Clinical Research Regulation For South Africa
Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Authorizing Body
Clinical Trial Lifecycle
Submission Process
Submission Content
Timeline of Review
Trial Initiation
Safety Reporting
Progress Reporting
Sponsorship
Definition of Sponsor
Trial Authorization
Insurance
Compensation
Quality, Data & Records Management
Site/Investigator Selection
Informed Consent
Documentation Requirements
Required Elements
Compensation Disclosure
Participant Rights
Special Circumstances/Emergencies
Vulnerable Populations
Children/Minors
Pregnant Women, Fetuses & Neonates
Prisoners
Mentally Impaired
Investigational Products
Definition of Investigational Product
Manufacturing & Import
IMP/IND Quality Requirements
Labeling & Packaging
Product Management
Specimens
Definition of Specimen
Specimen Import & Export
QUICK FACTS
Clinical trial application language English
Regulatory authority & ethics committee review may be conducted at the same time Yes
Clinical trial registration required Yes
In-country sponsor presence/representation required No
Age of minors Under 18
Specimens export allowed Yes
Regulatory Authority > Regulatory Authority
Last content review/update: July 23, 2020
Requirements
(1) (Legislation) Medicines and Related Substances Act (Act No. 101 of 1965) (MRSA) (Amended 2015)
Parliament
Relevant Sections: 1, 2, 3, and 35
(2) (Proclamation) Proclamation No. 20 of 2017 (Proc20of2017) (May 22, 2017)
President
(3) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: 30
(4) (Guidance) Electronic Submission of Clinical Trial Documents (G-CTA-Electronic) (April 2019)
South African Health Products Regulatory Authority
Summary

Overview

As stated in the MRSA, Proc20of2017, and Additional Resource (A), the South African Health Products Regulatory Authority (SAHPRA) (formerly the Medicines Control Council (MCC)) is the regulatory authority overseeing medicines and clinical research, as well as medical devices and radiation safety. Per Additional Resource (B), SAHPRA assumed the roles of the MCC and the Directorate of Radiation Control (DRC), which were housed at the National Department of Health (NDOH). As stated in the MRSA, GRMRSA, and Additional Resource (C), SAHPRA is responsible for clinical trial oversight, approval, and inspections in South Africa. It grants permission for clinical trials to be conducted in South Africa in accordance with the provisions of the GRMRSA.

Per the MRSA and Additional Resource (B), the SAHPRA is an independent, state-owned entity established to oversee the regulation of medicines in South Africa. According to Additional Resources (B), this agency is responsible for ensuring that all clinical trials of both non-registered medicines and new indications of registered medicines comply with the essential requirements for safety, quality, and efficacy.

Per the MRSA and as described in Additional Resource (D), SAHPRA is a state-owned entity within the public administration but outside the public service. It acts through a Board appointed by South Africa’s Minister of NDOH. For details on the Board appointments, see Additional Resources (B) and (E). As delineated in the MRSA, the CEO will be appointed for a term of five (5) years and may be reappointed for one (1) additional term. Reporting to the Board, the CEO will appoint and supervise staff and determine the structure and policies for SAHPRA. When fully established, SAHPRA will conduct the monitoring, evaluation, regulation, investigation, inspection, registration, and control of clinical trials. Among other functions, SAHPRA will ensure that clinical trial protocols are being assessed according to prescribed ethical and professional criteria and standards.

As described in Additional Resource (C), SAHPRA is reorganizing into a program structure that comprises:

  • Corporate Services Program
  • Health Product Authorization Program
  • Inspectorate and Regulatory Compliance Program
  • Evaluation for Registration Program
  • Medical Devices and Radiation Control

Additional Resource (C) describes the Health Product Authorization Program as the core of SAHPRA’s regulatory functions. Sponsors (also referred to as applicants) will interact with portfolio coordinators, whose roles will be to steer applications through the prescribed processes. Per Additional Resource (F), SAHPRA’s Clinical Trials Committee (CTC) will continue to provide scientific expertise and support. Additional Resource (H) states that CTC operates within SAHPRA’s Clinical Trial Unit, 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 medicine for the purpose of conducting clinical trials.

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

South African Health Products Regulatory Authority Contact Information:

Postal Address:
South African Health Products Regulatory Authority
Private Bag X828
Pretoria
0001
South Africa

Physical Address:
CSIR
Reception Building 38a
Meiring Naudé Road
Brummeria
Pretoria
South Africa

Clinical Trial Unit Emails

As provided in the G-CTA-Electronic and Additional Resource (H), the following are the SAHPRA Clinical Trial Unit emails.

New Clinical Trial Applications (CTA) and Responses to Reviews of CTAs: ctcresponses@sahpra.org.za

Protocol Amendments during Conduct of Clinical Trials: ctcamendments@sahpra.org.za

Additional Investigators and Sites during Conduct of Clinical Trials: ctcinvestigators@sahpra.org.za

Bioequivalence Studies: ctcbeprotocols@sahpra.org.za

Notifications and Notification Studies: ctcnotifications@sahpra.org.za

Individual Serious Adverse Events: ctcsaes@sahpra.org.za

Clinical Evaluation – Pre-Registration Contact:
Tohlang Sehloho
Phone: 012 842 7589
082 302 0222

Clinical Evaluation – Post-Registration Contact:
Linda Thomson
Phone: 079 914 2033

Clinical Trials Contact:
Dorah Diale
Phone: 012 842 7606
060 548 4332

eCTD: ectd@mccza.com

Pharmacovigilance Contact:
Florah Matlala
Phone: 012 842 7610
083 387 3358

For General Enquiries:
enquiries@sahpra.org.za (For general, non-product specific enquiries only.)

Additional Resources
South African Health Products Regulatory Authority
Relevant Sections: 4
(B) (Website) Who We Are (Current as of March 20, 2020)
South African Health Products Regulatory Authority
(C) (Document) Who or What is SAHPRA? (May 8, 2019)
Talent 360
Neil Kirby, TimesLIVE
(E) (Website) The SAHPRA Board (Current as of March 20, 2020)
South African Health Products Regulatory Authority
(F) (Article) The South African Regulatory System (December 4, 2018)
Keyter, Andrea; Banoo, Shabir; Salek, Sam; and Walker, Stuart; Frontiers in Pharmacology
Relevant Sections: The South African Health Products Regulatory Authority and Figure 3
South African Health Products Regulatory Authority
(H) (Website) Clinical Trials (Current as of March 17, 2020)
South African Health Products Regulatory Authority
Convention on Biological Diversity, United Nations
(J) (Website) Country Profile: South Africa (Current as of July 17, 2020)
Access and Benefit-sharing Clearing-house, Convention on Biological Diversity, United Nations
Regulatory Authority > Scope of Assessment
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) Medicines and Related Substances Act (Act No. 101 of 1965) (MRSA) (Amended 2015)
Parliament
Relevant Sections: 1, 2, 3, and 35
(2) (Proclamation) Proclamation No. 20 of 2017 (Proc20of2017) (May 22, 2017)
President
(3) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: Part 30 (1)
(4) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.5.1, Appendices D and F
(5) (Guidance) Clinical Guideline (G-Clin) (Version 2) (July 2019)
Registrar of Medicines, South African Health Products Regulatory Authority
Relevant Sections: 3
(6) (Guidance) General Information (G-GenInfo) (Version 10) (July 2019)
Registrar of Medicines, South African Health Products Regulatory Authority
Relevant Sections: 13.5
(7) (Guidance) Capacity Building and Transformation in Clinical Research in South Africa (G-Capacity) (July 2019)
South African Health Products Regulatory Authority
(8) (Guidance) Procedure for Consultation Meetings with Clinical Trial Applicants (G-ConsultMtg) (November 2019)
South African Health Products Regulatory Authority
Summary

Overview

As stated in the MRSA, Proc20of2017, and Additional Resources (A) and (B), the South African Health Products Regulatory Authority (SAHPRA) is the regulatory authority overseeing medicines and clinical research, as well as medical devices and radiation safety. In accordance with the GRMRSA, the SA-GCPs, and the G-Clin, the 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.

Additional Resource (A) 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. Any amendments required during the conduct of the study must be approved by SAHPRA. As per G-GenInfo, the CTU is specifically charged with evaluating the following:

  • Clinical trial applications and clinical trial amendments
  • Adverse event reports arising from a clinical trial
  • Applications for named patient use (compassionate use) of unregistered medicines
  • Applications for the use of unregistered medicines for clinical trial purposes

The SA-GCPs’ clinical trial evaluation checklist states that the review should evaluate previous research relating to the safety and potential benefit of intervention, assess trial methods, and consider ethical issues.

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. Mandatory training in Good Clinical Practice (GCP) forms a part of capacity building. To support transformation and capacity building, SAHPRA requires 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.

Clinical Trial Review Process

As indicated in the SA-GCPs, the Clinical Trials Committee (CTC) within the CTU will consider the scientific, medical, and ethical issues of the applications, and ensure that the submissions provide proof of safety, quality, and efficacy of the investigational product for both unregistered and registered medicines. Prior to this committee review, per Additional Resource (A), there is a preliminary screening by the CTU, which 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 submission of the application. The applicant must respond within seven (7) working days after receipt of the screening review. Responses must be sent by hard copy to SAHPRA reception and emailed to ctcresponses@sahpra.org.za. 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 CTC (which includes an expert committee of specialists, as needed) reviews the proposed clinical trials pursuant to the schedule on SAHPRA’s website. (See Additional Resource (C) for 2020 dates). Clinical trial reviews will result in one 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

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.

(See the Clinical Trial Lifecycle topic, Submission Process subtopic for detailed submission requirements.)

Additional Resources
(A) (Website) Clinical Trials (Current as of March 17, 2020)
South African Health Products Regulatory Authority
(B) (Document) Who or What is SAHPRA? (May 8, 2019)
Talent 360
South African Health Products Regulatory Authority
Regulatory Authority > Regulatory Fees
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) Medicines and Related Substances Act (Act No. 101 of 1965) (MRSA) (Amended 2015)
Parliament
Relevant Sections: 35
(2) (Guidance) General Information (G-GenInfo) (Version 10) (July 2019)
Registrar of Medicines, South African Health Products Regulatory Authority
Relevant Sections: 2.9 and 4.8
(3) (Regulation) Fees Payable in Terms of the Provisions of the Medicines and Related Substances Act, 1965 (Act No. 101 of 1965) (No. 695) (MRSA-Fees) (May 24, 2019)
National Department of Health
Relevant Sections: 5. Use of Unregistered Medicines, 6. In respect of licenses, and 7. Inspections to assess the quality of medicines
(4) (Guidance) Guideline for the Direct Transmission of Fees Payable to SAHPRA (G-SAHPRAFees) (Version 4) (March 2020)
South African Health Products Regulatory Authority
Summary

Overview

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 G-GenInfo, the MRSA-Fees, and Additional Resource (A), applicants are responsible for paying several non-refundable fees to submit a clinical trial application. The various fee types include the following:

  • Authorization of the use of an unregistered medicine requires an application fee payable with the full submission of the application: company-sponsored trial fee (9,900 South African Rand (ZAR)); institution-sponsored trial fee (4,950 ZAR); any other clinical trial fee (2,420 ZAR)
  • Registration fee, payable when the application complies with all the registration requirements, and which is payable prior to a registration certificate being issued
  • Annual retention fee to maintain a manufacturing license (2,200 ZAR)
  • Clinical trial amendments - (i) technical amendments (2,310 ZAR per amendment); (ii) administrative amendment (715 ZAR per amendment)
  • Manufacturing site inspection(s) - local manufacturing site (715 ZAR per hour); international manufacturing site (4,400 ZAR per hour)
  • Manufacturing New license (23,980 ZAR)
  • Manufacturing Renewal license (20,900 ZAR)

Instructions for Payment of Clinical Trial Application Fees

The G-SAHPRAFees delineates that applicants should transfer fees directly into SAHPRA’s bank account by electronic or manual deposit. Check payments should not be made. As soon as the deposit has been made, an email confirmation of such deposit should be sent to naazneed.babamia@health.gov.za. This confirmation must also clearly indicate the reference for the deposit—screening fee for application number xxxxx, as well as a deposit reference number. For administrative purposes, SAHPRA requests one (1) payment per transaction. If payments for more than one (1) item are made per transaction, a clear breakdown must be supplied with the proof of payment. Electronic transfers must include a reference to at least the applicant’s name and telephone number, the product application number, or purpose of the payment. In the reference field, preference should be given to the telephone number if space is an issue.

Bank and account details are:

Account name: South African Health Products Regulatory Authority
Special Name: The Medicines Control Council Account
Account type: Cheque 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

Further details regarding procedures for payment are available in the G-SAHPRAFees and the G-GenInfo.

