be documented in the agreement. A declaration must be signed by the sponsor and PI stating that sufficient funds are available to complete the study. The sponsor is also responsible for securing agreements to ensure direct access to all trial-related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor, and inspection by domestic and foreign regulatory authorities.

Clinical Trial Registration

According to the SA-GCPs, NHAParticipants, and ZAF-32, the PI or the sponsor must enter the trial information in the South African National Clinical Trials Register (SANCTR) (ZAF-48). The SA-GCPs indicates that the National Department of Health (NDOH) then issues a unique SANCTR National Register Number. ZAF-32 has instructions for registering either online or via email.

ZAF-48 states that SANCTR fulfills the requirements of the International Committee of Medical Journal Editors (ICMJE) publication mandates and has a formal partnership with the Pan African Clinical Trials Registry (ZAF-50), which is recognized by the WHO.

General Objectives and Requirements of Pharmaceutical Services

4 and 5

1.2, 2.6, 4.4, 6.1-6.2, 6.4, 6.9, 7.11, and 9.2

3

Part 30 (2)

Safety Reporting

Last content review/update: June 16, 2023

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 ADRs 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 when requested by HC. A DSUR may be submitted voluntarily to HC when important new safety information on a drug needs to be conveyed by a clinical trial sponsor. In these cases, a rationale/justification for the filing of the DSUR should be included in the cover letter. For additional details, see the G-DSUR.

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

Form Completion & Delivery Requirements

As per the G-CanadaCTApps, 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.

Additionally, the G-DSUR indicates that HC recommends that DSURs in electronic Common Technical Document (eCTD) format be submitted via the Common Electronic Submission Gateway (CESG). For information on eCTD format, refer to the ElecSubms. For technical questions on eCTD filings, contact ereview@hc-sc.gc.ca as instructed in the G-DSUR. Per the Non-eCTDformat, DSURs in "non-eCTD electronic-only" format should be sent via email to brdd.cta-dec.dmbr@hc-sc.gc.ca for biologic and radiopharmaceutical drugs and pdd-pv-dmp@hc-sc.gc.ca for pharmaceutical drugs. The subject line of the email should include the statement: "DSUR – drug name", and the zipped file should be named: "DSUR-drugname".

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

3.4.3

Chapter 11 (Article 11.8)

Part C (Division 5 (C.05.001 and C.05.014))

Last content review/update: December 18, 2023

Safety Reporting Definitions

In accordance with the SA-GCPs, the G-EthicsHR-ZAF, and the G-SafetyRpt, the following definitions provide a basis for a common understanding of South Africa’s safety reporting requirements:

Adverse Event/Experience (AE) – Any untoward medical occurrence that may present during treatment with a medicine, but which does not necessarily have a causal relationship with this treatment
Adverse Drug Reaction or Adverse Reaction (ADR) – A noxious and unintended response to a medicine in humans or animals, including lack of efficacy, and which occurs at any dosage and can also result from overdose, misuse, or abuse of a medicine
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any untoward medical occurrence that at any dose: results in death, is life-threatening, requires patient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect
Unexpected Adverse Drug Reaction – One in which the nature, specificity, severity, and outcome is inconsistent with the applicable product information (i.e., with the approved package inserts for registered medicines, the investigator’s brochure, or other product information for unregistered medicines being used)

Furthermore, ZAF-30 provides clarification on the definition of a serious suspected unexpected adverse reaction (SUSAR), which is a reporting requirement in the updated G-SafetyRpt. Per ZAF-30, a SUSAR is an adverse reaction that is unexpected but suspected to be drug related. It must fulfil the criteria for “serious” as per the definition of SAEs. In addition, all SUSARs are SAEs but not all SAEs are SUSARs.

Per the G-EmergencyProc, all clinical trial sites must have an emergency standard operating procedure that should be available for inspection by the South African Health Products Regulatory Authority (SAHPRA). In addition, each clinical trial site should have adequately trained investigators to manage medical emergencies. Further, there must be an emergency 24-hour contact number for trial participants who experience an unexpected AE.

Safety Reporting Requirements

Investigator Responsibilities

As specified in the SA-GCPs and the G-EthicsHR-ZAF, the principal investigator (PI) must inform the sponsor immediately, or within the time specified in the protocol, of any serious and/or unexpected AEs occurring during the study. The initial reporting form and any relevant follow-up information should be sent to the sponsor. The G-SafetyRpt directs the investigator to report AEs to the sponsor in a manner defined in the protocol. Per the SA-GCPs, AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations must be reported to the sponsor in accordance with the reporting requirement and within the time periods specified in the protocol. In the case of participant deaths, the PI must supply the sponsor, the ethics committee (EC), and SAHPRA with any additional information, as requested. The initial and follow-up reports must identify the affected participants by the participant identification code.

Sponsor Responsibilities

As delineated in the GRMRSA and the G-EthicsHR-ZAF, the sponsor is required to report all expected or unexpected SAEs/SADRs on an expedited basis to all concerned parties, including the investigator(s) and institution(s), the SAHPRA, and the ECs. Pursuant to the G-SafetyRpt, the sponsor is required to submit the following safety reports to SAHPRA:

Reports of SUSARs occurring in the clinical trial using the SAHPRA SAE form (ZAF-19), CIOMS form (ZAF-15), or Annex B of G-SafetyRpt
Reports of all SUSAR and trends occurring with the investigational product (IP) in South Africa
Six-month progress report
Annual Development Safety Update Reports (DSURs) that includes information gathered from all clinical experience with the IP, whether in South Africa or elsewhere
Final Progress Report
Final Study Report

The SA-GCPs states that the sponsor is responsible for performing an ongoing safety evaluation of the IP and must promptly provide written notification to the investigator and SAHPRA of findings that may adversely affect the safety of participants or the conduct of the trial, and/or change the EC's approval to continue the trial. The commitment to provide safety information must be included in the clinical trial agreement signed between the sponsor and the investigator.

The G-SafetyRpt delineates the following reporting timeframes:

The sponsor should initially report all fatal or life-threatening SAEs in local reports within seven (7) calendar days after first knowledge, using CIOMS format (ZAF-15)/SAHPRA SAE form (ZAF-19). The follow-up report should be submitted within an additional eight (8) calendar days.
All fatal or life-threatening SAEs in foreign reports should initially be reported within 30 calendar days after first knowledge by the sponsor. The follow-up report should be submitted within an additional six (6) months as part of the progress report. If the SAEs result in premature study closure, the reporting times are shorter—seven (7) days for the initial report and within an additional eight (8) days for the follow-up report. These reports should be in a line listing format. Note that these reporting requirements also cover foreign reports of “special concern,” which is a significant safety issue defined for each clinical trial that requires urgent attention from the regulatory authority. An adverse reaction of special concern from a foreign jurisdiction should be based on the decision of its regulatory authority. A safety issue leading to international regulatory action is considered to be significant at all times and hence reportable.
Local reports of other serious events (unexpected, not fatal or life threatening) within 15 calendar days of the event and every six (6) months in the CIOMS format (ZAF-15)/SAHPRA SAE form (ZAF-19)
A line listing of all local reports—serious (unexpected and expected) AEs—and any other issues of special concern outside South Africa should be submitted every six (6) months (using the progress report form in ZAF-18).
An initial detailed report of new information impacting the risk-benefit profile of the IP or conduct of trial should be submitted within three (3) calendar days; a follow-up report should be submitted within an additional six (6) months.
An initial detailed report of other major safety concerns (e.g., changes in nature, severity, or frequency of risk factors) should be submitted within 15 days of knowledge of the concern; a follow-up report should be submitted within an additional six (6) months.
DSURs should be submitted within one year from approval of the study and annually thereafter.

In addition, SAHPRA reserves the right to impose additional reporting timelines on an individual protocol basis, and it may require expedited reporting of AEs of special interest, whether serious or not.

See the G-SafetyRpt for details on the contents of the reports and other safety report requirements.

Form Completion & Delivery Requirements

Per the G-SafetyRpt and ZAF-19, the SAHPRA’s Safety Reporting During Clinical Trials Form (ZAF-19) should be used to complete SAE/ADR reports—for both initial and follow-up safety reports. The G-SafetyRpt indicates that adverse drug reactions occurring during post-marketing studies (Phase 4 and observational studies) should be reported to the Vigilance Unit of SAHPRA, and adverse drug reactions occurring during the use of concomitant and/or comparator medicine in a clinical trial should be reported to the Clinical Trial Unit of SAHPRA. Reportable safety information must be sent to:

ctcsaes@sahpra.org.za for clinical trials (per ZAF-47, ctcsaes@sahpra.org.za should be used for individual patient SAEs and related queries)
adr@sahpra.org.za or e2b@sahpra.org.za for post-marketing studies
section21@sahpra.org.za for reporting of SAEs for medicines used under Section 21

As per ZAF-47, the following is the contact information for pharmacovigilance-related submissions:

ADR reports in an e2b in an xml format: e2b@sahpra.org.za
All other ADR reports: adr@sahpra.org.za
Pharmacovigilance related queries: pvqueries@sahpra.org.za
Documentation relating to identified safety concerns, responses to recommendations, and Risk Management Plans (RMPs): pvsubmissions@sahpra.org.za

G-CTA-Electronic details the requirements for electronic submission of individual SAEs. All SAEs should be submitted to ctcsaes@sahpra.org.za with a cover letter detailing:

The title of the study
The SAHPRA reference number
Protocol number
Name of site
Patient study ID
Cause of SAE
Causality and SAE reporting form
Other applicable information

The email subject line should include the following information: SAE, protocol number, and SAHPRA database tracking number.

Part B

Clinical Evaluation and Management (Pharmacovigilance)

1, 2, and 6

4.5.1 and Appendix 1

8

4.1-4.2, 4.6-4.7, 5.2, 6.1-6.4, and 7.1-7.3

5.12, 6.4, 6.9, and 12

1 and 30(7)

Progress Reporting

Last content review/update: June 16, 2023

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.