Additional Resources
(A) (Website) Fees (Current as of March 23, 2020)
South African Health Products Regulatory Authority
Ethics Committee > Ethics Committee
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 9, Sections 72 and 73
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.7, 1.5.3, 1.5.4, 1.6, 2.2, 2.3, 8.3, 8.4, and 8.5
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 4.2, 4.4, 5.1, 5.2, and 5.3
Summary

Overview

South Africa has a centralized registration process for ethics committees (ECs). (Note: ECs are referred to as health research ethics committees (HRECs) in South Africa). Per Additional Resources (A) and (B), the National Health Research Ethics Council (NHREC) is a statutory body established under the NHA. NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals. Further, NHREC observes and advises on international developments in health ethics issues with relevant international organizations. 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 norms and standards for conducting 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

Section 73 of 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 NHREC website provides a list of registered ECs and the application form to register an EC, which are also available through Additional Resources (C) and (D), respectively. Please refer to Authorizing Body subtopic for additional information.

EC Composition

As delineated in the SA-GCPs and the G-EthicsHR, 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.

Specifically, the EC composition should:

  • Represent the communities served and reflect its demographic profile
  • Have at least nine (9) members, with 60% representing a quorum; if there are more than 15 members, the quorum may be 33%
  • Have a chairperson
  • Include members of both genders; not more than 70% of its members should be one (1) gender
  • Include at least one (1) lay person; however, the SA-GCPs, an older guideline, requires two (2) lay persons who have no affiliation with the institution, are not currently involved in medical, scientific, or legal work, and are preferably from the community in which the research is to take place
  • Include at least one (1) member with knowledge of and current experience in areas of research likely to be regularly considered by the EC
  • Include at least one (1) member with knowledge of and current experience in the medical profession, counseling, and/or treatment of people
  • Include at least one (1) member who has professional training in both qualitative and quantitative research methodologies
  • Include at least one (1) member who is legally trained
  • Ensure that the membership is equipped to address all relevant considerations arising from the research areas likely to be submitted
  • Be adequately informed on all aspects of a research protocol, including its scientific and statistical validity, that are relevant to deciding whether the protocol is ethically acceptable

Terms of Reference and Review Procedures

In addition to complying with composition requirements, an institution or organization must select EC members according to prescribed recruitment and appointment procedures. As stated in the SA-GCPs and the G-EthicsHR, 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.

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. For detailed EC procedures and information on other administrative processes, see Sections 4 and 5 of the G-EthicsHR and Section 8 of the SA-GCPs.

Additional Resources
(A) (Website) National Health Research Ethics Council (Current as of June 18, 2020)
National Health Research Ethics Council
(B) (Website) Research Ethics Committee (Current as of June 18, 2020)
South African National Clinical Trials Register, National Department of Health
National Health Research Ethics Council, National Department of Health
(D) (Form) NHREC Application Form to Register an HREC (Version 2.2) (November 6, 2019)
National Health Research Ethics Council, National Department of Health
Ethics Committee > Scope of Review
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 9, Sections 72 and 73
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.7, 1.5.4, 1.6, 2.2, 2.3, 4.1, 4.2, 8, and Appendix F
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 2, 4, 5, and Appendix 1
(4) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 3
Summary

Overview

In accordance with the NHA, the SA-GCPs, and the G-EthicsHR, 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:

  • Review protocols to ensure that research involving human participants will promote health, and prevent or cure disability and disease
  • Ensure that human participants’ rights are protected, that they are treated with dignity, that their safety and well-being is not compromised, and that informed consent is obtained
  • Grant approval for research where the protocols meet the ethical standards of the institution, agency, or establishment

An EC must also pay special attention to protecting the welfare of certain classes of participants deemed to be vulnerable (See Informed Consent topic, and the subtopics of Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired for additional information about these populations).

Role in Clinical Trial Approval Process

As per the G-EthicsHR, 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.

Please see Additional Resource (C) for detailed information on issues that the EC should consider when reviewing a proposed study.

The National Health Research Ethics Council (NHREC) is responsible for establishing a research tracking system for the ECs. According to Additional Resources (A) and (B), the PI or the sponsor must register his/her clinical trial information on the South African Human Research Electronic Application System (Ethicsapp) website, and then the system will generate an NHREC application/registration number. Once the EC or SAHPRA approval is obtained, the PI or the sponsor should enter these regulatory approval numbers using the NHREC number on the South African National Clinical Trials Register (SANCTR) website. The National Department of Health (NDOH) then issues the SANCTR National Register Number. The SANCTR number will be generated within two (2) working days. This will be done either by email or fax and will be sent to both the relevant EC(s) and the PI or the sponsor. Receipt of the SANCTR number provides the research team with the authority to commence the study pending the approval of other relevant clearances, such as provincial and hospital approvals. See Additional Resources (A) and (B) for detailed registration instructions.

Per Additional Resource (D), 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 on the Application for Protocol Amendment to an Approved Trial (Additional Resource (D)).

Additional Resources
(A) (Website) South African National Clinical Trial Register – How to Register (Current as of June 18, 2020)
National Department of Health
(B) (Website) South African Human Research Electronic Application System (Current as of June 18, 2020)
National Health Research Ethics Council, National Department of Health
(C) (Website) Research Ethics Committee (Current as of June 18, 2020)
South African National Clinical Trials Register, National Department of Health
(D) (Form) Application for Protocol Amendment to Approved Trial (Version 3) (CTF2) (March 2020)
South African Health Products Regulatory Authority
Relevant Sections: 3 (Part 4)
Ethics Committee > Ethics Committee Fees
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 4.2 and 4.3.1
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 8.5
Summary

Overview

Based on the G-EthicsHR, and the SA-GCPs, ethics committees (ECs) may independently decide whether to charge fees for a protocol review. The EC procedures section of both the G-EthicsHR and the SA-GCPs state that an EC should establish and record working procedures concerning fees charged, if any.

Although South African ECs may decide on their own whether to charge a research review fee, ECs typically only charge to review research funded outside of the institution or industry-sponsored research. No charge is assessed to review investigator-driven research conducted for academic purposes within the institution.

Additional Resources
No additional resources
Ethics Committee > Authorizing Body
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 9, Sections 72 and 73
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.7, 1.5.3, 1.5.4, 2.2, 8.2, and Appendix F
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 4.6, 5.2, and 5.4
Summary

Overview

Per Additional Resource (A), the National Health Research Ethics Council (NHREC) is the central statutory body responsible for the registration and auditing of ethics committees (ECs) in South Africa. As per the terms of Section 72 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.

As delineated in the NHA, the SA-GCPs, and the G-EthicsHR, the NHREC’s core responsibilities center on promoting, ensuring, and monitoring compliance by ECs. This includes conducting the following activities:

  • Determining guidelines for EC operations
  • Registering and auditing ECs
  • Setting norms and standards for conducting research on humans and animals, including norms and standards for conducting clinical trials
  • Adjudicating complaints about the functioning of ECs and handling researcher discrimination complaints

NHREC Composition

According to the NHA and the G-EthicsHR, the Minister of Health is authorized to appoint 15 members to the NHREC and the NHREC elects its own chairperson. The Council meets four (4) times per year, and submits an annual report to advise the Minister about policy. The Council is also provided with secretariat support from the National Department of Health (NDOH)’s Research Directorate. For additional information on the NHREC, see the NHA and the NHREC website.

Registration and Auditing

As delineated in the NHA, the G-EthicsHR, and the SA-GCPs, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study. (See Additional Resource (C) for the application form.) The EC registration is then recorded and publicly listed by the NHREC. The NHREC then performs an audit of the application, and depending on the EC’s structure and function, will categorize the committee as either a Level 1 or Level 2 EC. Level 1 ECs include those that have the capacity to assess straightforward research designs involving minimal risk to human participants. These include research proposals that do not involve drug research, biomedical research involving human tissues, high-budget research, or high-technology research. Level 2 ECs comprise those that may review all types of research proposals.

The NHREC’s categorization of ECs is based on the principles set forth in the SA-GCPs, the Declaration of Helsinki, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum). The NHREC audits occur as part of an annual review process. EC categorization may change based on these annual reviews to reflect new ethical concerns or standards that have arisen in South Africa or internationally. The Council will publish any additional requirements that emerge on its website. See G-EthicsHR for detailed information on the NHREC registration, auditing, and categorization process.

Additional Resources
(A) (Website) National Health Research Ethics Council (Current as of June 18, 2020)
National Health Research Ethics Council
National Health Research Ethics Council, National Department of Health
(C) (Form) NHREC Application Form to Register an HREC (Version 2.2) (November 6, 2019)
National Health Research Ethics Council, National Department of Health
(D) (WMA Guidance) Declaration of Helsinki (October 19, 2013)
World Medical Association
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Clinical Trial Lifecycle > Submission Process
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Electronic Submission of Clinical Trial Documents (G-CTA-Electronic) (April 2019)
South African Health Products Regulatory Authority
(2) (Guidance) Procedure for Consultation Meetings with Clinical Trial Applicants (G-ConsultMtg) (November 2019)
South African Health Products Regulatory Authority
(3) (Guidance) Application to Conduct a Clinical Trial – Guidance in Conditions of a Public Health Emergency (G-CTAPHEmerg) (Version 1) (April 2020)
South African Health Products Regulatory Authority
(4) (Guidance) General Information (G-GenInfo) (Version 10) (July 2019)
Registrar of Medicines, South African Health Products Regulatory Authority
Relevant Sections: 2.4, 2.5, and 13.5
(5) (Legislation) Medicines and Related Substances Act (Act No. 101 of 1965) (MRSA) (Amended 2015)
Parliament
Relevant Sections: 21 and 35
(6) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: Application for the Registration of a Medicine – Part 16 (4)
Summary

Overview

Per Additional Resource (A), 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. Per Additional Resource (B), the same process applies to the review and approval of an amendment to the protocol. In addition, 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).

Submitting the Clinical Trial Application

Per Additional Resource (C), researchers must submit a completed application on predetermined dates (Additional Resource (D)) and obtain proof of delivery (see below in Delivery Address for information on proof of delivery). SAHPRA’s Clinical Trial Unit (CTU), which includes the Clinical Trials Committee (CTC), 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 CTU receives, processes, and evaluates the applications for approval to conduct the study within South Africa. G-CTA-Electronic delineates the electronic submission and communication process in SAHPRA’s 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 and proof of payment. In the subject of the e-mail, provide type of application, protocol number, and SAHPRA predetermined cycle (See Additional Resource (D)). Per Additional Resource (C), during the preliminary screening, SAHPRA’s 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 submission of the application. The applicant must respond within seven (7) working days after receipt of the screening review. Hardcopy responses must be delivered to SAHPRA Reception and emailed to ctcresponses@sahpra.org.za. If an application is rejected, no response is required; the screening checklist should be used as guidance for resubmission during the next review cycle.

For phase IV trials of approved products, the applicant must notify SAHPRA following the instructions provided in Additional Resource (E).

Next, the CTC (which includes an expert committee of specialists, as needed) reviews the proposed clinical trial pursuant to SAHPRA’s schedule (Additional Resource (D) for 2020 dates). CTC 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, the next cycle
  • 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

Applicants will 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. To respond to the review recommendation letter from the expert CTC, the applicant should submit all responses to SAHPRA Reception and obtain proof of delivery. Subsequently, the applicant should submit copies of the documents including the proof of delivery to the CTU by e-mail to ctcresponses@sahpra.org.za. In the subject of the email, the applicant should provide the type of application, protocol number, and SAHPRA database tracking number. These email submissions should comply with the following requirements:

  • Responses submitted to CTC’s recommendation in MS Word format
  • All other accompanying documents submitted in Portable Document Format (PDF) (See G-CTA-Electronic for specific PDF settings)
  • The maximum size of documents allowed per e-mail is 5 MB

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. (See the Submission Content and Special Circumstances/Emergencies subtopics 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 conduct of clinical trials, bioequivalence studies, notifications and notification studies, and individual serious adverse events. (Also see Sponsorship topic, Site/Investigator Selection subtopic and Clinical Trial Lifecycle topic, Safety Reporting subtopic for information about these submittal processes.)

Delivery Address for Clinical Trial Application

As indicated in the G-GenInfo and Additional Resource (C), clinical trial applications and correspondence should be delivered to SAHPRA Reception:

South African Health Products Regulatory Authority

Chief Executive Officer
CSIR
Reception Building 38a
Meiring Naude Road
Brummeria
Pretoria
South Africa

Per Additional Resource (C), upon receipt of the clinical trial application at the 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.

Per the G-GenInfo, all applications and correspondence should be clearly coded as specified in the following list:

  • TGC – General correspondence
  • TCA – Application to conduct a clinical trial
  • TCV – Amendment of an existing clinical trial
  • TCR – Response to CTC resolution
  • TAE – Report of adverse drug events arising from a clinical trial
  • TUM – Applications related to unregistered medicines as per the MRSA

Assembly and Number of Copies

Additional Resources (A), (B), and (F) delineate the following requirements for the assembly and number of copies for a clinical trial application.

  • Two (2) hard copies of the cover letter (letter of application)
  • Two (2) hard copies of the proof of payment
  • Two (2) Compact Discs (CDs) containing the complete clinical trial application with all the required documents
  • One (1) USB flash drive containing the complete clinical trial application with all the required documents

The following requirements apply to the CDs:

  • Include complete clinical trial application documents, including the cover letter (one (1) signed in PDF and one (1) in MS-Word format) and two (2) completed copies of the clinical trial application (Additional Resources (A) and (B))—one (1) signed in PDF and one (1) in MS-Word format.
  • Include the following statement in the letter of application, after having confirmed that the submission is virus-free: “We confirm that the CD burning session is closed and the submission is checked with an up-to-date and state-of-the art virus checker: [name of the antivirus software and version of the virus checker] and is virus-free". CD (CD-ROM) conforming to ISO 9660 or ISO 13346 can be accepted.
  • The use of re-writable disks is discouraged. When using a re-writable disk, all open sessions must be closed before sending the CD.
  • The CD should be packed adequately to prevent damage to the media.
  • Each CD should include the following label information, clearly presented and printed on the media: the applicant’s name, the protocol number, and the submission date (MM-YYYY).
  • The data on the CD should not be packed into a zip-file, rar-file, or any other file format that has been compressed.
  • One-time security settings or password protection is not acceptable during transportation from the applicant to SAHPRA.

The following requirements apply to the USB flash drive:

  • Include complete clinical trial application documents, including the cover letter (one (1) signed in PDF and one (1) in MS-Word format) and two (2) completed copies of the clinical trial application (Additional Resources (A) and (B))—one (1) signed in PDF and one (1) in MS-Word format.
  • The packaging should include the following label information, clearly presented and printed on the packaging: the applicant’s name, the protocol number, and the submission date (MM-YYYY).
  • The data on it should not be packed into a zip-file, rar-file, or any other file format that has been compressed.
  • One-time security settings or password protection are not acceptable during transportation from the applicant to SAHPRA.

Clinical Trial Application Language Requirements

As per the G-GenInfo and 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.

Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
(B) (Form) Application for Protocol Amendment to Approved Trial (Version 3) (CTF2) (March 2020)
South African Health Products Regulatory Authority
(C) (Website) Clinical Trials (Current as of March 17, 2020)
South African Health Products Regulatory Authority
South African Health Products Regulatory Authority
South African Health Products Regulatory Authority
(F) (Form) Notification Studies Template: Phase IV (Version 2) (May 2019)
South African Health Products Regulatory Authority, National Department of Health
South African Health Products Regulatory Authority
Clinical Trial Lifecycle > Submission Content
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 9, Sections 72 and 73
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.5.3, 1.5.4, 1.6, 2.2, 3.1, 4.1, and Appendix B
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 2.1, 2.3, 4, and 5.5
(4) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 3
(5) (Guidance) Application to Conduct a Clinical Trial – Guidance in Conditions of a Public Health Emergency (G-CTAPHEmerg) (Version 1) (April 2020)
South African Health Products Regulatory Authority
Summary

Overview

In accordance with the NHA, the SA-GCPs, the G-EthicsHR, and the NHA Participants, a sponsor (or the principal investigator when there is no sponsor) must apply to the South African Health Products Regulatory Authority (SAHPRA) and an accredited ethics committee (EC) to conduct a clinical trial for a non-registered drug or a registered drug for new indications.

SAHPRA Requirements

As per Additional Resource (A), the following documentation must be submitted to the SAHRPA:

  • Two (2) hard copies of the cover letter (letter of application)
  • Two (2) hard copies of the proof of payment
  • Two (2) Compact Discs (CDs) containing complete clinical trial application documents with all the required documents
  • One (1) USB flash drive containing complete clinical trial application documents with all the required documents

The CDs and flash drive must contain these completed documents:

  • Two (2) cover letters (one (1) signed in PDF and one (1) in MS-Word format)
  • Two (2) completed copies of the clinical trials application (one (1) signed in PDF and one (1) in MS-Word format)
  • Checklist
  • Protocol
  • Patient information leaflets and informed consent forms (PIL/ICF); include standardized SAHPRA contact details (Annex 1 of Additional Resource (A))
  • Relevant questionnaires
  • Investigators Brochure (IB)/SAHPRA and other regulatory authorities’ approved professional information (Package insert(s))
  • Certificate of analysis of the product
  • Signed investigator(s) Curriculum Vitae(s) (CV) in SAHPRA format (Annex 2 of Additional Resource (A))
  • Signed declaration by co- or principal investigator(s) (PI) (Annex 3 of Additional Resource (A))
  • Signed joint declaration by sponsor/national PI (Annex 4 of Additional Resource (A))
  • Signed declaration by applicant
  • Signed declaration by national PI (See page 4 and Annex 3 (Additional Resource (A))
  • Signed declaration by sub-investigators (Annex 5 of Additional Resource (A))
  • CV(s) and signed declaration by regional monitor (Annexes 2 and 6 of Additional Resource (A))
  • Proof of application to register the trial on the South African National Clinical Trials Register
  • Active insurance certificate for clinical trial
  • Proof of sponsor indemnity for investigators and trial site(s) (Annex 7 of Additional Resource (A))
  • Good Clinical Practice Certificates (not more than three (3) years old)
  • Workload forms for investigators (Annex 8 of Additional Resource (A))
  • Proof of registration with professional statutory bodies
  • Proof of professional indemnity (malpractice insurance) of trialist(s)
  • EC approval letter or copy of letter submitted to EC
  •  Study budget
  • Citations
  • Proof of payment

In addition, as outlined in Additional Resource (A), a sponsor is required to include the following investigational product (IP) information in the clinical trial application:

  • Name(s) and details of IP(s)
  • Properties of IP, such as mechanism of action
  • Summary of pre-clinical findings
  • Summary of clinical findings
  • Name(s) and details of comparator product(s)
  • Name(s) and details of concomitant medication(s) including rescue medications required in the protocol
  • Registration status of IP
  • Estimated quantity of trial material (each drug detailed separately) for which exemption will be required
  • If any of the above drugs are available in South Africa, an explanation for not using what is available in South Africa
  • Details of IP supply management and accountability (e.g., receipt from supplier, storage, dispensing, packaging, and labelling)
  • Details of the manufacture, quality control, and stability of the IP
  • Details of intention to register and justify if registration is not planned
  • Previous studies using this IP that have been approved by SAHPRA (or its predecessor Medicines Control Council) and include SAHPRA approval number, title, protocol number, date of approval, national PI, principal investigator, date(s) of progress report(s), and date of final report.

See Additional Resource (B) for additional information. For phase IV trials of approved products, the application must notify SAHPRA following the instructions provided in Additional Resource (C).

Additional Resource (D) 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 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 (Additional Resource (A)), when available. This means that repeat evaluations of an application may be necessary.

EC 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 Additional Resources (E), (F), (G), (H), and (I) 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 Informed Consent topic, Children/Minors subtopic 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
  • National Health Research Ethics Council (NHREC) trial registration form
  • Declaration of trialists (PI and subinvestigators) in SAHPRA format
  • Insurance certificate

Clinical Protocol

As delineated in Additional Resource (A) and Appendix B of the SA-GCPs, the clinical protocol should contain the following information (Note: the regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

  • General information
  • Background information
  • 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
  • Ethical and administrative issues
  • Data and safety monitoring plan
  • Data handling/recordkeeping
  • Statistical measures
  • Financing/insurance
  • Publication policy

For detailed information on these elements, please refer to Additional Resource (A) and the SA-GCPs.

Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
(B) (Website) Clinical Trials (Current as of March 17, 2020)
South African Health Products Regulatory Authority
(C) (Form) Notification Studies Template: Phase IV (Version 2) (May 2019)
South African Health Products Regulatory Authority, National Department of Health
(D) (Form) Application for Protocol Amendment to Approved Trial (Version 3) (CTF2) (March 2020)
South African Health Products Regulatory Authority
Biomedical Research Ethics Committee, University of Kwazulu-Natal
(F) (Form) Research Ethics Committee Application Form (Version 1) (May 28, 2010)
Human Sciences Research Council (HSRC), South Africa
(H) (Website) Human Research Ethics Committee - Forms and Instructions (Current as of June 18, 2020)
Faculty of Health Science, University of Cape Town
(I) (Website) Ethics Resources (Current as of June 18, 2020)
Pharma-Ethics Independent Research Ethics Committee
Clinical Trial Lifecycle > Timeline of Review
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 5.5
(2) (Guidance) Procedure for Consultation Meetings with Clinical Trial Applicants (G-ConsultMtg) (November 2019)
South African Health Products Regulatory Authority
Summary

Overview

Based on Additional Resource (A), 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.

In addition, as described in the G-EthicsHR and Additional Resource (B), 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. While the submission requirements differ for each provincial health committee, generally, upon receipt of EC approval, the sponsor or investigator should register the study online at the National Health Research Database (Additional Resource (C)).

SAHPRA Approval

In general, per Additional Resource (D), 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 would be sent within 10 weeks of submission due date. There are cases where this turnaround time might be prolonged, such as unfamiliar investigational product which may be referred to external reviewers or other SAHPRA committees for input.

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 submission of the application. The applicant must respond within seven (7) working days after receipt of the screening review. Hardcopy responses must be sent to SAHPRA Reception and emailed to ctcresponses@sahpra.org.za. 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 CTC reviews the proposed clinical trials. Per Additional Resource (E), the CTC meets on a 6-weekly basis and typically reviews approximately between 20-40 studies during each cycle (approximately 240 per year). Additional Resource (F) provides the dates of the 2020 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. Additional Resource (D) 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.

EC 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 various EC procedures.

Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
The Clinical Research Centre at the University of Cape Town
Relevant Sections: Chapter 4 – South Africa (MCC, HREC, Provincial/Hospital (full ebook only available for purchase)
(C) (Website) National Health Research Database (Current as of June 18, 2020)
National Department of Health
(D) (Website) Clinical Trials (Current as of March 17, 2020)
South African Health Products Regulatory Authority
South African Health Products Regulatory Authority
Relevant Sections: 5.1 (i)
South African Health Products Regulatory Authority
Clinical Trial Lifecycle > Trial Initiation
Last content review/update: June 18, 2020
Requirements
(1) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: Part 30 (2)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.5, 1.5.5, 1.5.7, 1.6, 3.2, and 4.3
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 4 and 5
(4) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 3
(5) (Guidance) Good Pharmacy Practice in South Africa (SA-GPPs(4th Edition) (2010)
South African Pharmacy Council
Relevant Sections: General Objectives and Requirements of Pharmaceutical Services
Summary

Overview

In accordance with the GRMRSA, the SA-GCPs, the G-EthicsHR, 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, and the GRMRSA. Also, per the SA-GCPs, all clinical trials must be conducted in a laboratory complying with Good Laboratory Practices (GLP). See Additional Resource (B) for the World Health Organization’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.

South African National Clinical Trials Register (SANCTR) Recording Requirements

According to the SA-GCPs, NHAParticipants, and Additional Resources (A) and (C), once the trial has obtained approval from the SAHPRA and the EC, the sponsor or the PI must register his/her clinical trial information on the South African Human Research Electronic Application System (Ethicsapp) website, and then the system will generate a National Health Research Ethics Council (NHREC) application/registration number. Once the ethics or SAHPRA approval is obtained, the PI or the sponsor should enter these regulatory approval numbers using the NHREC number on the South African National Clinical Trials Register (SANCTR) website. The National Department of Health (NDOH) then issues a unique SANCTR National Register Number. The SANCTR number will be generated within two (2) working days. This will be done either by email or fax and will be sent to both the relevant EC(s) and the PI or the sponsor. Receipt of the SANCTR number provides the research team with the authority to commence the study pending the approval of all other relevant regulatory clearances. See Additional Resources (A) and (C) for detailed registration instructions.

In addition, per the SA-GCPs, because multi-center trials and multi-sponsor trials are susceptible to duplicate registration, sponsors must be attentive when registering the trials. For multi-sponsored trials, the lead sponsor should take responsibility for registration. It is critical that investigators and sponsors work together to ensure that a trial is registered only once with SANCTR.