4.10 and 4.13

2.8

5.12 and 5.13

Chapter 11 (Article 11.8)

Part C (Division 5 (C.05.012 and C.05.013))

Last content review/update: December 18, 2023

Interim and Annual Progress Reports

In accordance with the GRMRSA, the person authorized by the South African Health Products Regulatory Authority (SAHPRA) to conduct a clinical trial (i.e., the sponsor) must submit progress reports to the SAHPRA every six (6) months from the application approval date. The SA-GCPs requires the investigator to submit written progress reports to the ethics committee (EC) annually and to SAHPRA every six (6) months. ECs and SAHPRA may request reports more frequently.

Per the GRMRSA, the SA-GCPs, and G-SafetyRpt, the six-month report (ZAF-18) must include the following (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

SAHPRA database tracking number
Study title
Protocol number
Details of the sponsor
Progress to date or the outcome in case of completed research
Whether participant follow up is still active or has been completed
List of all active trial sites, addresses, and principal investigators (PIs)
Trial information, including date of approval of study, treatment hold (if applicable), and expected date of completion
Number of participants per site and current enrollment status
Sponsor comment on progress to date
Summary Data Safety Monitoring Board or Safety Committee recommendations and relevant safety data
Serious adverse events and suspected unexpected serious adverse reactions for all participants per site in South Africa, including identification of previous safety reports submitted to SAHPRA concerning a similar suspected adverse reaction and an analysis of their connection
Any safety issues of special concern outside of South Africa
Line listing of all critical and major protocol violations/noncompliance and resolutions/actions taken at a site or conditions of approval
Principal investigator (PI) comment on other major safety concerns
Signature of the PI
Signature of the sponsor

Note that the SA-GCPs directs the investigator to promptly provide written reports to the sponsor/applicant, the EC, and where applicable, the institution on changes that significantly affect trial conduct and/or increase the risk of participant harm.

Final Report

The sponsor is required to submit a final progress report to the SAHPRA 30 days following the trial’s completion as stated in the GRMRSA and the G-SafetyRpt. Further, per G-SafetyRpt, a final study report should be submitted within 180 days of clinical trial completion or termination.

In addition, per the SA-GCPs, upon the trial’s end, the investigator must inform the institution (if applicable), the EC, and SAHPRA and provide them with a summary of the trial outcome and other required reports.

The SA-GCPs specifies that the sponsor must ensure that trial results and outcomes are reported to the investigators, SAHPRA, and the National Department of Health (NDOH) via the South African National Clinical Trials Register (SANCTR) (ZAF-48) within one (1) year of the study’s completion. The sponsor and the PI are responsible for appropriate dissemination of the trial findings.

6.1-6.2 and 7.3.1

5.5, 5.11, 5.14, and 6.15

Part 30 (6)

Definition of Sponsor

Last content review/update: June 16, 2023

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.

1.53, 5.1, and 5.2

2.1

5.1 and 5.5

Part C (Division 5 (C.05.001, C.05.005, C.05.015))

Last content review/update: December 18, 2023

As defined in the SA-GCPs, a sponsor is the person or organization responsible for the initiation, management, or financing of a clinical trial. A sponsor can be a pharmaceutical company, the principal investigator (PI), a funding body, or an individual or organization designated by the funding body or academic institution. An applicant can be an individual, company, institution, or organization that acts on behalf of the sponsor to initiate and manage the trial as its local representative. In the case of an international sponsor, a local applicant designated by the sponsor is responsible for initiation and management of the trial in the local context.

Per the SA-GCPs, a sponsor may transfer any or all trial-related duties and functions to a contract research organization (CRO). However, the sponsor is always ultimately responsible for the study data quality and integrity. Further, per the G-Monitor, the sponsor is solely responsible for adequate oversight of clinical trial conduct, including the justification for and selection of monitoring methods. Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing. The sponsor retains those responsibilities not specifically transferred to and assumed by a CRO.

1

6

Site/Investigator Selection

Last content review/update: June 16, 2023

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 to represent the sponsor, and sign and date the application and the clinical trial attestation form.

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

1.25, 5.5, 5.6, and 5.23

2.1 and 2.7.2

5.5

Chapter 11 (Article 11.7)

Part C (Division 5 (C.05.005))

Last content review/update: December 18, 2023

Overview

As set forth in the SA-GCPs, the sponsor is responsible for using qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians), as appropriate, throughout all stages of the trial process. Sponsors should select investigator(s) who are qualified by training and experience and have adequate resources to conduct the proposed clinical trial. Further, per the G-Monitor, the sponsor should consider previous experience with the investigator or site, workload of the investigator, and resource availability at the study site during investigator and site selection. Per the G-Capacity, clinical trial applications should include evidence and activity plans to build capacity at each study site as well as enhancing research activities and skills of professionals from historically disadvantaged groups. Mandatory training in Good Clinical Practice (GCP) forms a part of capacity building. To support transformation and capacity building, the South African Health Products Regulatory Authority (SAHPRA) states that the sponsor must have a policy on “Capacity Building and Transformation in Clinical Research in SA” in place, and preferentially select sites that are compliant. See G-Capacity, for detailed information on actions that will comply with this requirement.

According to the SA-GCPs, the sponsor must also define and allocate all study related duties and responsibilities to the investigator prior to initiating the study.

In addition, per ZAF-21, to add or change investigators and/or additional sites to an approved clinical trial, the sponsor must submit a signed application to SAHPRA. See ZAF-21 for details.

Per the G-CTInvestigators, SAHPRA will recognize and approve categories of investigators for trial leadership. The principal investigator (PI) must be a South Africa-based scientist, who has sole or joint responsibility for the design, conduct, and delegation of trial responsibilities, analysis, and reporting. The PI is accountable to the sponsor and regulatory authorities. The PI can designate and supervise sub-principal investigator(s) (Sub-PI) of which at least one (1) must be a clinician and registered with the appropriate statutory entity to provide clinical oversight within their scope of practice. Further, the SAHPRA recognizes a category of co-principal investigator (co-PI), which allows for a team consisting of two (2) co-PIs to lead a study at a site. At least one (1) of the co-PIs must be a clinician registered with the appropriate statutory body and qualified to provide clinical oversight within their scope of practice. For multi-center studies, there must be a national PI appointed, who may or may not be a site PI. The national PI must have appropriate experience and expertise in that field and must be responsible for the application to the SAHPRA to conduct the study. The national PI must meet all other requirements to be a PI and sign a declaration accepting the responsibility as national PI and sign off on the clinical trial application. For more information on PI requirements, roles, and responsibilities, see the G-CTInvestigators.

Per the SA-GCPs, all parties involved in the conduct of a trial should be familiar with the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. Additionally, the investigator must agree to conduct the trial in compliance with the SA-GCPs, ZAF-27, SAHPRA requirements, and the ethics committee approved protocol. In the event of an interpretation conflict between the SA-GCPs and an international guideline, the SA-GCPs take precedence.

Foreign Sponsor Responsibilities

As required in the SA-GCPs, if South Africa is selected as a clinical trial site but the country of origin or other high-income countries are not, the sponsor must explain the reason(s) why and provide a clear ethical justification. Further, multi-national trials should ensure that a reasonable proportion of project team members are South African researchers, including scientists and health care professionals and those from previously disadvantaged backgrounds.

Data and Safety Monitoring Board

Per the SA-GCPs, the sponsor may establish an independent Data Safety Monitoring Board (DSMB) to assess the progress of a clinical trial, including safety data and critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The DSMB must have written standard operating procedures and must maintain written records of all its meetings.

Multicenter Studies

Per the SA-GCPs, if the trial is a multicenter and/or multi-country trial, any differences in trial designs between the South African and other sites must be clearly documented and explained in the trial protocol and/or related documents. In addition, international research groups must comply with South African regulatory requirements, and researchers must adapt the trial design and informed consent procedures to take into account local conditions and characteristics.

1.25, 5.5, and 5.6

5

3 and 4

1.2, 5.9, 6.2, 6.4, and 7.12

Insurance & Compensation

Last content review/update: June 16, 2023

Insurance

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.

Compensation

Injury or Death

The Canadian regulations do not require compensation for trial participants in the event of trial-related injuries or death. However, the 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. Note that per HCNotice-CA-ICH-GCPs, HC-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

Trial Participation

The Canadian regulations do not require compensation for trial participation. However, as per the G-TCPS2 and the CA-ICH-GCPs, the informed consent form (ICF) should contain a statement with a description of the anticipated prorated payment to the participant(s) that is reasonably expected for participation in the trial. Any compensation or incentive to participants must not be so excessive that it may unfairly influence participants or cause them to overlook important facts and risks. CAN-35 further 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.

Policies, Guidelines, and Resources, Consent Process (Consent Form Template)

4.8 and 5.8

Chapter 3 (Article 3.2)

Last content review/update: December 18, 2023

Insurance

As set forth in the G-Insurance and the SA-GCPs, all clinical trial sponsors and investigators must obtain adequate insurance and indemnity to cover any liability claims during the conduct of a clinical trial, in accordance with the responsibilities described in the SA-GCPs. As delineated in the SA-GCPs and G-Insurance, a sponsor must follow the principles set forth in the Association of the British Pharmaceutical Industry’s (ABPI) guidelines (ZAF-26 and ZAF-25) to comply with South Africa’s clinical trial insurance requirements. Per the SA-GCPs, research participants should not bear any financial cost to rectify harms that occur as a result of trial participation. The insurer pays the medical costs of necessary treatment to restore the previous position of the participant, if possible, when bodily or other injury is attributable to trial participation. Only bodily injuries of an enduring and disabling character (including exacerbation of an existing condition) and/or death are covered by the insurance. Temporary pain or discomfort or less serious or curable complaints are generally not regarded as trial-related, bodily injury. In the case of an in-utero injury due to the mother’s participation, payment for medical expenses proceeds as though the unborn child is a research participant. For additional details on limitations on liability, dispute resolution, weighting of risk factors, and insurance settlements, see the SA-GCPs.