Per Additional Resource (D), SANCTR is not an International Committee of Medical Journal Editors (ICMJE)-recognized register. The ICMJE will only consider publishing reports of trials in a register that is part of the World Health Organization (WHO) registry network (e.g., Pan African Clinical Trials Registry). Therefore, if sponsors want their trial results published, they must also register in a WHO-affiliated registry.

Clinical Trial Agreement

According to the SA-GCPs, before the trial begins, a sponsor must prepare a written agreement, which includes any information not covered in the protocol. The agreement must be signed by the sponsor and the PI, and any other parties involved (e.g., institutions) with the trial to confirm the contract terms.

The sponsor should also obtain the investigator's agreement to:

  • Conduct the trial in compliance with the SA-GCPs, the SAHPRA requirements, 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, 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.

EC Confirmation of Review

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:

  • EC member profiles (names and addresses)
  • Documented approval of EC’s favorable opinion
  • Copy of EC recommendations in case it has based its approval on change(s) in any aspect of the study (e.g., protocol modifications, written informed consent form, or any other written information or other procedures)

The sponsor should also obtain from the PI documentation and dates relating to any EC re-evaluations, re-approvals, withdrawals, or suspensions of approval. (See Ethics Committee topic, Scope of Review subtopic and Clinical Trial Lifecycle topic, Submission Content subtopic for additional details on EC review process).

Additional Resources
(A) (Website) South African National Clinical Trial Register – How to Register (Current as of June 18, 2020)
National Department of Health
World Health Organization
(C) (Website) South African Human Research Electronic Application System (Current as of June 18, 2020)
National Health Research Ethics Council, National Department of Health
Sibanda, Mncengeli; Summers, Robert; and Meyer, Johanna Catharina; The Pan African Medical Journal
Relevant Sections: Introduction
Clinical Trial Lifecycle > Safety Reporting
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 3.12, 4.19, and Appendix F
(2) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 4.5.1 and Appendix 1
(3) (Guidance) Safety Reporting During Clinical Trials in South Africa (G-SafetyRpt) (Version 3) (November 2019)
South African Health Products Regulatory Authority
Relevant Sections: 4.1-4.2, 4.6-4.7, 5.2. 6.1-6.4, and 7.1-7.3
(4) (Guidance) Emergency Procedures for Clinical Trial Sites (G-EmergencyProc) (Version 2) (May 2019)
South African Health Products Regulatory Authority
Relevant Sections: 1, 2, and 6
(5) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: 1 and 30(7)
(6) (Guidance) Electronic Submission of Clinical Trial Documents (G-CTA-Electronic) (April 2019)
South African Health Products Regulatory Authority
Relevant Sections: G
Summary

Overview

In accordance with the SA-GCPs, the G-EthicsHR, 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, Additional Resource (B) provides clarification on the definition of serious suspected unexpected adverse reaction (SUSAR), which is a reporting requirement in the updated G-SafetyRpt. Per Additional Resource (B), a SUSAR is an adverse reaction that is unexpected but suspected to be drug related. It must fulfil the criteria for “serious” as per 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.

Reporting Requirements for AEs/ADRs

As specified in the SA-GCPs and the G-EthicsHR, the principal investigator (PI) must inform the sponsor, within the time specified in the protocol, of any unexpected SADRs/SAEs occurring during the study. The initial SAE/SADR 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. According to an in-country subject matter expert, investigators may forward reports directly to the ethics committee (EC) as relevant and as permitted by the EC’s standard operating procedures.

As delineated in the GRMRSA, the SA-GCPs, and the G-EthicsHR, the sponsor is required to report all expected or unexpected SAEs/SADRs on an expedited basis to all concerned parties, including 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 (Additional Resource (A), CIOMS form (Additional Resource (C)), 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)
  • Final Safety Report
  • Final Study Report

Per Additional Resource (D), the following must be reported and signed by the PI and the sponsor as part of the six-month progress reports:

  • All SAEs and SUSARs for studies in South Africa (and any other issues of special concern outside South Africa) for all participants per site in a line listing format
  • All critical and major protocol violations at each site in a line listing format
  • PI comment on other major safety concerns, including information impacting the risk-benefit profiles such as changes in the nature, severity, or frequency of risk factors

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 (Additional Resource (C))/SAHPRA SAE form (Additional Resource (A)). 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. These reports should be in a line listing format.
  • 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 (Additional Resource (C))/SAHPRA SAE form (Additional Resource (A))
  • 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 Additional Resource (D)).
  • 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.
  • A progress report should be submitted six (6) months after the initial approval of the clinical trial and every six (6) months thereafter (Additional Resource (D)).
  • The final progress report should be submitted within 30 days of the completion or termination of the clinical trial; the final study report should be submitted within 180 days of the completion or termination of the clinical trial.
  • The annual DSURs must be submitted annually.

If the study is multi-centered, the SA-GCPs states that the sponsor should ensure that all SAEs/SADRs occurring at any study site are reported without delay to the investigator(s)/institution(s), the SAHPRA, and the ECs.

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 Additional Resource (A), the SAHPRA’s Safety Reporting During Clinical Trials Form should be used to complete SAE/ADR reports—for both initial and follow-up safety reports. The G-SafetyRpt indicates that the safety reports during a clinical trial should be reported to the Clinical Trial Unit of SAHPRA:

Chief Executive Officer
SAHPRA
CSIR Campus
Brummeria
Pretoria 0001
South Africa
Tel: (012) 842 7602/7606
E-mail: ctcsaes@sahpra.org.za

Safety information for post-marketing studies must be sent to the Vigilance Unit of SAHPRA:

Chief Executive Officer
SAHPRA
CSIR Campus
Brummeria
Pretoria 0001
South Africa
Tel: (012) 842 7609/7610
E-mail: adr@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
Additional Resources
(A) (Form) Safety Reporting During Clinical Trials Form (Version 2) (November 2019)
South African Health Products Regulatory Authority
(B) (Presentation) Safety Reporting in Clinical Trials (November 2019)
Ruff, Paul, University of the Witwatersrand, Member of SAHPRA Clinical Trials Committee
(C) (Form) CIOMS Form I (Date Unavailable)
Council for International Organizations of Medical Sciences
(D) (Form) Six Monthly Progress Report Form for Clinical Trials (Version 2) (June 2018)
South African Health Products Regulatory Authority, National Department of Health
Relevant Sections: Part B
Clinical Trial Lifecycle > Progress Reporting
Last content review/update: June 18, 2020
Requirements
(1) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: Part 30 (6)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 3.14 and 6.4
(3) (Guidance) Safety Reporting During Clinical Trials in South Africa (G-SafetyRpt) (Version 3) (November 2019)
South African Health Products Regulatory Authority
Relevant Sections: 6.1-6.2
Summary

Overview

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 date of approval of an application and 30 days after the completion or termination of the clinical trial. The SA-GCPs requires the principal investigator (PI) to submit progress reports as required by the sponsor, the SAHPRA, and/or the relevant ethics committee(s) (ECs) on the status of a clinical trial.

Progress Reports

Per the GRMRSA and Additional Resource (A), the SAHPRA requires the sponsor to submit a six-month progress report from the date of approval of the clinical trial by SAHPRA. This six-month report (Additional Resource (A)) requires the following:

  • SAHPRA database tracking number
  • Study title
  • Protocol number
  • Details of the sponsor
  • List of all active trial sites, addresses, and PIs
  • Trial information, including date of approval of study, treatment hold (if applicable), and expected date of completion
  • Number of participants per site
  • Sponsor comment on progress to date
  • Summary Data Safety Monitoring Board or Safety Committee recommendations
  • Serious adverse events and suspected unexpected serious adverse reactions for all participants per site in this study in South Africa
  • Any safety issues of special concern outside of South Africa
  • Line listing of all critical and major protocol violations and resolutions/actions taken at a site
  • PI comment on other major safety concerns
  • Signature of the PI
  • Signature of the sponsor

As per the SA-GCPs, the PI is obligated to submit progress reports to the sponsor, SAHPRA, and the ECs. These reports should contain the following information:

  • Study status
  • Number of participants included in relation to the number expected
  • Number of dropouts and withdrawals
  • Adverse events/adverse drug reactions
  • If the planned time schedule is still appropriate

Final Study Reports

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 the completion or termination of the clinical trial.

In addition, per the SA-GCPs, upon the trial’s end, the PI, where applicable, should provide the EC, the SAHPRA, and other relevant regulatory authorities with a summary of the trial’s outcomes, and a statement that the trial has been conducted in accordance with the GRMRSA and the SA-GCPs.

The SA-GCPs also specifies that the protocol, statistical, and clinical aspects of the trial be integrated to obtain a final study report that is consistent with the study data generated. Essential elements to include are:

  • Baseline comparisons between the treatment groups
  • Number of participants actually randomized into the study by treatment group, and the number of participants excluded from any of the analyses, by reason, and by treatment group
  • Major efficacy and safety results by treatment group using tables, graphs, test variables, and statistical parameters as appropriate
  • An assessment of between-group differences with confidence intervals

In multicenter studies, an evaluation of the center effect may also be included, and should always be conducted where significant center variation is suspected.

An account must also be made of missing, unused, or spurious data during statistical analyses. All omissions of this type must be documented to enable review to be performed. The sponsor or the PI is responsible for recording the final study results in the South African National Clinical Trials Register (SANCTR) within one (1) year of the study’s completion.

Additional Resources
(A) (Form) Six Monthly Progress Report Form for Clinical Trials (Version 2) (June 2018)
South African Health Products Regulatory Authority, National Department of Health
Sponsorship > Definition of Sponsor
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.5.6, 4, and 4.5
(2) (Guidance) Oversight and Monitoring in Clinical Trials (G-Monitor) (Version 2) (October 2019)
South African Health Products Regulatory Authority
Relevant Sections: 1
(3) (Legislation) Protection of Personal Information Act, 2013 (Act No. 4 of 2013) (POPIA) (November 19, 2013)
Parliament
Relevant Sections: Chapter 1 (1)
Summary

Overview

As defined in the SA-GCPs, a sponsor is the person or organization responsible for the initiation, management and 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 PI. A sponsor may be domestic or foreign.

Per the SA-GCPs and the Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum), a sponsor may transfer any or all of his/her trial-related duties and functions to a contract research organization (CRO). However, he/she 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 the conduct of a clinical trial, 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.

For 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.

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 5.1 and 5.2
Sponsorship > Trial Authorization
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.6 and 4.1
Summary

Overview

In accordance with the SA-GCPs, a sponsor or his/her designated contract research organization (CRO) is responsible for submitting a clinical trial application to the South African Health Products Regulatory Authority (SAHPRA) to obtain approval to conduct a study. As indicated in Additional Resource (A), if there is no sponsoring organization, the principal investigator (PI) must clearly state in the protocol who will be assuming the sponsor’s role of initiating, managing, or funding the clinical trial.

To complete the clinical trial application package, a sponsor must use the SAHPRA’s Application to Conduct Clinical Trials form (CTF1) listed in Additional Resource (A). In addition to the completed application, a sponsor must also provide the protocol, the patient information leaflet and informed consent form, a signed joint declaration by the sponsor and PI, a financial declaration signed by the sponsor, and other documentation covered in the Clinical Trial Lifecycle topic, Submission Content subtopic. It is both the sponsor’s and the PI’s responsibility to ensure that the protocol satisfies the requirements of the protocol checklist in Additional Resource (A). For more information on SAHPRA’s clinical trial application process, see Additional Resource (B).

Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
(B) (Website) Clinical Trials (Current as of March 17, 2020)
South African Health Products Regulatory Authority
Sponsorship > Insurance
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Liability Insurance for Clinical Trials (G-Insurance) (November 2019)
South African Health Products Regulatory Authority
Relevant Sections: 1-5 and 7
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.2 and 4.11
Summary

Overview

As set forth in the G-Insurance, all sponsors and investigators of clinical trials 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 Association of the British Pharmaceutical Industry’s (ABPI) guidelines (Additional Resources (A) and (B)) to comply with South Africa’s clinical trial insurance requirements. A sponsor must ensure that he/she has obtained insurance and indemnity to cover his/her liability in a clinical trial.

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. Notwithstanding the absence of a legal commitment, the sponsor should pay compensation to all participants including healthy volunteers suffering bodily injury, including death, in accordance with the G-Insurance. The following should be considered in compensation of participants:

  • If, on the balance of probabilities, the injury is attributable to the administration of an investigational product (IP) or any clinical intervention or procedure provided for by the protocol that would not have occurred but for the inclusion of the participant in the trial.
  • Compensation should be paid for a child injured in-utero through the participation of the biological parent in a clinical trial as if the child were a patient-volunteer with the full benefit of SAHPRA guidelines.
  • Compensation should only be paid for a serious injury of an enduring or disabling nature (including exacerbation of an existing condition) and not for temporary pain or discomfort or less serious occurrences.
  • Where there is an adverse reaction to an IP under trial 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 under trial.
  • The sponsor is under strict liability in respect of injuries caused by the IP or procedures provided for by the protocol that would not have occurred but for the inclusion of the participant in the trial, regardless of whether the participant is able to prove negligence on the part of the sponsor or that the IP is defective.

As delineated in the G-Insurance and Additional Resource (C), an insurance certificate and indemnity must be included in the clinical trial application submitted to the 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
Additional Resources
Association of the British Pharmaceutical Industry, United Kingdom
Association of the British Pharmaceutical Industry, BioIndustry Association, and Clinical Contract Research Association, United Kingdom
Relevant Sections: 3 and 4
(C) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
National Health Research Ethics Council, National Department of Health
Sponsorship > Compensation
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Clinical Trial Participant Time, Inconvenience & Expense (TIE) Compensation Model (G-TIECompensation) (June 2018)
South African Health Products Regulatory Authority
Relevant Sections: Cover, 1 and 2
(2) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.1.7
(3) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.2 and 4.11
(4) (Guidance) Post Clinical Trial Access (PTA)/Continued Access (G-PostCTAccess) (Version 2) (April 2019)
South African Health Products Regulatory Authority
Summary

Overview

As specified in the G-TIECompensation, the sponsor or his/her designated representative is responsible for providing compensation to research participants. Additional Resource (A) states that the South African Health Products Regulatory Authority (SAHPRA) must be given details of compensation to clinical trial participants. Per the G-EthicsHR and the G-TIECompensation, compensation should be based on time, inconvenience, and expenses. In addition, the G-EthicsHR also addresses researcher requirements to budget for participant travel and other expenses. (See the G-EthicsHR for detailed information).

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.

As per the SA-GCPs, the sponsor must follow the principles set forth in the Association of the British Pharmaceutical Industry’s guidelines (Additional Resources (B) and (C)) to comply with South Africa’s participant compensation and treatment requirements due to trial-related injuries.

The guidelines state that the sponsor should furnish written assurance to the investigator that he/she will agree to pay compensation to participants and/or his/her legal heirs in the event of trial-related injuries or death. The investigator, in turn, communicates this information to the relevant ethics committee(s).

The G-PostCTAccess guides sponsors in when to consider post-trial or continued access (PTA/CA) to the investigational product (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 IP.

Compensation Principles

The SA-GCPs and Additional Resource (B) provide several basic principles to guide sponsors in fulfilling their compensation obligations. Compensation should be paid as follows:

  • When it can be demonstrated that a causal relationship exists between a participant’s injury and his/her participation in a trial
  • When a child is injured in utero through his/her mother’s participation in a clinical trial
  • 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 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 him/her from being eligible for compensation. (See the aforementioned guidelines and the Informed Consent topic, Compensation Disclosure subtopic for additional information on a participant’s right to compensation).

Payment Procedures and Requirements

According to the SA-GCPs and Additional Resource (B), 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

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 his/her 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 the SA-GCPs and Additional Resource (B) 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.

Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
Association of the British Pharmaceutical Industry, United Kingdom
Association of the British Pharmaceutical Industry, BioIndustry Association, and Clinical Contract Research Association, United Kingdom
Relevant Sections: 3
National Health Research Ethics Council, National Department of Health
Sponsorship > Quality, Data & Records Management
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 4.4, 4.8, 5.2, 6.5, 6.7, and 7
(2) (Guidance) Oversight and Monitoring in Clinical Trials (G-Monitor) (Version 2) (October 2019)
South African Health Products Regulatory Authority
Relevant Sections: 1 and 4
(3) (Legislation) Protection of Personal Information Act, 2013 (Act No. 4 of 2013) (POPIA) (November 19, 2013)
Parliament
Relevant Sections: Chapter 1 (2), Chapter 2 (4), Chapter 3, and Chapter 5 (55-56)
(4) (Regulation) Regulations Relating to the Protection of Personal Information, 2018 (No.R.1383) (POPIA-Regs) (December 14, 2018)
Department of Justice and Constitutional Development
Relevant Sections: 2-4
Summary

Overview

As clinical trial oversight manager, the sponsor must implement and maintain quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol and the SA-GCPs. 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. Agreements made by the sponsor with the principal investigator and any other involved parties should be in writing either as part of the protocol or in a separate agreement. 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, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Data Protection

Per the POPIA, the sponsor (known as the “responsible party” in data protection legislation), 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)

For additional information about consent, see the Informed Consent topic, Documentation Requirements and Required Elements subtopics.

Electronic Data Processing System

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 he/she maintains SOPs for using these systems. Refer to the SA-GCPs for detailed information on electronic trial data systems. 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.

Independent Data Monitoring Committee

The sponsor is permitted to establish an Independent Data Monitoring Committee (IDMC) to assess the trial’s progress. The IDMC would review the safety data and critical efficacy endpoints at intervals, and recommend to the sponsor whether to continue, modify, or stop a trial. The IDMC should also have written SOPs and maintain written records of all its meetings.

Record Management

As set forth in the SA-GCPs, the sponsor should inform the investigator(s) and institution(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.

Following the trial’s completion, a sponsor should retain copies of all study-related documentation that does not contain participant identifying information. The files should also include information on study site personnel responsible for maintaining the participant lists, and those responsible for archiving investigator documents. These documents should be saved for 15 years after the trial’s termination, and preferably for the product’s commercial lifetime. Refer to the SA-GCPs for additional record retention requirements.

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.

Audit Requirements

As part of its QA system, the sponsor should perform a clinical trial audit. No specific timeframe is provided for the audit process. The audit should be conducted separately and independently from other routine monitoring or QC functions. It should evaluate study conduct and compliance with the protocol, the SOPs, and the SA-GCPs. The sponsor may appoint qualified external auditors who have appropriate documentation. The sponsor must also ensure that the audit is conducted in accordance with his/her own SOPs, that the auditor observations are archived, and that data is available as needed for the South African Health Products Regulatory Authority (SAHPRA) and ethics committee (EC) review. The person responsible for auditing must submit a report to the SAHPRA when evidence of Good Clinical Practice non-compliance exists.

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

If a trial is prematurely terminated or suspended, a sponsor must promptly notify the investigator(s), the institution(s), the EC, and the SAHPRA accordingly. The notification should document the reason(s) for the termination/suspension. The sponsor is also responsible for ensuring that the South African National Clinical Trials Register (SANCTR) is updated as well.

Multicenter Studies

In the event of a multicenter clinical trial, the sponsor must make administrative arrangements to ensure the protocol is followed by investigators at different institutions. Some of the tasks requiring special consideration include:

  • Ensuring strict adherence to the protocol
  • Confirming case report forms (CRFs) are designed to capture the required data at all multi-center trial sites
  • Documenting the responsibilities of coordinating investigator(s) and the other participating investigators
  • Supplying investigators with instructions on following the protocol, on complying with a uniform set of standards to assess clinical and laboratory findings, and on completing the CRFs
  • Facilitating communication between investigators
Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 1.65, 5.0, 5.1, 5.2, 5.5, 5.18, 5.19, 5.21, 5.23, 6.10, and 8
Sponsorship > Site/Investigator Selection
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 4.2, 4.6, 4.7, 4.9, and 4.10
(2) (Guidance) Oversight and Monitoring in Clinical Trials (G-Monitor) (Version 2) (October 2019)
South African Health Products Regulatory Authority
Relevant Sections: 5
(3) (Guidance) Capacity Building and Transformation in Clinical Research in South Africa (G-Capacity) (July 2019)
South African Health Products Regulatory Authority
(4) (Guidance) Clinical Trial Investigators (G-CTInvestigators) (Version 2) (May 2019)
South African Health Products Regulatory Authority
Relevant Sections: 1 and 2
Summary

Overview

As set forth in the SA-GCPs, the sponsor is responsible for selecting the investigator(s) and institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must ensure that the investigator(s) are qualified by training and experience, and that they have adequate resources to properly conduct the 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 and Additional Resource (A) for more information on investigator workload.

Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the involved parties with the protocol and an up-to-date investigator’s brochure, and allow them sufficient time to review this documentation. The sponsor must also define and allocate all study related duties and responsibilities to the respective identified person(s) and organization(s) prior to initiating the study. In addition, if a multi-center trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigator(s).

In addition, per Additional Resource (B), to add or change investigators and/or for additional sites to an approved clinical trial, the sponsor must submit a signed application to SAHPRA. See Additional Resource (B) 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, delegation of trial responsibilities, analysis, and reporting of the trial. 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 his/her 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 his/her 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.

In the case of a multi-country study, the sponsor must ensure that any differences in trial designs between the South African site and other sites must be clearly documented and explained in the study protocol and related documents.

Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Additional Resources
South African Health Products Regulatory Authority
South African Health Products Regulatory Authority
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 1.25, 5.5, and 5.6
Informed Consent > Documentation Requirements
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 9 (71)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.8, 2.1, 2.2, 3.5, and 8.6.2
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 1.3, 1.4, 1.5, 1.6, 2.3, 3.1, 3.2, 4.3, and 5.2
(4) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 3.4 and 6.3
(5) (Guidance) Guidelines for Good Practice in the Health Care Professions: Seeking Patients’ Informed Consent: The Ethical Considerations, Booklet 4 (G-GPHlthCare-IC) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 11, 12.3, and 15.1.3
(6) (Guidance) General Information (G-GenInfo) (Version 10) (July 2019)
Registrar of Medicines, South African Health Products Regulatory Authority
Relevant Sections: 2.4 and 2.5
Summary

Overview

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, the SA-GCPs, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

As per the SA-GCPs, the G-EthicsHR, 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 Informed Consent topic, Required Elements subtopic 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 his/her 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 ICF content should be briefly and clearly presented, without coercion or unduly influencing a potential participant to enroll in the clinical trial.

According to the SA-GCPs, the G-EthicsHR, the G-GPHlthCare, and the G-GPHlthCare-IC, in all cases, both written informed consent must be obtained. The SA-GCPs also states that verbal consent must be obtained. Where the participant is illiterate and/or his/her 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.

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.

Language Requirements

According to the SA-GCPs, the G-EthicsHR, and the G-GenInfo, the ICF and any patient information sheet(s) should be written in English and in the 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.

Documentation Copies

As stated in the SA-GCPs, the G-EthicsHR, 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, his/her 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 for his/her record. 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. The SA-GCPs also requires contact information for the EC and for the SAHPRA be provided in the ICF.

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 3 and 6
(B) (WMA Guidance) Declaration of Helsinki (October 19, 2013)
World Medical Association
Informed Consent > Required Elements
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.8, 1.5.4, 2.1, 2.2, 3.1, 3.5, 3.11, 8.2, Appendix A, and Appendix F
(2) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 2.3.6 and 3.3.6
(3) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 6.3
(4) (Legislation) Protection of Personal Information Act, 2013 (Act No. 4 of 2013) (POPIA) (November 19, 2013)
Parliament
Relevant Sections: Chapter 3 (11)
(5) (Regulation) Regulations Relating to the Protection of Personal Information, 2018 (No.R.1383) (POPIA-Regs) (December 14, 2018)
Department of Justice and Constitutional Development
Relevant Sections: 2-4
(6) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 5
Summary

Overview

As delineated in the SA-GCPs, the G-EthicsHR, and the G-GPHlthCare, prior to beginning a research study, the principal investigator (PI) is required to obtain ethics committee (EC) approval for the written informed consent form (ICF), and for all information being provided to the research participant and his/her legal representative(s) or guardian(s).

Information should be presented in an easily understandable and unambiguous language in both written and oral form. Adequate time should be given to the participant and/or his/her legal representative(s) or guardian(s) to inquire about the details of the study, and have all questions answered to his/her satisfaction. Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Per the POPIA, and the POPIA-Regs, personal information may only be processed if the data subject and/or his/her legal representative(s) or guardian(s) consents to the processing. The responsible party (sponsor) bears the burden of proof for the consent. The data subject and/or his/her 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.

No Coercion

None of the oral or written information concerning the study, including the written ICF, should contain any language that causes the participant and/or his/her legal representative(s) or guardian(s) to waive or to appear to waive his/her legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or his/her representatives from his/her liabilities for any negligence.