Per the G-Insurance, the application to conduct a clinical trial must include evidence of comprehensive no fault insurance for serious injury and harm and/or death. In addition, the sponsor must provide indemnification for all investigators and trial sites involved in their clinical studies on compliance with the protocol requirements. In cases where the investigators/site staff were negligent and/or did not comply with the protocol requirements, personal malpractice insurance would apply.

As delineated in the G-Insurance and ZAF-23, an insurance certificate and indemnity must be included in the clinical trial application submitted to the South African Health Products Regulatory Authority (SAHPRA). Per the G-Insurance, the sponsor must include details of the insurance, including the following:

Name and local address of the insurance company, including contact name and telephone number
Title and protocol number of the clinical trial
Date of commencement and termination of coverage
Liability limit – per occurrence and total per occurrence and total for the study. Note that the limit should be adequate enough to cover extended stay in an intensive care unit or hospital
Date of issuance of the insurance policy and expiry thereof
Original or electronic signature of the insurer
Special conditions if any. It is unacceptable to have special conditions which may invalidate or abate the clinical trial cover
Any additional coverage
Declaration of compliance with the SA-GCPs and ABPI guidelines on the certificate and in the patient information leaflet
Where the insurance is not provided by a local company, a local insurance vendor must be identified with full details
Insurance policy number
The amount insured

Compensation

Injury or Death

As set forth in the G-Insurance, all clinical trial sponsors and investigators must have adequate insurance to cover any liability claims during the conduct of a clinical trial, in accordance with the responsibilities as described in the SA-GCPs. As delineated in the SA-GCPs and G-Insurance, a sponsor must follow the principles set forth in the ABPI guidelines (ZAF-26 and ZAF-25) to comply with South Africa’s participant compensation and treatment requirements for trial-related injuries. The guidelines state that the sponsor should furnish written assurance to the investigator that the sponsor will agree to pay compensation to participants and/or their legal heirs in the event of trial-related injuries or death. The investigator, in turn, communicates this information to the relevant ethics committee (EC).

The SA-GCPs, the G-Insurance, and ZAF-26 provide several compensation principles to guide sponsors in fulfilling their obligations (Note: the sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

Compensation should be paid when it can be demonstrated that a causal relationship exists between a participant’s injury and their participation in a trial
Compensation should be paid when the injury results in permanent injury or disability to the participant
When there is an adverse reaction to a medicinal product under trial, and injury is caused by a procedure adopted to deal with that adverse reaction
The sponsor/applicant is under strict liability with respect to injuries caused by the investigational product (IP), and research participants should not bear any financial cost to rectify harms that occur as a result of trial participation
The insurer should pay the medical costs of necessary treatment to restore the previous position of the participant, if possible
In the case of an in-utero injury due to the mother’s participation, payment for medical expenses proceeds as though the unborn child is a research participant
In principle, only bodily injuries of an enduring and disabling character (including exacerbation of an existing condition) and/or death are covered by the insurance; temporary pain or discomfort or less serious or curable complaints are generally not regarded as trial-related, bodily injury
Where there is an adverse reaction to an IP and the injury is caused by a procedure adopted to deal with that adverse reaction, compensation should be paid for such injury as if it were caused directly by the IP
Payment for medical expenses is made without acknowledgement of any legal liability and is thus to be understood to be an ex-gratia payment
The provision of insurance cover and payment of medical expenses does not mean that an injured participant may not pursue legal action against the sponsor for loss or harm not covered by the insurance; however, an argument that pain and suffering, loss of income, and other possible claims should be paid for by the sponsor’s insurer is not sound in South African law and will not succeed
The likelihood of an adverse reaction, or the fact that the participant has freely consented (whether in writing or otherwise) to participate in the trial should not exclude the participant from being eligible for compensation

According to the SA-GCPs and ZAF-26, the amount of compensation to be paid to the participant should be appropriate to the nature, severity, and persistence of the injury. The compensation should also be generally consistent with the amount of damages commonly awarded for similar injuries. The amount paid in compensation should be abated, or in certain circumstances excluded, in light of the following factors (which will depend on the risk level the participant can reasonably be expected to accept):

The seriousness of the disease being treated

The degree of probability that adverse reactions will occur and any warning given

The risks and benefits of the established treatments relative to those known or suspected of the trial medicines

ZAF-26 provides that in any case where the sponsor agrees to pay the participant, but the two (2) parties differ on what is the appropriate level of compensation, it is recommended that the sponsor agree to seek, at the sponsor’s own cost, the opinion of a mutually acceptable independent expert. This opinion should then be made available to the participant(s), and the expert’s opinion should be given substantial weight by the sponsor in reaching a decision on the payment amount.

Additionally, any participant claims pursuant to ZAF-26 should be made to the sponsor, preferably via the investigator. The participant should include details on the nature and background of the claim, which the sponsor should review expeditiously. The review process may be delayed if the participant requests an authority to examine any medical records relevant to the claim.

Trial Participation

As specified in the G-TIECompensation and the SA-GCPs, the sponsor or the designated representative is responsible for providing compensation to research participants. The SA-GCPs state that before the clinical phase of the trial commences, the EC must approve the documentation on participant compensation. Per the G-EthicsHR-ZAF, the SA-GCPs, and the G-TIECompensation, compensation should be based on time, inconvenience, and expenses. In addition, the G-EthicsHR-ZAF and the SA-GCPs also address researcher requirements to budget for participant travel and other expenses. (See the G-EthicsHR-ZAF for detailed information). See ZAF-5 for an analysis of ethical considerations regarding payment of trial participants in South Africa.

The G-TIECompensation guides sponsors of approved clinical trials and proposes a model for minimum compensation that can be paid. It is not intended as an exclusive approach and the SAHPRA reserves the right to request any additional information. In addition, G-TIECompensation is not applicable to Phase I clinical trials, which pose a higher risk for participants and should be compensated on a different scale.

Post-Trial Access

The G-PostCTAccess guides sponsors on when to consider post-trial or continued access (PTA/CA) to the IP following the trial’s conclusion. Only those participants who derive benefit from the IP will be considered (this excludes participants on standard of care, placebo, and registered medicines). Where appropriate and available, the possibility of PTA/CA should be disclosed to and discussed with potential participants during the initial informed consent process or via a separate consent process. Where appropriate and/or available, details of potential PTA/CA should be included in the clinical trial application form, informed consent form, and patient information leaflet. Additional considerations include the following:

PTA/CA is not applicable for Phase I and II studies. However, PTA/CA may be necessary for particular diseases (e.g., cancer or rare diseases).
PTA/CA should be considered for Phase III studies when there is no registered and marketed standard of care in South Africa, provided that data from interim or final analyses shows that access is clinically justifiable.
PTA/CA is not applicable to Phase IV studies
A minimum of four (4) years after completion of the study is recommended as the acceptable time period to provide PTA/CA to the participants, unless there are compelling reasons for determining otherwise.
During the PTA/CA period, the sponsor must ensure monitoring and oversight of participants using the IP.

3 and 4

Cover, 1 and 2

1-5 and 7

3.1.7

1.2, 2.7, 6.2, 7.14, 9.2, and 10.2

Risk & Quality Management

Last content review/update: June 16, 2023

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.

As indicated in the CA-ICH-GCPs, he 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.

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

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.

Purpose and Scope, and Glossary

5.0-5.2, 5.18, 5.19, 5.21, and 6.10

5.10 and 5.15

Part C (Division 5 (C.05.007-008, C.05.010, and C.05.015))

Last content review/update: December 18, 2023

Quality Assurance/Quality Control

Per the SA-GCPs, the sponsor is responsible for implementing a quality management system to manage quality throughout the design, conduct, recording, evaluation, reporting, and archiving of clinical trials. This quality management system should adopt a risk-based approach for risk identification, evaluation, control, communication, and reporting. The sponsor should focus on trial activities that promote human participant protection and reliability of trial results, which include using qualified individuals, designating qualified medical personnel to respond to trial-related medical questions, and ensuring all aspects of the trial are operationally feasible and avoiding unnecessary complexity, procedures, and data collection. With respect to quality assurance (QA) and quality control (QC), the sponsor is responsible for implementing and maintaining QA and QC systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, good clinical practice, and the applicable regulatory requirement(s).

Per the G-Monitor, the responsibility for adequate oversight of the conduct of a clinical trial, including the justification for and selection of monitoring methods, remains that of the sponsor solely.

Per the SA-GCPs, all parties involved in the conduct of a trial should be familiar with guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. Additionally, the investigator must agree to conduct the trial in compliance with the SA-GCPs, ZAF-27, South African Health Products Regulatory Authority (SAHPRA) requirements, and the ethics committee (EC) approved protocol. In the event of an interpretation conflict between the SA-GCPs and an international guideline, the SA-GCPs take precedence.

Monitoring Requirements

In accordance with the SA-GCPs, the sponsor must conduct an independent audit to evaluate trial conduct and compliance with the protocol, procedures, good clinical practice, and the applicable regulatory requirements. The sponsor must appoint individuals who are independent of the clinical trials to conduct the audits and ensure that the auditors are qualified by training and experience to conduct audits properly. The sponsor's audit plan and procedures for a trial audit must be guided by the number of participants in the trial, the type and complexity of the trial, the level of risks to the trial participants, and any identified problem(s). Observations and findings of the auditors must be documented. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities.

In addition, per the G-Monitor, the sponsor’s monitoring plan should include planned audits to ensure that monitoring activities are in accordance with the monitoring plan, applicable regulations, guidance, and sponsor’s plans and policies.