ICF Required Elements

Based on the informed consent essential elements checklists in the SA-GCPs, the G-EthicsHR, the G-GPHlthCare, and the NHAParticipants, the ICF should include the following statements or descriptions, as applicable:

  • The study involves research and an explanation of its nature and purpose
  • The procedures to be followed
  • The participant’s responsibilities
  • Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
  • 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 anticipated prorated payment, if any, to the participant for participating in the trial
  • PI and co-investigator(s) contact information
  • The sponsor’s identity, and any potential conflicts of interest
  • The consequences of a participant's decision to withdraw from the study
  • Alternative procedures or treatment that may be available to the participant
  • The study has been approved by an accredited South African-based EC, and EC contact information
  • The approximate number of participants in the research study
  • The expected duration of the participant's participation
  • Information regarding a multicentered study, if applicable
  • An explanation of whom to contact in the event of research-related injury
  • Additional costs to the participant that may result from participation in the study
  • Foreseeable circumstances under which the investigator(s) may remove the participant without his/her consent
  • The participant and/or his/her 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
  • If the research involves collecting biological materials, participants must be provided with an explanation on how the specimens will be managed at the end of the study. If samples will be stored for future use, separate consent should be obtained

See the Informed Consent topic, Compensation Disclosure and Vulnerable Populations subtopics as well as the Specimens topic, Consent for Specimen subtopic for further information.

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 4.4 and 4.8
Informed Consent > Compensation Disclosure
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 2.2, 3.5, 4.11, and 4.12
(2) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.1.7 and 3.5.3
(3) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 6.1
(4) (Guidance) Post Clinical Trial Access (PTA)/Continued Access (G-PostCTAccess) (Version 2) (April 2019)
South African Health Products Regulatory Authority
(5) (Guidance) Liability Insurance for Clinical Trials (G-Insurance) (November 2019)
South African Health Products Regulatory Authority
Relevant Sections: 6
Summary

Overview

In accordance with the SA-GCPs, the G-EthicsHR, and the G-GPHlthCare, the informed consent form (ICF) should contain a statement describing the compensation or benefits a participant may receive for participating in a clinical trial. In addition, as specified in the SA-GCPs, sponsors and investigators must also comply with the Association of the British Pharmaceutical Industry’s (ABPI) guidelines relating to participant compensation and treatment requirements due to trial-related injuries (See Additional Resources (B) and (C)). Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Compensation for Participation in Research

As per the SA-GCPs, the ICF should contain a statement with a description of the anticipated prorated payment to the participant(s) that is reasonably expected for participation in the trial. The ICF should also contain a statement indicating whether any compensation and medical treatment will be made available if injury occurs.

Per the SA-GCPs and the G-GPHlthCare and as described in Additional Resource (A), the sponsor must ensure that participants are reimbursed for all reasonable costs incurred by their participation in the trial. As described in the G-EthicsHR and Additional Resource (A), the researcher should reimburse participants using a fair rate calculated using a formula that accounts for time, inconvenience, and expenses to determine costs. However, 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.

If the studies are multicentered, information regarding incentives to be given to participants at the different sites must be provided, and the differences across sites must be explained.

The G-PostCTAccess guides sponsors in when to consider post-trial or continued access (PTA/CA) to the investigational product (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, ICF, and patient information leaflet. See Sponsorship topic, Compensation subtopic for additional considerations.

Compensation for Injury

As per the SA-GCPs, the G-EthicsHR, the G-GPHlthCare, the G-Insurance, and Additional Resources (A) and (B), a statement must be included in the ICF regarding compensation or treatment for research-related injuries available to the participant(s). If applicable, this should include a statement regarding compensation for any potential injury received by a child in utero or a nursing child, through the mother’s participation in a research study.

The South African Health Products Regulatory Authority (SAHPRA) and the ethics committee(s) (ECs) require a sponsor to provide comprehensive insurance for injury and damage to all trial participants as described in the SA-GCPs, and Additional Resources (B) and (C). A sponsor must furnish written assurance to the investigator that he/she will agree to pay compensation to participants who incur research-related injuries or death. The investigator, in turn, communicates this information to the relevant EC(s).

The SA-GCPs and Additional Resource (B) also provide the following basic principles to guide compensation payment to participants:

  • A causal relationship exists between a participant’s injury and his/her participation in a trial
  • A child is injured in utero through his/her mother’s participation in a trial, and should be treated as if he/she were a participant
  • For more serious injuries of an enduring and disabling nature, and not for temporary pain or discomfort, or less serious or curable complaints
  • An adverse drug reaction (ADR) occurs to a participant using a medicinal product under trial, and injury is caused by a procedure adopted to deal with that ADR. The injury should be treated as if it were caused directly by the medicinal product under trial
  • Any trial-related injuries, regardless of the participant’s ability to prove that the sponsor has been negligent in relation to the research or development of the medicinal product under trial, or, that the product is defective

The participant should be eligible for compensation even if he/she freely consented (in writing or otherwise) to participate in the trial, or he/she was aware that there was a likelihood of an ADR. (See the aforementioned guidelines and the Sponsorship topic, Compensation subtopic for additional information on sponsor compensation responsibilities; the Informed Consent topic, Required Elements subtopic for additional details on what should be included in the ICF.)

Additional Resources
National Health Research Ethics Council, National Department of Health
Relevant Sections: 4
Association of the British Pharmaceutical Industry, United Kingdom
Association of the British Pharmaceutical Industry, BioIndustry Association, and Clinical Contract Research Association, United Kingdom
Relevant Sections: 3 and 4
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 3.1 and 4.8
Informed Consent > Participant Rights
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.8, 2.1, 2.3, 3.5, and Appendix A
(2) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 1.1, 2.3 and 3.1
(3) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 2, 3, 4, and 6
(4) (Guidance) Guidelines for Good Practice in the Health Care Professions: Seeking Patients’ Informed Consent: The Ethical Considerations, Booklet 4 (G-GPHlthCare-IC) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 1, 2, and 3
(5) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 2 and 5
(6) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 1 (2), Chapter 2 (8 and 11), and Chapter 9 (71)
(7) (Legislation) Promotion of Access to Information Act (Act No. 2 of 2000) (POAIA) (February 3, 2000)
Parliament
Relevant Sections: Act, Preamble, and Chapter 2
(8) (Legislation) Protection of Personal Information Act, 2013 (Act No. 4 of 2013) (POPIA) (November 19, 2013)
Parliament
Relevant Sections: Preamble and Chapter 2 (5)
Summary

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, the SA-GCPs, the G-EthicsHR, the G-GPHlthCare, the G-GPHlthCare-IC, the NHAParticipants, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum), 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 Informed Consent topic, Required Elements and Vulnerable Populations subtopics 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 his/her legal representative(s) or guardian(s) should be informed that participation is voluntary, that he/she may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

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 Informed Consent topic, Required Elements subtopic 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.

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. For more information about the sponsor’s (called the “responsible party” in South Africa) data protection requirements, see the Sponsorship topic, Quality, Data & Records Management subtopic.

The Right of Inquiry/Appeal

Per the G-GPHlthCare-IC, the research participant and/or his/her 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 his/her rights. It is also required that the South African Health Products Regulatory Authority (SAHPRA) address and contact information be provided. (See the Informed Consent topic, Required Elements subtopic for more detailed information regarding participant rights.)

The Right to Safety and Welfare

The SA-GCPs and the Declaration of Helsinki 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.

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(B) (WMA Guidance) Declaration of Helsinki (October 19, 2013)
World Medical Association
Informed Consent > Special Circumstances/Emergencies
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 2 (7, 8, and 9)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.3.3, 2.3.6.5, 2.3.9, 5, 5.9, and 5.14
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.1, 3.2, and 3.4
(4) (Guidance) Application to Conduct a Clinical Trial – Guidance in Conditions of a Public Health Emergency (G-CTAPHEmerg) (Version 1) (April 2020)
South African Health Products Regulatory Authority
Relevant Sections: 11.5 - 11.6 and Annex 1
(5) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 6.3.8
Summary

Overview

The NHA, the SA-GCPs, and the G-EthicsHR make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by special circumstances. Special circumstances can be medical emergencies, or when a research participant is mentally incapacitated, or has physical impairments requiring special considerations. Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Medical Emergencies

As per the SA-GCPs and the G-EthicsHR, the ethics committee (EC) may approve emergency medical research when informed consent cannot be obtained from the participant or his/her legal representative(s) or guardian(s) if the investigator(s) ensures the protocol meets the following requirements:

  • Reasonable steps are being taken to ascertain the participant’s religious and cultural sensitivities
  • The participant’s condition precludes giving consent
  • Inclusion in the trial is not contrary to the interests of the patient
  • The research is intended to be therapeutic, and poses no more risk than is inherent to the participant’s condition, or would be caused by alternative treatments
  • The participant, his/her 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 participant will be informed, and consent obtained, once he/she has undergone the necessary emergency procedures and regained consciousness
  • 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.

Research Involving Unconscious Persons

The SA-GCPs, the G-EthicsHR, 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), include any relevant statutory authorities, on that person's behalf. Because of their extreme vulnerability, unconscious persons should be excluded from all but minimally invasive observational research.

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 4.8
Informed Consent > Vulnerable Populations
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 1 (2(c)(iv)), Chapter 2 (7, 8, and 11), and Chapter 9 (70(2)(d)) and 71)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.2.8, 2.1, 2.3, and 3.5
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 1.3, 2.3, 3.1, 3.2, 3.4, and 4.5
(4) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 1, 2.4.6, 3.1, 4.1.2, 4.1.3, and 6.3
(5) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 1 and 4
Summary

Overview

In all South African clinical trials, research participants from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

The NHA, the SA-GCPs, the G-EthicsHR, 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, and other vulnerable groups such as collectivities, and persons in dependent relationships. Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

The ethic committees (ECs) must pay special attention to protecting participants from vulnerable populations. The ECs may impose additional measures such as requiring post-research investigations to be conducted. 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 risk are assessed and minimized, and appropriate consent procedures are followed

See Informed Consent topic, and the subtopics of Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired for additional information about these populations. Information on the other vulnerable populations specified in the SA-GCPs and the G-EthicsHR is provided below.

Persons in Dependent Relationships or Hierarchical Situations

Participants whose proposed involvement in research arises from dependent or hierarchical relationships need additional attention, and the EC must be satisfied 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

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 his/her medical treatment.

Terminally Ill Patients

Terminally ill patients require additional protection as they are more vulnerable to developing unrealistic expectations of benefits. Investigators must ensure that the prospective benefit from participation is neither exaggerated nor used to justify a higher risk than that involved in the patient’s current treatment. Investigators must also respect the participants’ wishes to spend time as they choose, particularly with family members.

The Elderly

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

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
Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 1.61, 3.1, and 4.8
Informed Consent > Children/Minors
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 2.3, 2.3.1, 2.3.1.1, 2.3.1.2, and 2.3.1.3
(2) (Guidance) Guidelines for Good Practice in the Health Care Professions: Seeking Patients’ Informed Consent: The Ethical Considerations, Booklet 4 (G-GPHlthCare-IC) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 8.5
(3) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 9 (71)
(4) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.2
(5) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 5, 6.3 and 8.5
(6) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 4 and 7
(7) (Guidance) Ministerial Consent for Non-therapeutic Health Research with Minors: Operational Guidelines (G-MinisterConsent) (2015)
National Health Research Ethics Council, National Department of Health
Relevant Sections: 1-6 and Appendices 1-3
(8) (Legislation) Protection of Personal Information Act, 2013 (Act No. 4 of 2013) (POPIA) (November 19, 2013)
Parliament
Relevant Sections: Chapter 3 (35)
Summary

Overview

The SA-GCPs state that a minor is a person under 21 years of age and that assent from the minor should be obtained where he/she is capable of understanding.

On the other hand, 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.

According to the NHA, the G-EthicsHR, 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 where he/she 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, 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 he or she is capable of understanding

See the NHAParticipants for detailed application requirements.

In addition, 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 SA-GCPs, the G-EthicsHR, 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. Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Assent Requirements

The SA-GCPs and the G-EthicsHR 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 he/she fails to object during the informed consent process. It is necessary for the minor/child and his/her legal representative(s) or guardian(s) to be in agreement on participation. The minor’s/child’s refusal to participate is final.

Conflict in Laws Regarding Minors/Children

As per the G-GPHlthCare, South African law has been inconsistent in its approach to addressing the capacity of minors/children to consent. Currently, there are no clear legal statutes specifying when children can independently consent to research.

Data Protection

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.
Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 4.8
Informed Consent > Pregnant Women, Fetuses & Neonates
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: 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))
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 2.3.2.1 and 2.3.2.3
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.2
Summary

Overview

As per the NHA, the SA-GCPs, and the G-EthicsHR, any research studies involving pregnant women, women who may become pregnant, or fetuses, required 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 potential for additional health concerns that may arise during pregnancy, and the need to avoid unnecessary risk to the fetus.

The following conditions are required for research to be conducted involving pregnant women and fetuses:

  • Appropriate studies on animals and non-pregnant individuals have been completed
  • The risk to the fetus is minimal and is the least possible risk for achieving the study’s objectives, except where the purpose of the study is to meet the health needs of the mother and the fetus, and the foreseeable benefits outweigh the potential risks
  • Individuals engaged in the study have no part in deciding the timing, method, and procedures to be used to terminate the pregnancy, or in determining the viability of the fetus at the termination of the pregnancy

Pregnant women and fetuses may not be involved as research participants unless the mother and the fetus will be placed at risk to the minimum extent necessary to achieve the study’s health objectives, the purpose of the research is to meet the mother’s health needs, and the mother is legally competent, and has given informed consent after having been fully informed about the possible impact on the fetus.

In certain circumstances, recognition should be given to the interests of the father of the fetus to participate in decision making. However, the father's informed consent is not required if the purpose of the research is to meet the mother’s health needs, the father’s identity or whereabouts cannot reasonably be ascertained, the father is not reasonably available, or the pregnancy is a result of rape.

Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum). (See the Informed Consent topic, Required Elements subtopic for general informed consent form requirements).

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 4.8
Informed Consent > Prisoners
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 2 (7, 8, and 11) and Chapter 9 (71)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 2.3, 2.3.4, and 2.3.5
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.2
(4) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 4
Summary

Overview

According to the NHA, the SA-GCPs, the G-EthicsHR, and the NHAParticipants, a prisoner may not, even with his/her consent, participate in any scientific experimentation, research study, or clinical trial except under limited conditions . A research study may involve a prisoner as a participant only after the ethics committee (EC) has ensured that the clinical trial involves the following:

  • The study of the possible causes, effects, and processes of incarceration, and of criminal behavior
  • No more than minimal risk and inconvenience to the participants
  • The study of prisons as institutional structures or of prisoners as incarcerated persons
  • Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on diseases that may be more prevalent in prisons, and research on social and psychological problems such as alcoholism, drug addiction, and sexual assaults) only after appropriate experts have been consulted
  • Research on practices, both innovative and accepted, that have the intent and probability of improving the health or well-being of prisoners
  • The rights of prisoners, including but not limited to the rights to dignity, privacy, bodily integrity, and equality, will be protected
  • The Department of Correctional Services’ procedures and guidelines will be followed

An EC reviewing the protocol involving prisoners must also ensure that:

  • A majority of the EC members have no association with the prisoner(s) involved
  • Where possible, a prisoner or an ex-prisoner should be an EC member
Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 1.61
Informed Consent > Mentally Impaired
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 2 (7, 8, and 11), and Chapter 9 (71)
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 2.3, and 2.3.3
(3) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 2.3 and 3.2
(4) (Guidance) Guidelines for Good Practice in the Health Care Professions: General Ethical Guidelines for Health Researchers, Booklet 13 (G-GPHlthCare) (September 2016)
Health Professions Council of South Africa
Relevant Sections: 4 and 6.3
(5) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 4
Summary

Overview

According to the NHA, the SA-GCPs, the G-EthicsHR, 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.

Research involving these populations must conform to the following requirements:

  • Be relevant to mental disabilities or substance abuse related disorders so that it is necessary to involve people who have a mental disability or a substance abuse related disorder(s)
  • Justify the involvement, as the study population of institutionalized persons with mental disabilities
  • Ensure appropriate evaluation procedures for ascertaining the participants’ ability to give informed consent. If participants are deemed unable to understand or to make a choice, then an appropriate individual who is able to consent on their behalf must be identified
  • Ensure that consent is free from coercion and risk to participants
  • Ensure that only minimal risk is involved, and that the risk is outweighed by the anticipated benefits for the participants, and by the importance of the knowledge that will be gained from the research

In addition, persons with mental or intellectual impairment should not participate in research that might be conducted equally well with persons without those impairments. Consent to conduct research must be obtained from:

  • The participant, whenever he/she is competent to give informed consent
  • The participant’s legal representative(s) or guardian(s) where the participant is deemed not competent to do so
  • An authority, organization, or person having that responsibility by law

Consent cannot be given for participation in research that is contrary to the interests of the person with the mental or intellectual impairment. The mentally or intellectually impaired person's refusal to participate in research must always be respected. Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 1.61 and 3.1
Investigational Products > Definition of Investigational Product
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1 and Appendix F
(2) (Guidance) PIC/S Guide to Good Manufacturing Practice for Medicinal Products, PE009-14 (PIC-S-GMP-Guide) (July 1, 2018)
The Pharmaceutical Inspection Co-operation Scheme
Relevant Sections: Annex 13
(3) (Guidance) SA Guide to Good Manufacturing Practice for Medicines (SA-GMPs) (Version 6) (December 2017)
South African Health Products Regulatory Authority
Relevant Sections: 2
Summary

Overview

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

Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 1.33
Investigational Products > Manufacturing & Import
Last content review/update: July 23, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 3.6, and 4.15
(2) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: 23
(3) (Legislation) Medicines and Related Substances Act (Act No. 101 of 1965) (MRSA) (Amended 2015)
Parliament
Relevant Sections: 21
(4) (Guidance) SA Guide to Good Manufacturing Practice for Medicines (SA-GMPs) (Version 6) (December 2017)
South African Health Products Regulatory Authority
Relevant Sections: 2
(5) (Guidance) PIC/S Guide to Good Manufacturing Practice for Medicinal Products, PE009-14 (PIC-S-GMP-Guide) (July 1, 2018)
The Pharmaceutical Inspection Co-operation Scheme
Relevant Sections: Annex 13
(6) (Guidance) Post Clinical Trial Access (PTA)/Continued Access (G-PostCTAccess) (Version 2) (April 2019)
South African Health Products Regulatory Authority
Summary

Overview

According to the SA-GCPs and the GRMRSA, the South African Health Products Regulatory Authority (SAHPRA) is responsible for authorizing the manufacture of investigational products (IPs) in South Africa. In addition, IPs which are unregistered medicines may only be brought into the country after the clinical protocol has been approved by the SAHPRA.

The SA-GCPs states that the clinical trial application approval document issued by the SAHPRA also serves as the importation permit for the unregistered IP under MRSA. (See Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics and Regulatory Authority topic, Regulatory Fees subtopic for detailed application requirements).

Pursuant to the SA-GMPs, South Africa adopted the PIC-S-GMP-Guide for the manufacturing of therapeutic goods. In addition, as per Additional Resources (A) and (B), the SAHPRA requires a Certificate of Analysis to be issued by the manufacturer for all IPs to be used in a clinical trial. Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

The G-PostCTAccess guides sponsors in 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. See Sponsorship topic, Compensation subtopic for additional considerations.

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

Additional Resources
WHO Technical Report Series, World Health Organization
(B) (Document) Regulatory Requirements for the ZA CTD (September 15, 2010)
Southern African Pharmaceutical Regulatory Affairs Association
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 2.12 and 5.13
Convention on Biological Diversity, United Nations
(E) (Website) Country Profile: South Africa (Current as of July 17, 2020)
Access and Benefit-sharing Clearing-house, Convention on Biological Diversity, United Nations
Investigational Products > IMP/IND Quality Requirements
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 3.2, 4.14, 4.15, 4.16, and Appendix F
(2) (Guidance) PIC/S Guide to Good Manufacturing Practice for Medicinal Products, PE009-14 (PIC-S-GMP-Guide) (July 1, 2018)
The Pharmaceutical Inspection Co-operation Scheme
Relevant Sections: Annex 13
(3) (Guidance) SA Guide to Good Manufacturing Practice for Medicines (SA-GMPs) (Version 6) (December 2017)
South African Health Products Regulatory Authority
Relevant Sections: 2
Summary

Overview

The SA-GCPs states that the information required to support the quality of the investigational product (IP) in South Africa is based upon the principles set forth in Section 7 (Investigator’s Brochure (IB)) of the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

IB Content Requirements

The SA-GCPs and the ICH-GCPs-Addendum 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; regulatory and postmarketing experiences)
  • Summary of data and guidance for the investigator(s)
  • Bibliography

See Section 7 of the ICH-GCPs-Addendum for detailed content guidelines.

The sponsor is also accountable for supplying the IP, including the comparator(s) and placebo, if applicable. As defined in the SA-GCPs, he/she must ensure that the products are manufactured in accordance with the good manufacturing practices as prescribed in Annex 13 of the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). (See Investigational Products topic, IMP/IND Quality Requirements subtopic for additional information on IP supply, storage, and handling requirements).

In addition to including the IB with the clinical trial application submission, the South African Health Products Regulatory Authority (SAHPRA) also requires the application to provide a detailed review of the IPs to be used in the study. As indicated in Additional Resource (A), the following information must be furnished:

  • IP name(s) and details (e.g., formulation(s) and strength(s))
  • Comparator product(s) name(s) and details
  • Concomitant name(s) and details including rescue medications
  • Estimated quantity of trial material (each drug detailed separately) for which exemption will be required
  • 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
  • Date SAHPRA registration applied for or envisioned date of application for trial medication; explain if registration is not envisioned
  • Registration status of entity, for the indication to be tested in this trial, in other countries

See Additional Resource (A) for detailed instructions on IP submission requirements.

Certificate of Analysis

As stated in the Manufacturing & Import subtopic, the SAHPRA requires a Certificate of Analysis (CoA) to be issued by the manufacturer for all IPs to be used in a clinical trial. The CoA should identify the compound, dose, batch numbers, expiration dates, excipients, stability information (if available), and include a statement that the product is manufactured according to any applicable good manufacturing practices as described in the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). For the placebo group, the CoA must demonstrate that no active component exists in the formulation. If a comparator drug product is to be used in the trial, the CoA should confirm the appearance, dose, composition, expiration dates, stability (if available), and batch numbers for the product.

Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
WHO Technical Report Series, World Health Organization
(C) (Document) Regulatory Requirements for the ZA CTD (September 15, 2010)
Southern African Pharmaceutical Regulatory Affairs Association
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 7
Investigational Products > Labeling & Packaging
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1 and 4.15
(2) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: 10 and 30 (9)
(3) (Guidance) PIC/S Guide to Good Manufacturing Practice for Medicinal Products, PE009-14 (PIC-S-GMP-Guide) (July 1, 2018)
The Pharmaceutical Inspection Co-operation Scheme
Relevant Sections: Annex 13
(4) (Guidance) SA Guide to Good Manufacturing Practice for Medicines (SA-GMPs) (Version 6) (December 2017)
South African Health Products Regulatory Authority
Relevant Sections: 2
Summary

Overview

Investigational product labeling in South Africa must comply with the requirements set forth in the SA-GCPs, the GRMRSA, and the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs). The GRMRSA states that for an investigational product (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.

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, specialised 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.

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

Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 5.13
Investigational Products > Product Management
Last content review/update: June 18, 2020
Requirements
(1) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 2.1, 3.6, 4.14, 4.15, 4.16, 4.9, Appendix C (3.1), and Appendix F
(2) (Legislation) Medicines and Related Substances Act (Act No. 101 of 1965) (MRSA) (Amended 2015)
Parliament
Relevant Sections: 21
(3) (Guidance) PIC/S Guide to Good Manufacturing Practice for Medicinal Products, PE009-14 (PIC-S-GMP-Guide) (July 1, 2018)
The Pharmaceutical Inspection Co-operation Scheme
Relevant Sections: Annex 13
(4) (Guidance) SA Guide to Good Manufacturing Practice for Medicines (SA-GMPs) (Version 6) (December 2017)
South African Health Products Regulatory Authority
Relevant Sections: 2
(5) (Guidance) Good Pharmacy Practice in South Africa (SA-GPPs(4th Edition) (2010)
South African Pharmacy Council
Summary

Overview

In accordance with the SA-GCPs, the sponsor is responsible for providing the investigator(s) with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational product(s) (IPs) including chemical, pharmaceutical, toxicological, pharmacokinetic, and pharmacodynamic data obtained from studies in animals as well as in humans, and the results of earlier clinical trials, if applicable. The information provided should be accurate and adequate to justify the nature, scale, and duration of the proposed trial, and to evaluate the potential safety and need for special precautions. Moreover, a sponsor must bring any new and relevant information arising during the study to the attention of the principal investigator(s) (PI(s)) and the ethics committee(s) (ECs), and update the IB, as required. The sponsor should also include all of the information contained in the IB in the clinical protocol. Refer to the Clinical Trial Lifecycle topic, Submission Content subtopic for additional IP requirements.