Premature Study Termination/Suspension

Per the SA-GCPs, if a trial is prematurely terminated or suspended for any reason, the investigator must promptly inform the trial participants and ensure appropriate therapy and follow-up for them. If the investigator, sponsor, institution, SAHPRA, or the EC terminate or suspend a trial, the investigator must promptly inform the other parties with a detailed written explanation for the termination or suspension. The sponsor is also responsible for ensuring that the South African National Clinical Trials Register (SANCTR) (ZAF-48) is updated as well.

1.65, 5.0-5.2, 5.5, 5.18, 5.19, 5.21, 5.23, 6.10, and 8

1 and 4

Introduction, 1.2, 5.10, 5.13, 6.1, 6.4, and 6.12

Data & Records Management

Last content review/update: June 16, 2023

Electronic Data Processing System

Per the CA-ICH-GCPs, 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 standard operation procedures (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 Health Canada (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. Per the G-FDR-0100, sponsors may also be required to maintain records under provincial law, institutional policies, and contractual agreements with investigators, ethics committees (ECs), or others. Where it is not possible to comply with both sets of requirements, the CanadaFDR would govern and the records must be maintained for 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 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.

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.

1.65, 5.5, 6.10, and 8

5.12

Part C (Division 5 (C.05.012))

Regulatory Impact Analysis Statement

Last content review/update: December 18, 2023

Electronic Data Processing System

Per the SA-GCPs, the sponsor must ensure that the electronic data processing system conforms to the specific documented requirements for completeness, accuracy, reliability, and consistency of intended performance, and that standard operating procedures for using these systems are maintained. In addition, the sponsor must:

Ensure that the systems are designed to document data changes without deleting previously entered data (i.e., maintain an audit trail)
Maintain a security system that prevents unauthorized access to the data
Maintain a register of persons authorized to make data changes
Maintain adequate data backup
Ensure that blinding, if any, is maintained during data entry and processing
Ensure the integrity and confidentiality of data, including any that describe the context, content, and structure of the data – especially when making changes to computerized systems
If data are transformed during processing, it must be possible to compare the original data and observations with the processed data
Use an unambiguous participant identification code that allows identification of all data reported for each participant
Report any transfer of ownership of the data to South African Health Products Regulatory Authority (SAHPRA)

Per the G-Monitor, when developing a study’s monitoring plan, the sponsor should consider how it uses electronic data capture (EDC) systems. EDC systems that are capable of assessing quality metrics in real time will help identify high-risk sites that need more intensive monitoring.

Records Management

As set forth in the SA-GCPs, the sponsor should inform the investigator(s) in writing of the need for record retention, and should notify these parties in writing when the trial related records are no longer needed. The sponsor, or other data owners, must retain all the sponsor-specific essential documents pertaining to the trial for not less than 10 years or until at least two (2) years have elapsed since the formal discontinuation of clinical development of the investigational product (IP).

4

Introduction, 1.2, 5.10, 6.4

Personal Data Protection

Last content review/update: June 16, 2023

Responsible Parties

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

Data Protection

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

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

Consent for Processing Personal Data

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

Chapter 2 (Article 2.1) and Chapter 5 (A. Key Concepts)

Part I (2, 6.1, and 7)

3, 7, and 8

Last content review/update: December 18, 2023

Responsible Parties

For the purposes of data protection requirements, the POPIA provides that the “responsible party” is a public or private body or any other person that, alone or in conjunction with others, determines the purpose of and means for processing personal information.

Data Protection

Per the POPIA, participants have the right to privacy, which includes a right to protection against the unlawful collection, retention, dissemination, and use of personal information by public and private bodies. This right to privacy is subject to justifiable limitations that are aimed at protecting other rights and interests (e.g., the right of access to information). Additional information on the rights of data subjects is provided in the POPIA.

The POPIA states that the responsible party must protect the constitutional right to privacy by safeguarding personal information when it is processed. The law provides conditions under which personal information may be gathered and processed.

Accountability – The responsible party must ensure that the conditions and all the measures in the POPIA are complied with at the time of the purpose and means of processing is determined
Processing limitation – Personal information may only be processed in a fair and lawful manner and only with the consent of the data subject
Purpose specification – Personal information may only be processed for specific, explicitly defined, and legitimate reasons
Further processing limitation – Personal information may not be processed for a secondary purpose unless that processing is compatible with the original purpose
Information quality – The responsible party must take reasonable steps to ensure that the personal information collected is complete, accurate, not misleading, and updated where necessary
Openness – The data subject whose information you are collecting must be aware that you are collecting such personal information and for what purpose the information will be used
Security safeguards – Personal information must be kept secure against the risk of loss, unlawful access, interference, modification, unauthorized destruction and disclosure
Data subject participation – Data subjects may request whether their personal information is held, as well as the correction and/or deletion of any personal information held about them

The POPIA establishes a duty requiring a public or private body to register its Information Officer with the Information Regulator (South Africa). Per the POPIA, the Information Officer is responsible for compliance with lawful processing of information and working with and responding to requests by the Regulator. Per the POPIA-Regs, the Information Officer has further responsibilities to:

Develop, implement, monitor, and maintain a compliance framework
Conduct a personal information impact assessment to ensure compliance with the conditions for the lawful processing of personal information
Develop, monitor, and maintain a manual; and make it available upon request by any person, provide copies of the manual to any person upon request and payment of a fee to be determined by the Information Regulator from time to time
Develop internal measures and systems to process requests for information or access
Conduct internal awareness sessions on protection of personal information requirements
Provide reasonable assistance free of charge to the data subject in objecting to processing of personal information (using Form 1 in the POPIA-Regs) and/or correcting or revising a record of personal information (using Form 2 in the POPIA-Regs)

The POPIA provides that records of personal information for research may be retained longer than is necessary for achieving the purpose for which the information was collected or processed if the responsible party has established appropriate safeguards against the records being used for any other purposes.

For additional guidance on processing personal data, including guidance on “special personal information” (e.g., health history) and personal information of children, see the Information Regulator website.

Consent for Processing Personal Data

Per the POPIA and the POPIA-Regs, personal information may only be processed if the data subject and/or the legal representative(s) or guardian(s) consents to the processing. The responsible party bears the burden of proof for the consent. The data subject and/or the legal representative(s) or guardian(s) may withdraw consent at any time if the lawfulness of the processing of personal information will not be affected.

Preamble, Chapter 1 (1-2), Chapter 2 (4-5), Chapter 3, and Chapter 5 (55-56)

2-4

Documentation Requirements

Last content review/update: June 16, 2023

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 the 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 the 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 the 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 a continuous duty to provide participants with all information relevant to their ongoing consent to participate in the research. Consent begins with the initial contact (e.g., recruitment) and carries through to the end of participation in the study. Throughout the clinical trial, researchers have a continuous responsibility to provide participants and ECs with all information relevant to participants’ ongoing consent to participate in the research. The researcher also must notify participants of any changes to the research project that may affect them. These changes may have ethical implications, may be relevant to their decision to continue in the study, or may be unique to the particular circumstances of individual participants. Specifically, researchers must disclose changes to the risks or potential benefits of the research. Change in participant capacity is an important element of ongoing consent. Rather than an age-based approach to consent, researchers should use an approach based on decision-making capacity in compliance with any laws governing research participation. This includes those whose decision-making capacity is in the process of development, those whose decision-making capacity is diminishing or fluctuating, and those whose decision-making capacity remains only partially developed. Mechanisms should be in place from the outset to identify and address any changes that could affect consent. 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 G-TCPS2, the CA-ICH-GCPs, and CAN-35, the participant and/or the 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 the 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 the legal representative(s) and/or guardian(s)
The participant and the 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 the 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 the legal representative(s) and/or guardian(s) to waive or appear to waive the participant’s 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 can use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (e.g., a consent log, audio or video recordings, or other electronic means). Evidence of consent may also be documented via completed questionnaires (in person, by mail, 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 change to consent requirements is unlikely to adversely affect the welfare of participants
It is impossible or impracticable to carry out the research and to address the research question properly, given the research design, if the prior consent of participants is required
In the case of a proposed alteration, the exact nature and extent of any proposed alteration is defined
There is a plan to brief participants and offer the option of refusing consent and/or withdrawing data and/or human biological materials

Policies, Guidelines, and Resources; Consent Process (Key Considerations)

4.8, 8.2, and 8.3

5.5, 5.6, 5.8, and 5.10

Chapters 3 and 10

Part C (Division 5 (C.05.005, C.05.006, C.05.008, and C.05.010))

Last content review/update: December 18, 2023

Obtaining Consent

In all South African clinical trials, a freely given, written informed consent is required to be obtained from each participant in accordance with the principles set forth in the NHA, the Declaration of Helsinki (ZAF-44), the SA-GCPs, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27).

As per the SA-GCPs, the G-EthicsHR-ZAF, and the G-GPHlthCare, the informed consent form (ICF) and patient information sheet(s) are essential documents that must be reviewed and approved by an accredited ethics committee (EC) based in South Africa and provided to the South African Health Products Regulatory Authority (SAHPRA) with the clinical trial application. (See the Required Elements section for details on what should be included in the form.) The principal investigator (PI), or a person designated by the PI, should provide research study information to the participant and/or the legal representative(s), or guardian(s). When drafting and presenting the ICF, special consideration must be taken with regard to the participant’s culture, traditional values, intelligence, and education. The informed consent document should be non-technical and understandable to the participant and in a participant’s preferred written language. The ICF content should be briefly and clearly presented, without coercion or unduly influencing a potential participant to enroll in the clinical trial.

The SA-GCPs directs that none of the oral or written information concerning the study, including the written ICF, should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or to appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or the representatives from the sponsor’s liabilities for any negligence.

Re-Consent

The G-GPHlthCare-IC states that the participant must be informed of any relevant new findings over the course of the study, and be given the choice to continue to participate or withdraw from the study. Per the SA-GCPs, written informed consent documentation and other participant-related information should be revised when new information that may be relevant to a participant’s consent or willingness to continue to participate in the trial becomes available. Any revisions must be submitted for ethics review and approval before implementation. Communication of the new information to participants must be documented.