Per the SA-GCPs, the sponsor should also follow the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum).

Investigational Product Supply, Storage, and Handling Requirements

As defined in the SA-GCPs, the sponsor must also supply the PIs/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor should not supply the PI(s)/institution(s) with the IP(s) until the sponsor obtains approvals from the South African Health Products Regulatory Authority (SAHPRA) and the EC. The SAHPRA approval is also a written authorization document to import unregistered drug products under MRSA.

The sponsor must provide the PI(s)/institution(s) with written procedures to follow for IP(s) handling and storage. The sponsor must ensure the following:

  • Timely delivery of IP(s) to the PI(s)/institution(s)
  • Maintenance of records documenting IP(s) shipment, receipt, disposition, return, and destruction
  • Maintenance of a system for retrieving IPs and documenting this retrieval
  • Maintenance of a system to dispose of unused IP(s) and corresponding documentation
  • Ensuring the IP(s) are stable over the period of use
  • Maintenance of sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary
  • Maintenance of records of batch samples analyses and characteristics

The sponsor must also ensure that the products are manufactured in accordance with any applicable Good Manufacturing Practices which are described in the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs), and are coded and labeled in a manner that protects the blinding, if applicable. IP labeling should comply with the PIC-S-GMP-Guide labeling requirements. 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.

In blinded trials, 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. 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 available prior to its use in the clinical trial. Refer to the SA-GCPs for detailed sponsor-related IP requirements.

Record Requirements

The sponsor is required to retain essential documents for at least 15 years, or, until at least two (2) years after the last approval of a marketing application and until there are no pending or contemplated marketing applications, or, at least 15 years have elapsed since the formal discontinuation of clinical development of the IP. These documents should be retained for a longer period however if required by the applicable regulatory requirement(s) or if needed by the sponsor.

The sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial related records are no longer needed.

Additional Resources
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
Relevant Sections: 5.5, 5.12, 5.13, 5.14, and 7
Specimens > Definition of Specimen
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to the Registration of Microbiological Laboratories and the Acquisition, Importation, Handling, Maintenance and Supply of Human Pathogens (No.R.178) (NHARegMicroLabs) (March 2, 2012)
Parliament
Relevant Sections: 1
(2) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: Chapter 3 (3.3) and Appendix 1
(3) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to the Use of Human Biological Materials (No.R.177) (NHABiol) (March 2, 2012)
Parliament
Relevant Sections: 1
(4) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to the Import and Export of Human Tissue, Blood, Blood Products, Cultured Cells, Stem Cells, Embryos, Foetal Tissue, Zygotes and Gametes (No.R.181) (NHABlood&Cells) (March 2, 2012)
National Department of Health
Relevant Sections: 1
(5) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: 1
(6) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Tissue Banks (R.182) (NHATissue) (March 2, 2012)
National Department of Health
Relevant Sections: 1
(7) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Stem Cell Banks (R.183) (NHAStemCell) (March 2, 2012)
National Department of Health
Relevant Sections: 1
Summary

Overview

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, 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 follows the G-EthicsHR 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 defines “human biological materials” with the same definition as is used for “biological specimen.”

In addition, the NHABlood&Cells generally refers to substances of human origin as biological substances.

Please refer to the G-EthicsHR, the NHABiol, the NHA, the NHABlood&Cells 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.

Additional Resources
No additional resources
Specimens > Specimen Import & Export
Last content review/update: June 18, 2020
Requirements
(1) (Regulation) Medicines and Related Substances Act, 1965 (Act No. 101 of 1965): General Regulations (No. 859) (GRMRSA) (Effective Date: May 2, 2003; Latest Amendment: August 25, 2017)
National Department of Health
Relevant Sections: 23
(2) (Guidance) Guidelines for Good Practice in the Conduct of Clinical Trials With Human Participants in South Africa (SA-GCPs) (2nd edition) (2006)
National Department of Health
Relevant Sections: 1.6 and 4.3
(3) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Research with Human Participants (No.R.719) (NHAParticipants) (September 19, 2014)
Parliament
Relevant Sections: 3
(4) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 8 (54, 57, 60, and 68)
(5) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to the Import and Export of Human Tissue, Blood, Blood Products, Cultured Cells, Stem Cells, Embryos, Foetal Tissue, Zygotes and Gametes (No.R.181) (NHABlood&Cells) (March 2, 2012)
National Department of Health
Relevant Sections: 2, 3, 4, 5, and 7, and Annexures 1-6
(6) (Legislation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to the Registration of Microbiological Laboratories and the Acquisition, Importation, Handling, Maintenance and Supply of Human Pathogens (No.R.178) (NHARegMicroLabs) (March 2, 2012)
Parliament
Relevant Sections: 2-13 and Forms 1 and 2
(7) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Tissue Banks (R.182) (NHATissue) (March 2, 2012)
National Department of Health
Relevant Sections: 1, 3, and 16
(8) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Stem Cell Banks (R.183) (NHAStemCell) (March 2, 2012)
National Department of Health
Relevant Sections: 1 and 2
Summary

Overview

As delineated in the GRMRSA, the SA-GCPs, and the NHAParticipants, to conduct a clinical trial using biological substances, a sponsor or his/her designated contract research organization (CRO) must submit a clinical trial application to receive approval from the South African Health Products Regulatory Authority (SAHPRA) and the local accredited ethics committee(s) (ECs). In addition, per the NHA, the NHABlood&Cells, 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 SAHPRA approval letter and the NDOH import/export permit must be included with each biological substance shipment. See also the Clinical Trial Lifecycle topic, Submission Content subtopic for information on completing a clinical trial application.

NDOH Application Requirements

As set forth in the NHA, the NHABlood&Cells, 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 NHABlood&Cells, 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 NHABlood&Cells 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 he/she is satisfied that the submission meets the NHA, the NHABlood&Cells, 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 NHABlood&Cells 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 NHABlood&Cells and Additional Resource (B), 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 NHABlood&Cells. 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 NHABlood&Cells 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.
Additional Resources
(A) (Form) Application to Conduct a Clinical Trial (Version 6) (CTF1) (March 2020)
South African Health Products Regulatory Authority
(B) (Booklet) Biological Substances Export/Import Permits (Date Unavailable)
TNT and South African Clinical Research Association (SACRA)
Specimens > Consent for Specimen
Last content review/update: June 18, 2020
Requirements
(1) (Legislation) National Health Act, 2003 (Act No. 61 of 2003) (NHA) (July 23, 2004)
Parliament
Relevant Sections: Chapter 8 (55, 56, 57, 62, 67, and 68)
(2) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Regarding the General Control of Human Bodies, Tissue, Blood Products, and Gametes: Amendment (NHASpecAmend) (April 26, 2017)
National Department of Health
Relevant Sections: 1 and 2
(3) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to the Use of Human Biological Materials (No.R.177) (NHABiol) (March 2, 2012)
Parliament
Relevant Sections: 3, 4, and 7
(4) (Legislation) Children’s Act 38 of 2005 (Children’s Act) (Effective April 1, 2010)
Parliament
Relevant Sections: Chapter 7 (Part 3, Section 129)
(5) (Guidance) Ethics in Health Research: Principles, Processes and Structures (G-EthicsHR(2nd Edition) (2015)
National Department of Health
Relevant Sections: 3.3
(6) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Tissue Banks (R.182) (NHATissue) (March 2, 2012)
National Department of Health
Relevant Sections: 6
(7) (Regulation) National Health Act, 2003 (Act No. 61 of 2003): Regulations Relating to Stem Cell Banks (R.183) (NHAStemCell) (March 2, 2012)
National Department of Health
Relevant Sections: 2 and 5
Summary

Overview

In accordance with the NHA, the NHASpecAmend, and the NHABiol, prior to removing or withdrawing any biological material from the body of a living person for research purposes, consent must be obtained from that person in writing, before a competent witness. In the event that the person is a minor, the parents or guardians of that person must provide consent. Furthermore, when withdrawing blood, the NHASpecAmend requires written consent from persons older than 16 years.

The NHABiol specifically states that when taking biological samples from a child, where the person is younger than 18 years, Part 3, Section 129 of the Children’s Act must be followed.

Additionally, the NHABiol requires the following consent for the removal or withdrawal of biological samples to treat a person with mental illness:

  • His/her consent, if he/she is capable;
  • A court appointed curator, spouse, next of kin, parent or guardian, major child, brother, or sister, partner or associate, if the mentally ill person is incapable of giving consent; and
  • The head of the health institution in the case of an emergency

Similarly, the NHA and the NHABiol include consent provisions for the donation of human bodies and the tissue of deceased persons. These documents state that any person who is competent to make a will may donate his/her body or any specified tissue to be used after his/her death for medical and dental purposes, as long as he/she signs the will in the presence of at least two (2) competent witnesses. The person may also give consent to a post-mortem examination of his/her body for research purposes, and may select an institution or person as the recipient. In the absence of a donation as described above, the individual’s spouse, child over 18 years, parent, guardian, or brother/sister over 18 years may donate his/her body or any specific tissue to an institution or person for research purposes. Please refer to the NHA, and the NHABiol for detailed requirements. (See the Informed Consent topic, Required Elements and Participant Rights subtopics for additional information on informed consent).

Human Tissue Sample Consent Requirements

The G-EthicsHR presents separate consent provisions for the use of human tissue samples. With reference to human tissue samples, donor consent should be obtained where it is proposed to use tissue samples that have been held:

  • in storage following, or in association with, clinical investigations
  • in archives or banks, or removed during a clinical study, or used in research that may lead to harm, benefit, or injustice to a donor of such tissue

This guideline also requires that consent be voluntary and specific to the purpose for which the tissue is to be used. The participant must be given full information about the study, be advised on storage and future use of samples, and be assured of data related confidentiality and privacy.

In addition, per the NHATissue, tissue banks are required to develop donor record management systems in which the tissue donor register contains the full identity and relationship of the consenting person. The system will also document tissue banking processes, including the process of obtaining informed written consent.

Human Stem Cell Consent Requirements

The NHAStemCell similarly states that authorized stem cell banks must retain a record of the donor’s written informed consent. Further, no person shall use stem cells or its therapeutic research products for educational purposes unless he/she is authorized by the National Department of Health (NDOH) and complies with the following requirements:

  • Has obtained the donor’s informed written consent even in the case of residual tissue, blood or blood products; and
  • Is certain the donor has donated voluntarily and it is properly documented

The NHA also indicates that the NDOH Minister may permit research on stem cells and zygotes that are not more than 14 days old on a written application, and if the applicant documents the research for record purposes, and prior consent is obtained from the donor.

Human Genetic Research Consent Requirements

The G-EthicsHR states that the investigator or institution must obtain consent for human genetic research. Investigators and institutions must comply with numerous requirements to ensure participant consent, protection, and privacy rights are upheld with regard to the storage of genetic materials. See the G-EthicsHR for consent requirement details.

Consent Waivers

In reference to both human tissue sample and genetic research consent, the G-EthicsHR indicates that an ethics committee may sometimes waive the consent requirement in cases where there is minimal risk of commercial exploitation or privacy violations. For additional details, see section 3.3 of the G-EthicsHR.

Additional Resources
M S Pepper, South African Journal of Bioethics and Law
Sections Country Announcement
Country Announcement
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COVID-19 Guidance

In June 2020, the South African Health Products Regulatory Authority (SAHPRA) released the 2-Weekly Abridged COVID-19 Interim Progress Report Form for Clinical Trials, which is to be completed two-weekly from SAHPRA’s approval date of the clinical trial. This form does not replace the required six-monthly progress report form for clinical trials.

African regulatory agencies, ethics committees to expedite COVID-19 clinical trial reviews (April 20, 2020)

On April 13, 2020, the SAHPRA issued GCP Training and Expedited Review of Clinical Trial Applications during COVID-19 Pandemic. The notice states that SAHPRA has amended requirements for in-person good clinical practice (GCP) training to allow for online training during the COVID-19 pandemic. The notice also states that SAHPRA is committed to reviewing COVID-19 clinical trial applications within 7 to 10 working days and refers applicants to the newly released Application to Conduct a Clinical Trial: Guidance in Conditions of a Public Health Emergency.

On March 25, 2020, SAHPRA issued SAHPRA Policy on Conduct of Clinical Trials of Health Products during the Current COVID-19 Pandemic. The guidance covers items such as participant safety, maintaining compliance with GCPs, and minimizing risks to trial integrity.

This message was reviewed on August 14, 2020
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