Language Requirements

According to the SA-GCPs and the G-EthicsHR-ZAF, the ICF and any patient information sheet(s) should be written in English and in a vernacular language that the participant is able to understand. The G-GPHlthCare states that the researchers should provide information to the participants in a language that the participant understands and in a manner that takes into account the participant’s level of literacy, understanding, values, and personal belief systems.

Documenting Consent

As stated in the SA-GCPs, the G-EthicsHR-ZAF, and the G-GPHlthCare, the ICF should be signed by the participant and the PI, or the person designated by the PI. If the participant is incapable of giving an informed consent, the legal representative(s) or guardian(s) should sign the ICF. The original signed ICF and patient information sheet(s) should be retained by the investigator and a copy should be given to the participant. The SA-GCPs requires an additional copy of the signed ICF and a source document identifying the study and recording the participation dates should be placed in the participant’s medical records. According to the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the G-GPHlthCare-IC, in all cases, written informed consent must be obtained. Where the participant is illiterate and/or the legal representative(s) or guardian(s) is illiterate, verbal consent should be obtained in the presence of and countersigned by a literate witness. The participant and/or the participant’s legal representative(s) or guardian(s), the PI or person designated by the PI, and if applicable, a literate witness must personally sign the ICF. Further, the SA-GCPs states that the participant should indicate willingness to participate by making a mark (either a cross or a fingerprint). The witness signs to affirm that the participant willingly consented to participate. The witness dates the mark and signature.

Waiver of Consent

No information is currently available regarding conditions for waiving consent.

3, 4.4, 4.8, and 6

3.4 and 6.3

11, 12.3, and 15.1.3

1.3-1.6, 2.3, 3.1, 3.2, 4.3, and 5.2

2.5 and 5.9

Chapter 9 (71)

Required Elements

Last content review/update: June 16, 2023

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 sources 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 the 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 can be found in CAN-35.

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

Policies, Guidelines, and Resources, and Consent Process (Sample consent forms)

4.8

Chapter 3

Last content review/update: December 18, 2023

Based on the informed consent essential elements in the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants, the informed consent form (ICF) should include the following statements or descriptions, 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 nature and purpose
The procedures to be followed
Why the potential participant has been approached and their responsibilities
The aspects of the clinical trial that are experimental
Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant; information should include the probability and magnitude of the foreseeable risks of harm
Any benefits to the participant or to others that may reasonably be expected from the research; if no benefit is expected, the participant should also be made aware of this
A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
The probability for random assignment to each treatment
Participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
Compensation and/or medical treatment available to the participant in the event of a trial-related injury
The planned incentives, if any, to attract the participant and the planned reimbursements, if any, for time, inconvenience, and expenses
The extent to which confidentiality of records identifying the participant will be maintained, the possibility of record access by the sponsor, the ethics committee (EC), or the South African Health Products Regulatory Authority (SAHPRA)
EC contact details for information and concerns regarding the trial participants’ rights
The sponsor’s identity
Potential conflicts of interest of the principal investigator (PI)
The consequences of a participant's decision to withdraw from the study
Information about approval from the EC and SAHPRA
The approximate number of participants in the research study, locally and globally
The expected duration of participation
An explanation of whom to contact in the event of research-related injury
Foreseeable circumstances under which the investigator(s) may remove the participant without consent
The participant and/or the legal representative(s) or guardian(s) will be notified if significant new findings developed during the study which may affect the participant's willingness to continue

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

6.3

2.3.6 and 3.3.6

1.2, 2.5, 5.9, and 6.2

5

Participant Rights

Last content review/update: June 16, 2023

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 the legal representative(s) or guardian(s) should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

Per CAN-35, participants should be assured that their participation is completely voluntary, they are under no obligation to participate, and they 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 the 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 the legal representative(s) or guardian(s) should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or the participant’s rights.

The Right to Safety and Welfare

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

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

Consent Process (Consent Form Template)

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)

Part C (Division 5 (C.05.001 and C.05.005))

Last content review/update: December 18, 2023

Overview

South Africa’s ethical standards promote respect for all human beings and safeguard the rights of research study participants. In accordance with the principles held forth in the Declaration of Helsinki (ZAF-44), the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, the G-GPHlthCare-IC, the NHAParticipants, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (ZAF-27), a participant’s rights must be clearly addressed in the informed consent form (ICF) and during the informed consent process. Below are the basic rights for participants in clinical research studies. (See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.)

The Right to Participate, Abstain, or Withdraw

According to the NHA and the NHAParticipants, everyone has the right to participate in any decision affecting their health or treatment, including research. The participant and/or the legal representative(s) or guardian(s) should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

According to the G-GPHlthCare-IC, a potential research study participant has the right to be fully informed on the nature and purpose of the research study, its anticipated duration, the sponsor and investigator(s), any potential benefits or risks, study procedures, any compensation for participation, injury and/or treatment, and any significant new information regarding the research study. (See the Required Elements section for a more detailed list.)

Per POAIA, a participant may seek access to their clinical trial records, pursuant to their constitutional right of access to any information held by the State or by another person.

The Right to Privacy and Confidentiality

Per the G-GPHlthCare-IC, participants have the right to privacy and confidentiality, and the ICF must provide a statement identifying this right. It is the responsibility of the investigator to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

Per the G-GPHlthCare-IC, the research participant and/or the legal representative(s) or guardian(s) should be provided with contact information for the investigator(s), and the ethics committee to address clinical trial-related queries, in the event of any injury and/or to appeal against a violation of the participant’s rights. It is also required that the South African Health Products Regulatory Authority (SAHPRA) address and contact information be provided. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Safety and Welfare

The SA-GCPs and ZAF-44 clearly state that research participants have the right to safety and well-being, which must take precedence over the interest of science and society. The NHA and the NHAParticipants safeguard the rights of all South Africans including vulnerable populations.

2-4, and 6

1-3

1.1, 2.3, and 3.1

2.4-2.5 and 4.3

2 and 5

Chapter 1 (2), Chapter 2 (8 and 11), and Chapter 9 (71)

Act, Preamble, and Chapter 2

Emergencies

Last content review/update: June 16, 2023

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 the 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 (REB) in Canada) must approve the protocol in advance. The participant and/or the 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 the 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 the 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)

Last content review/update: December 18, 2023

The NHA and the G-EthicsHR-ZAF make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies. As per the G-EthicsHR-ZAF, the ethics committee (EC) may approve a delay in obtaining informed consent for emergency medical research if:

Inclusion in the trial is not contrary to the interests of the patient

The research poses no more risk than is inherent to the participant’s condition, or would be caused by alternative treatments

The participant, the participant’s next of kin, and/or legal representative(s) or guardian(s) will be informed as soon as is reasonably possible of the participant’s inclusion in the study, and have the option to withdraw from the study at any time

The research is based on valid scientific hypotheses, and offers a realistic possibility of benefit over standard care

Per the G-CTAPHEmerg, the South African Health Products Regulatory Authority (SAHPRA) states that during a public health emergency, informed consent and the patient information sheet(s) remain essential documents that must be reviewed and approved by an EC and provided to the SAHPRA with the clinical trial application.

11.5-11.6 and Annex 1

3.1, 3.2, and 3.4

Chapter 2 (7, 8, and 9)

Vulnerable Populations

Last content review/update: June 16, 2023

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)

Last content review/update: December 18, 2023

Overview

The NHA, the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants require special considerations for vulnerable populations, and characterize them by limited education, limited economic resources, inadequate protection of human rights, discrimination due to health status, limited ability to provide informed consent, limited availability of health care and treatment options, or an inadequate understanding of scientific research. Vulnerable populations include children/minors, mentally and physically disabled, pregnant women, substance abusers, prisoners, armed forces, the homeless, the elderly, members of a group with a hierarchical structure, patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, nomads, refugees, and other vulnerable groups such as persons in dependent relationships.

The SA-GCPs state that ethics committees (ECs) must pay special attention to protecting participants from vulnerable populations. The ECs may impose additional measures such as imposing additional protective measures for the informed consent process or requiring increased monitoring and interim reporting on the participants’ welfare. As per the NHAParticipants, research with vulnerable participants must comply with the following requirements:

Involve vulnerable persons only when non-vulnerable persons are not appropriate for inclusion

Not systematically avoid inclusion of vulnerable participants because it is unfairly discriminatory, and would prevent this population from benefiting from relevant research

Be responsive to health needs and priorities of vulnerable persons, and

Provide special attention in the ethical review to ensure research-related risks are assessed and minimized, and appropriate consent procedures are followed

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

Persons in Dependent Relationships or Hierarchical Situations

As indicated in the SA-GCPs and the G-EthicsHR-ZAF, participants whose proposed involvement in research arises from dependent or hierarchical relationships need additional attention, and particular attention should be given to ensuring that their consent is both adequately informed and voluntary. In addition, per the NHAParticipants, research is appropriate when research-related risks of harm are minimized. These types of relationships include, but are not limited to, those who are in junior or subordinate positions in hierarchically structured groups, such as prisoners and prison authorities, older persons and their caregivers, and patients and healthcare professionals.

Persons Highly Dependent on Medical Care

Per G-EthicsHR-ZAF, participants who are highly dependent on medical care may have a limited capacity to provide informed consent due to the gravity of their medical condition. In addition, their medical condition may require invasive measures resulting in greater risk. There may also be a perception of coercion if a participant is reluctant to refuse consent for fear that it may compromise the medical treatment. The EC may approve a delay in obtaining informed consent for research participants highly dependent on medical care if the following conditions are met:

Research is based on valid scientific hypotheses that support a reasonable possibility of more benefit than that offered by standard care
Participation is not contrary to their medical interests
Research interventions pose no more risk of harm than that inherent in the participant’s condition or alternative methods of treatment
As soon as reasonably possible, the participant must be informed and give delayed consent and advised of the right to withdraw from the research without any reduction in quality of care

Persons with Physical Disabilities

As described in the G-EthicsHR-ZAF, recruitment strategies for research participation in general should be sensitive to the possibility that persons with physical disabilities may wish to volunteer and therefore should ensure that there are no unintended barriers to such participation (e.g., the absence of ramps or a lift for wheelchair-bound potential participants). Research involving participants with physical disabilities should anticipate possible barriers and include measures to minimize them.

Elderly Persons

As per the G-GPHlthCare, research involving elderly persons requires consent to be provided by the participant’s legal representative(s) or guardian(s) on that person's behalf. Because of their vulnerability, the elderly should not be included in research unless the research is necessary to promote the health of this population and unless this research cannot instead be performed on legally competent persons.

Research Involving Collectivities

Per the G-EthicsHR-ZAF, a collectivity is a distinct group characterized by common beliefs, values, social structures, and other features identifying them as a separate group. Investigators are required to obtain EC approval for research involving a collectivity when any of the following conditions apply:

Property or information private to the group as a whole is studied or used

Research requires the permission of people occupying positions of authority, or involves members acknowledged as representatives to participate

1, 2.4.6, 3.1, 4.1.2, 4.1.3, and 6.3

1.3, 2.3, 3.1, 3.2, 3.4, and 4.5

1.2, 3.1, 3.4, 6.2, and 12

1 and 4

Chapter 1 (2(c)(iv)), Chapter 2 (7, 8, and 11), and Chapter 9 (70(2)(d) and 71)

Children/Minors

Last content review/update: June 16, 2023

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

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

Guidelines III and IV

Consent Process (Key Considerations)

4.8

1

Chapter 3 (Article 3.10) and Chapter 4 (Article 4.4)

Last content review/update: December 18, 2023

The SA-GCPs stipulate that minors are younger than 18 years old and are regarded as vulnerable persons due to their lack of legal capacity. The G-GPHlthCare-IC states that a person over the age of 18 years is an adult and is legally competent to decide on all forms of treatment and medical procedures. However, a child who is 12 years of age and older is legally competent to consent to a proposed investigation if the child is of sufficient maturity and is able to understand the benefits, risks, social, and other implications of the research. A minor's/child’s refusal to participate in research must be respected.

Per the SA-GCPs, documented permission from the legal representative(s) or guardian(s) must be obtained in advance prior to approaching the minor to request participation. According to the NHA, the G-EthicsHR-ZAF, the SA-GCPs, the G-GPHlthCare, and the G-GPHlthCare-IC, consent for minors/children to participate in research must be obtained from:

The legal representative(s) or guardian(s) in all but exceptional circumstances (such as emergencies)

The minor/child who is competent to make the decision

Any organization or person required by law (defined in the NHA)

Where the minor/child is not competent, assent from the minor/child and consent from the legal representative(s) and/or guardian(s)

According to the NHA, where research or experimentation is to be conducted on a minor for therapeutic purposes, the study may only be conducted when:

It is in the best interests of the minor/child

It is carried out in such manner and on such conditions as may be prescribed

The consent of the minor’s parent or guardian is provided

Where research or experimentation is to be conducted on a minor for non-therapeutic purposes, the NHA, the NHAParticipants, the SA-GCPs, and the G-MinisterConsent state that a study may only be conducted when:

It is carried out in such manner and on such conditions as may be prescribed

The consent of the Minister of Health is provided, or, where appropriate, consent from a delegated authority

The consent of the minor’s parent or guardian is provided

The consent of the minor is provided when the minor is capable of understanding

See the NHAParticipants for detailed application requirements.

In addition, per the G-MinisterConsent, the Minister of Health may not give consent if any of the following circumstances apply:

The study objective(s) can also be achieved if conducted on an adult

The research is unlikely to significantly improve scientific understanding of the minor’s/child's condition, disease, or disorder to such an extent that it will result in significant benefit to the minor(s)/child(ren)

The reasons for the consent to the research by the parent or guardian and, if applicable, the minor/child, are contrary to public policy

The research poses a significant risk to the health of the minor

The risk to the health or well-being of the minor is not significantly outweighed by the potential benefit

For more information on ministerial consent for non-therapeutic health research with minors, see the operational guidelines at the G-MinisterConsent.

As delineated in the G-EthicsHR-ZAF and the NHAParticipants, the following additional criteria must be met to conduct clinical trials with minors/children:

The research study presents minimal risk

The research study presents more than minimal risk, but potentially direct or anticipated benefit for the participant outweighs the risk

The research presents more than minimal risk (minor increase), and may not have a direct benefit to the participant, but has a high probability of producing important and relevant information, and that benefit may outweigh the risk

Adults are not appropriate participants for the research

In all cases, there should be sufficient reasons to justify why minors/children should be included as participants.

Assent Requirements

The SA-GCPs and the G-EthicsHR-ZAF require the ethics committee (EC) to ensure that adequate steps outlined in the clinical protocol are used to obtain a minor’s assent when, in the EC’s judgment, the minor is capable of providing such assent. When the EC determines that assent is required, it must also indicate whether and how such assent should be documented. A minor’s/child’s assent should not be assumed simply because of failure to object during the informed consent process. It is necessary for the minor/child and the legal representative(s) or guardian(s) to be in agreement on participation. The minor’s/child’s refusal to participate is final.

Consent for Processing Personal Data

Per the POPIA, there is a general prohibition on the processing of personal information of children. However, a responsible party may process personal information concerning a child for research purposes to the extent that:

The purpose serves a public interest, and the processing is necessary for the purpose; or
It appears to be impossible or would involve a disproportionate effort to ask for consent, and sufficient guarantees are provided to ensure that the processing does not adversely affect the individual privacy of the child to a disproportionate extent.

5, 6.3, and 8.5

8.5

1-6 and Appendices 1-3

3.2

1.2, 2.5, 3.2, and 6.2

4 and 7

Chapter 9 (71)

Chapter 3 (35)

Pregnant Women, Fetuses & Neonates

Last content review/update: June 16, 2023

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

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

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

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

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

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

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

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

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) and Chapter 12 (Articles 12.6-12.9)

Last content review/update: December 18, 2023

As per the NHA and the G-EthicsHR-ZAF, any research studies involving pregnant women, women who may become pregnant, or fetuses, require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. The ethics committee (EC) must provide particular attention to these participants due to the potential for additional health concerns that may arise during pregnancy, and the need to avoid unnecessary risk to the fetus.

The SA-GCPs stipulates that pregnant women, women planning to become pregnant, or breastfeeding women are usually excluded from human clinical trials where a new chemical entity (NCE) or medicines with no information on safety in pregnancy/lactation are investigated for treatment of a particular disease/condition or disorder. However, when safety and other relevant information is available, pregnant or breastfeeding women should be included in clinical trials to ensure that appropriate knowledge about NCEs for this group is developed.

3.2

1.2, 6.2, and 10.7

Chapter 1 (2(c)(iv)), Chapter 2 (7, 8, and 11), Chapter 9 (70(2)(d) and 71), and Chapter 11 (90(1)(s) and 90(2))

Prisoners

Last content review/update: June 16, 2023

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)

Last content review/update: December 18, 2023

According to the NHA, the G-EthicsHR-ZAF, and the NHAParticipants, a prisoner may not, even with consent, participate in any scientific experimentation, research study, or clinical trial except under limited conditions. Per the G-EthicsHR-ZAF, prisoners are considered a vulnerable class of persons because of the potential effect of incarceration on the voluntariness of the decision to participate in research. Neither coercion nor undue influence is acceptable in the informed consent process. Researchers should pay attention to whether their intended participants are prisoners who are awaiting trial or are convicted as different ethical issues arise for each group. The recruitment strategy design must pay careful attention to how coercion and undue influence will be avoided. Similarly, persons administering questionnaires or conducting interviews must be conscious of environmental factors that may influence voluntariness. The ethics committee (EC) should include, at least on an ad-hoc basis, a member with experience and knowledge of working with prisoners when deliberating on the protocol.

Per the G-EthicsHR-ZAF, research should be conducted on prisoners only if:

Their participation is indispensable to the research
The research cannot be conducted with non-prisoners
The research concerns a problem of relevance to prisoners
Sound informed consent processes can be ensured
Engagement with relevant role players about the proposed research has occurred

Generally, it is unlikely that independent consent by minor prisoners will be justifiable.

3.2

4

Chapter 2 (7, 8, and 11) and Chapter 9 (71)

Mentally Impaired

Last content review/update: June 16, 2023

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).

Per CAN-35, 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

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.

Consent Process (Key Considerations)

1.61 and 3.1

Chapter 3 (Article 3.7-3.10)

Last content review/update: December 18, 2023

According to the NHA, the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants, sufficient justification must be provided for any research or treatment involving a participant who has a mental or intellectual impairment or substance abuse related disorder, and the research must be relevant to the mental disability or substance abuse disorder.

Per the G-EthicsHR-ZAF, research involving these populations must conform to the following requirements:

The research, including observational research, is not contrary to the best interest of the participant
The research, including observational research, places the incapacitated adult at no more than minimal risk
The research involves greater than minimal risk but provides the prospect of direct benefit for the incapacitated adult; the degree of risk must be justified by the potential benefit
The research, including observational research, involves greater than minimal risk, with no prospect of direct benefit to the incapacitated adult, but has a high probability of providing generalizable knowledge
The legally appropriate person gives permission for the person to participate
Where appropriate, the person will assent to participation (Note that the incapacitated person’s refusal or resistance to participate, as indicated by words or behavior, takes precedence over permission by a proxy)

The G-EthicsHR-ZAF and the G-GPHlthCare state that research involving unconscious persons requires consent to be provided by the participant’s legal representative(s) or guardian(s) on that person's behalf. Unconscious persons should not be included in research unless the research is necessary to promote the health of the population represented and unless this research cannot instead be performed on legally competent persons.

4 and 6.3

2.3 and 3.2

1.2, 3.3, and 6.2

4

Chapter 2 (7, 8, and 11), and Chapter 9 (71)

Definition of Investigational Product

Last content review/update: June 16, 2023

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.

3.0

1.33

5.1

Part C (Division 5 (C.05.001))

Last content review/update: December 18, 2023

As delineated in the SA-GCPs and the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs), 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. This includes:

A product with a marketing authorization when used or assembled (formulated or packaged) in a different way from the approved form

When used for an unapproved indication

When used to gain further information about an approved use

2

Annex 13

1.2, 6.2, and 12

Manufacturing & Import

Last content review/update: June 16, 2023

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

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).

The G-CanadaCTApps, the G-HlthProdImprtExptReqs, the G-FDR-0100, and CAN-32 state that if a sponsor wants to import a drug into Canada for a clinical trial, a copy of HC’s authorization (i.e., the No Objection Letter (NOL)) issued by either the Pharmaceutical Drugs Directorate (PDD) or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) must be included for the applicable trial with the shipment. A copy of this authorization must be provided at the port of entry. The G-HlthProdImprtExptReqs states that drugs without a Drug Identification Number may be imported where authorized for a Canadian clinical trial and a NOL was issued. The G-FDR-0100 further states that if 30 days have passed and the NOL was not issued, specific requests to import IPs should be directed to the Health Product Border Compliance Program at the following email account: 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 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 interpretations of the relevant provisions of the CanadaFDR.

Appendix 1

Drug Importation

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

Part C (Divisions 2-5)

Last content review/update: December 18, 2023

Manufacturing

According to the SA-GMPs and the GRMRSA, the South African Health Products Regulatory Authority (SAHPRA) is responsible for authorizing the manufacture of investigational products (IPs) in South Africa. As delineated in the G-ManuImpExp, a manufacturer’s license for IPs is required for both total and partial manufacture, and for the various processes of dividing up, packaging, or presentation, in accordance with the MRSA. To obtain a license, the application form (ZAF-55) should be emailed to SAHPRA at gmplicensing@sahpra.org.za, accompanied by the following information:

Proof of payment
Existing SAHPRA license for renewal and amendment applications
Cover letter
Site Master File
Signed declaration
SAHPRA inspection resolution
Intellectual property documentation
Department of Health premises license
Registration of responsible pharmacist
South African Pharmacy Council (SAPC) Record of a Pharmacy
SAPC Record of a Pharmacy Owner
Municipal Approval/Zoning Certificate

Per ZAF-55, the license is valid for five (5) years and the application to renew the license must be submitted at least 180 days before the expiration of the current license.

In addition, per ZAF-23, a clinical trial application to SAHPRA must include a certificate of good manufacturing practice (GMP) for manufacture of the IP(s). The SA-GCPs also states that the sponsor must ensure that the IP (including active comparator and placebo, if applicable) is manufactured in accordance with applicable GMP standards.

Pursuant to the SA-GMPs, South Africa adopted the PIC-S-GMP-Guide for the manufacturing of therapeutic goods. The PIC-S-GMP-Guide includes requirements for a Certificate of Analysis to be issued by the manufacturer for all IPs to be used in a clinical trial. For GMP agreements with competent international regulatory authorities, the SA-GMPs states that these agreements do not permit automatic acceptance but may be used to enhance regulatory oversight and compliance. SAHPRA may request additional documentation and/or schedule an inspection to ensure GMP compliance. The following conditions demonstrate GMP compliance:

The site has been approved by a recognized regulatory authority (RA) within the previous three (3) years
The dosage form of the IP within the application is within the same dosage form grouping as the dosage form approved by the RA
The product type applied for is the same as the product type approved by the recognized RA
The activities applied for by the applicant are the same activities that have been approved by the recognized regulator

Import

The SA-GCPs states that IPs may be imported into South Africa only after approval of the protocol by SAHPRA. Samples of the IP to be imported before trial approval require a SAHPRA license under MRSA. The sponsor must ensure that the IP (including active comparator and placebo, if applicable) is manufactured in accordance with any applicable GMP standards. Per G-ManuImpExp to import an IP, the applicant must submit an application form (ZAF-55) to SAHPRA.

Per the G-ImprtPorts, SAHPRA’s Regulatory Compliance Unit is responsible for ensuring that health products at ports of entry meet importation requirements under MRSA, including for IPs. Imported IPs must be accompanied by the certificate of registration that proves authorization under the MRSA.

Please note: South Africa is party to the Nagoya Protocol on Access and Benefit-sharing (ZAF-8), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see ZAF-34.

1.1 and 3.1.2, and Appendices 1-2

3

Annex 13

1.2, 5.7, 6.2, and 6.6

21 and 22C

23

Quality Requirements

Last content review/update: June 16, 2023

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.

Quality Management

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-CAN, and G-GMP-Annex13, the sponsor must ensure that the products are manufactured in accordance with Good Manufacturing Practices (GMPs). The G-GMP-CAN 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.

4

2.12, 5.13, 7.3, and 8.2

4

2.8

5.1, 5.5, and 5.12

Part C (Division 5 (C.05.001, C.05.005, and C.05.012))

Last content review/update: December 18, 2023

Investigator’s Brochure

In accordance with the SA-GCPs, the sponsor is responsible for ensuring an up-to-date Investigator’s Brochure (IB) is available to the investigator; investigators must provide it to the responsible ethics committee (EC). In the case of an investigator-sponsored trial, the sponsor-investigator must determine whether an IB is available from the commercial manufacturer.

The SA-GCPs states that the IB should contain the following sections, each with literature references where appropriate:

Table of Contents
Summary: A brief summary (preferably not exceeding two (2) pages) to highlight the significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information available that is relevant to the stage of clinical development of the investigational product (IP)
A brief introductory statement with the chemical name (and generic and trade name for an approved product) of the IP, all active ingredients in the IP, its pharmacological class and expected position within this class (e.g., advantages), the rationale for conducting research with the IP, and the anticipated prophylactic, therapeutic, and/or diagnostic indications. Also include a description of the general approach to be followed in evaluating the IP.
Physical, chemical, and pharmaceutical properties and formulation parameters
Pre-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and postmarketing experiences)
Summary of data and guidance for the investigator(s)

Quality Management

As defined in the SA-GCPs, the sponsor must ensure that IPs are manufactured in accordance with good manufacturing practices (GMPs), including the requirements in Annex 13 of the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). (See Product Management section for additional information on IP supply, storage, and handling requirements). As indicated in ZAF-23, the following information must be furnished in the clinical trial application:

Whether the IP contains an active substance of chemical origin or of biological/biotechnological origin
IP name(s) and details (e.g., formulation(s) and strength(s))
Properties of the IP (e.g., mechanism of action)
Summary of pre-clinical findings (e.g., laboratory, animal, toxicity, or mutagenicity)
Summary of clinical findings
Comparator product(s) name(s) and details
Concomitant name(s) and details including rescue medications
Registration status of IP, concomitant, and/or comparator medicine(s); include the IB, South African Health Products Regulatory Authority (SAHPRA)-approved principal investigator (PI), and other international professional information (package inserts) if not approved in South Africa, and a Certificate of Analysis (CoA)
Whether the IP is modified in relation to its original registration for the purpose of the clinical trial
Estimated quantity of trial material (each drug detailed separately) for which exemption will be required, including for concomitant medicines to be imported
Explanation for use of imported drugs when the same product is available in South Africa
Details of receiving the drugs from supplier including storage, dispensing, and packaging of drugs
Details of intention to register the IP or explain if registration is not envisioned
Details of the manufacture, quality control, and stability of the IP (including IP destruction process) and include certificate of good manufacturing practice (GMP)
Previous studies using this medicine that have been approved by SAHPRA, including the SAHPRA approval number, study title, protocol number, date of approval, national PI/PI, date(s) of progress report(s), and date of final report

See ZAF-23 for detailed instructions on IP submission requirements.

Per the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs), the release of IPs should not occur until after the authorized person has certified that the relevant requirements have been met. CoAs should be issued for each batch of intermediate or active pharmaceutical ingredient, on request. CoAs should be dated and signed by authorized personnel of the quality unit(s) and should show the name, address, and telephone number of the original manufacturer. See the PIC-S-GMP-Guide for certification requirements.

2

Part II (11.4) and Annex 13

1.2, 5.7, 6.2, 6.5, 6.7, and 8

Labeling

Last content review/update: June 16, 2023

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.

In addition, the CA-ICH-GCPs state that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

8.7

5.13

2.8.7

5.11

Part C (Divisions 2 (C.02.006, C.02.011, C.02.015-016) and 5 (C.05.011))

Last content review/update: December 18, 2023

Investigational product (IP) labeling in South Africa must comply with the requirements set forth in the SA-GCPs, the GRMRSA, MRSA, and the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). The GRMRSA states that for an IP to be used in a clinical trial, it must be properly labeled in English and at least one (1) other official language, and should appear in clearly legible and indelible letters. As set forth in the PIC-S-GMP-Guide, the following labeling information must be included on both the outer packaging and the immediate container:

The name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator

The pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/potency

The batch and/or code number to identify the contents and packaging operation

A trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)

The trial participant identification number/treatment number and where relevant, the visit number

The investigator name (if not already included above)

Directions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)

“For clinical trial use only” or similar wording

The storage conditions

The period of use (use-by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity

“Keep out of reach of children” except when the product is for use in trials where the product is not taken home by the participant

In addition, precautions against mislabeling should be intensified by trained staff (e.g., label reconciliation, line clearance, and in-process control checks by appropriately trained staff).

The SA-GCPs specify that in blinded trials, the IP should be coded and labeled in a manner that protects the blinding. The IP(s) coding system should include a mechanism that permits rapid IP(s) identification in case of a medical emergency but does not permit undetectable breaks of the blinding.

2

Annex 13

1.2 and 6.6

35

10 and 30 (9)

Product Management

Last content review/update: June 16, 2023

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 investigational products (IP(s)), including the comparator and placebo, if applicable. The sponsor should not supply the IP(s) until approvals from Health Canada (HC) and the institutional ethics committee (EC) are obtained. 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

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 packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage. Refer to the CA-ICH-GCPs for detailed sponsor-related IP requirements.

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.

8.6

5.5, 5.12, 5.13, 5.14, and 7

5.1, 5.5, 5.10, and 5.12

Part C (Division 5 (C.05.001, C.05.005, C.05.010, and C.05.012))

Regulatory Impact Analysis Statement

Last content review/update: December 18, 2023

Supply, Storage, and Handling Requirements

As defined in the SA-GCPs, the sponsor is responsible for supplying a sufficient quantity of the investigational product (IP) after the sponsor obtains study approvals from the South African Health Products Regulatory Authority (SAHPRA) and the ethics committee (EC). The sponsor must ensure that written procedures include instructions and relevant documents for the investigator to follow for handling and storage of the IP for the trial. The procedures must address adequate and safe receipt, handling, storage, dispensing, retrieval of unused product from participants, and return of unused IP to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the SAHPRA-approved protocol). In addition, the sponsor must:

Ensure timely delivery of the IP to the investigator
Maintain records that document shipment, receipt, disposition, return, and destruction of the IP
Maintain a system for retrieving the IP and then documenting such retrieval (e.g., for deficient product recall, reclaim after trial completion, and expired product reclaim)
Maintain a system for disposal of unused IP and for its documentation
Take steps to ensure that the IP is stable over the period of use
Maintain sufficient quantities of the IP used in the trials to reconfirm specifications, if necessary, and maintain records of batch sample analyses and characteristics; to the extent that IP stability permits, samples should be retained until analyses of trial data are complete or as required by the applicable regulatory requirement(s), whichever is longer
Provide and maintain a system for retrieving and disposing of trial-related waste (e.g., syringes and needles)

Per the SA-GCPs, the sponsor should determine acceptable temperatures, conditions, times for IP storage, reconstitution fluids/procedures, and devices for product infusion, if any, that comply with the SA-GPPs. The sponsor must inform all parties involved (e.g., monitors, investigators, pharmacists, storage managers) of these determinations.

The SA-GCPs specify that if significant formulation changes are made in the IP(s) or comparator product(s) during the course of clinical development, the results of any studies of the newly formulated product(s) should be made available prior to its use in the clinical trial. Refer to the SA-GCPs for detailed sponsor-related IP requirements.

Regarding packaging, the PIC-S-GMP-Guide indicates that IPs are normally packed individually for each participant in the clinical trial. The number of units to be packaged should be specified prior to the start of the packaging operations, including units necessary for carrying out quality control and any retention samples to be kept. Sufficient reconciliations should take place to ensure the correct quantity of each product required has been accounted for at each stage of processing. During packaging, the risk of product mix up must be minimized by using appropriate procedures and/or, specialized equipment as appropriate and relevant staff training. 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. Similarly, the SA-GCPs state that the IPs must be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Record Requirements

Per the SA-GCPs, the sponsor, or other data owners, must retain all essential documents pertaining to the trial for not less than 10 years or until at least two (2) years have elapsed since the formal discontinuation of clinical development of the IP. In addition, the sponsor should obtain the investigator’s agreement to retain trial-related essential documents until the sponsor informs the investigator/institution that these documents are no longer needed.

Annex 13

1.2, 5.7, 6.2, 6.6-6.7, and 8.1-8.2

Definition of Specimen

Last content review/update: June 16, 2023

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).

Glossary

Chapter 12 and Glossary

Last content review/update: December 18, 2023

In South Africa, the NHARegMicroLabs refers to a specimen as a “diagnostic specimen,” and defines it as any human or animal material, including excreta, secreta, blood and its components, tissue or tissue fluids, that is to be used for the purpose of diagnosis, but does not include live infected animals. The G-EthicsHR-ZAF, in turn, refers to a specimen as a “biological specimen,” and defines it as material from a person including blood and blood products, DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies, and growth factors.

The term “specimen” appears to be used interchangeably with “biological material” in South Africa. The NHABiol and the MTA-Human follow the G-EthicsHR-ZAF definition of biological specimen, defining “biological material” as material from a human being including DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies, and growth factors from the same. The G-EthicsHR-ZAF defines “human biological materials” with the same definition as is used for “biological specimen.”

In addition, the NHABloodCells generally refers to substances of human origin as biological substances.

Please refer to the G-EthicsHR-ZAF, the NHABiol, the NHA, the NHABloodCells, the NHATissue, and the NHAStemCell for more specific definitions of selected terms including blood, cultured cells, embryonic tissue, human tissue, plasma, stem cell, and genetic material.

Chapter 3 (3.3) and Appendix 1

1

2.9

1

Specimen Import & Export

Last content review/update: June 16, 2023

Import/Export

According to the G-HlthProdImprtExptReqs, Health Canada (HC) does not have jurisdiction over human biological materials to be imported for testing or research purposes. The G-HlthProdImprtExptReqs further states that all blood samples as well as cultures, diagnostic specimens, or research tissue 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.

As specified in the HPTA, the HPTR, and CAN-2, individuals planning to conduct controlled activities (including producing, possessing, handling, using, storing, providing access to, transferring, disposing of, releasing, abandoning, or importing/exporting) with a human pathogen or toxin, whether imported or domestically acquired, must obtain a license. Per CAN-2, because all human biological materials are potential carriers of human pathogens, the PHAC has categorized these materials by risk group based on risk to the individual/animal and risk to the community. Risk Group 1 consists of microorganisms, nucleic acids, or proteins that are unable or unlikely to cause human or animal disease so they are generally not considered to be pathogens, and are therefore exempt from the HPTA and the HPTR licensing requirements. Risk groups 2 through 4 are considered to be pathogens or toxins with moderate to high individual risk and low to high community risk, and are subject to the HPTA and the HPTR licensing requirements. See CAN-2 and CAN-9 for detailed information and instructions on how to obtain a license for activities associated with Risk Groups 2 through 4.

Chapter 21

Chapters 1 and 2

Blood and blood components for transfusion

Purpose of the Act, Interpretation and Application, Obligation, Prohibitions, and Licenses

Licenses

Last content review/update: December 18, 2023

Import/Export

Per the NHA, the MTA-Human, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, a permit must also be obtained from the National Department of Health (NDOH) Director General to import or export biological substances. Both the South African Health Products Regulatory Authority (SAHPRA) approval letter and the NDOH import/export permit must be included with each biological substance shipment. See also the Submission Content section for information on completing a clinical trial application.

As set forth in the NHA, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, the NDOH Director-General, as delegated by the NDOH Minister, is responsible for establishing regulations related to the import and export of biological substances. In addition, only the Minister can authorize an institution or hospital to import or export biological substances for research purposes.

In accordance with the NHA, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, the NDOH Director-General reviews and approves all import or export requests by an institution or hospital. These requests must be submitted in writing using the application forms that may be obtained by contacting the NDOH Permit Programme at importexportpermit@health.gov.za. The forms also appear as Annexures 1-6 in the NHABloodCells and Form 1 in the NHARegMicroLabs.

Upon review of the application, the Director-General will issue a permit or certificate authorizing the import or export request if the Director-General is satisfied that the submission meets the NHA, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell requirements, as applicable. The permit will contain an expiration date for the approved biological substance(s).

General Import/Export Requirements for Biological Substances

The NHABloodCells states that each biological substance to be imported into South Africa must be accompanied by a certificate from the supplier stating that the substance has been exported in terms of the originating country’s applicable laws and regulations.

As per the NHABloodCells and ZAF-7, export permits for biological substances may only be issued by the Director-General to a Southern African Development Community (SADC) member state or to a South African citizen, provided that the country’s market requirements have been met. An applicant must also be registered with the Health Professions Council of South Africa (HPCSA) and operating in South Africa in order to apply for a permit to import or export biological substances. The applicant must also provide the Director-General with written information on stock levels for this substance along with the export application.

Applicants to whom a permit has been issued must keep a record of the import or export and submit this information using the register forms listed in Annexures 4, 5, and 6 of the NHABloodCells. The forms must be submitted to the Director-General annually before the end of February, for the preceding calendar year.

Import/Export Requirements for Specific Biological Substance Categories

The NHABloodCells provides details on unique application requirements for specific types of biological substances as outlined below:

Import of tissues being used for therapeutic purposes: application must be accompanied by donor health status
Export of tissues or gametes: application must include written proof that the donated biological substance complies with the NHA requirements
Import or export of placenta tissue, embryonic or fetal tissue, embryonic, fetal or umbilical stem cells: applications will only be approved with the Minister’s written consent
Import or export of blood or blood products: applications must be accompanied by a national blood transfusion service certificate and test results. If no documentation is included, the applicant must submit a letter to the Director-General explaining the reason. The Director-General will decide whether tests must be conducted, and the Minister is authorized to determine whether the applicant’s institution can be exempted from these requirements.

Material Transfer Agreement

Per the MTA-Human, all the providers and recipients of human biological material for use in research or clinical trials under the auspices of ethics committees (ECs) must use the “Material Transfer Agreement of Human Biological Materials” in MTA-Human. The agreement must be signed by the research institution’s authorized representative and the EC. The EC’s obligations are to:

Review and approve research proposals and protocols that require the transfer of human biological materials
Review and approve the material transfer agreement and ensure it adequately safeguards human biological material and ethical requirements
Review and approve all secondary use research if the material is to be transferred

The EC must be the last party to sign the agreement after all the provisions of MTA-Human have been satisfied.

2-13 and Forms 1 and 2

Chapter 8 (54, 57, 60, and 68)

2-5, 7, and Annexures 1-6

Cover page, 3, 4.1, and Annexure A

1 and 2

1, 3, and 16

Consent for Specimen