Clinical Research Regulation For South Africa and United Kingdom

Last content review/update: January 17, 2025

Overview

In accordance with the GRMRSA, the South African Health Products Regulatory Authority (SAHPRA) is responsible for reviewing and approving all clinical trial applications for an unregistered medicine, and for any new indication or dosage regimen of a registered medicine. The scope of the SAHPRA’s assessment includes all clinical trials (Phases I-IV) and bioequivalence/bioavailability studies. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and a registered ethics committee (EC) may be conducted in parallel. However, the G-EthicsHR-ZAF recommends that scientific review be completed prior to ethics review, and in cases where scientific review capacity is not available, the EC approval should be delayed until SAHPRA scientific approval has been provided.

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

Clinical Trial Review Process

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

As stated in ZAF-36, the CTU completes a preliminary screening of the application and sends an official letter to the applicant with the outcome and follow-up questions on a screening checklist. As indicated in ZAF-23, incomplete documentation or sub-standard submissions will be rejected. Additionally, applications submitted without clinical trial insurance will be rejected. Applicants will be allowed a maximum of two (2) rounds of queries to respond to, and if the responses are not satisfactory, the application will be rejected. Per ZAF-36, if an application is rejected, no response is required; the screening checklist should be used as guidance for resubmission during the next review cycle. Next, the CTU’s Clinical Trial Committee (CTC) (which includes an expert committee of specialists, as needed) reviews the proposed clinical trials pursuant to the schedule on SAHPRA’s website. (See ZAF-11 for 2025 dates). Per ZAF-1, clinical trial reviews will result in one (1) of the following outcomes:

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

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

Other Considerations

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

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

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

Review of Clinical Trials (Expert Committee Review)

9.3.2

3.1

Part 30 (1)

Last content review/update: January 21, 2025

Overview

In accordance with the MHCTR and the MHCTR2006, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). (Note: IPs are known as investigational medicinal products (IMPs) in the United Kingdom (UK)). The G-CTApp specifies that the scope of the MHRA’s assessment includes all clinical trials (Phases 1-4). Per G-CTApp and G-IRASCombRev, all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, which offers a single application route and parallel/coordinated review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Regarding licensing of biosimilars (i.e., generic biotech medicines), see the G-Biosimilars for details on the UK’s recent regulatory changes to ease or remove clinical trial requirements for the MHRA’s review and approval of biosimilars.

Clinical Trial Review Process

Per GBR-72, under combined review, research teams make a single application using a new part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78), which goes to both the MHRA and an EC at the same time. The regulatory and ethics reviews are done in parallel and any requests for further information are raised jointly. A single response to these requests leads to a single decision from both reviews. The G-CTApp states that the initial combined review assessment will be completed within 30 days of application submission. Applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and the MHRA will work with the EC to expedite these applications. When applications need expert advice, the MHRA will seek advice from the Clinical Trials, Biologicals and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM). In addition, the CHM will then discuss the trial at their meeting, which will take place later in the same week as the CTBV EAG meeting. See the G-CTApp for examples of which trials require expert advice and for detailed requirements. The MHRA also supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. These trial designs are characterized by the presence of prospective major adaptations, such as the addition of new IPs or introducing new trial populations. Before submitting a clinical trial application with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

The G-CTApp states that under the combined review process, the MHRA will inform applicants of the outcome of the submission along with the EC’s review and decision. The outcomes could be one (1) of the following:

Acceptance of the request for a clinical trial authorization
Acceptance of the request for a clinical trial authorization subject to conditions
Grounds for non-acceptance of the request for a clinical trial authorization

As indicated in the G-CTApp, with respect to grounds for non-acceptance, applicants will have the opportunity to respond, usually within 14 days; however, this may be extended on request. A communication informing the applicant of the combined MHRA and EC decision will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of a decision relating to a gene therapy product, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application, unless otherwise advised. Communications will be sent electronically via email from MHRA_CT_Ecomms@mhra.gov.uk. The MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the application is considered authorized. (See the Timeline of Review section for additional details.)

Per GBR-9, the EC’s ethical opinion applies for the duration of the study, which was stated in the clinical trial application and protocol. An extension of the study period is not in itself a substantial amendment, except where it is related to other amendments that would be substantial, such as an increase in target recruitment, addition of new procedures or sub-studies, or extension of follow-up. Where the duration of the study is to be extended beyond the period specified in the application form, the EC should be notified.

IRAS (GBR-78) is a single system for applying for the permissions and approvals for health and social care/community care research in the UK. It generates the IRAS ID and uses filters to ensure that the data collected and collated is appropriate to the type of study, and consequently the permissions and approvals required. The system helps applicants meet the regulatory and governance requirements. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For details on HRA’s assessment criteria and standards for approval, see GBR-29.

UK-wide Research

The UKwide-Rsrch specifies that the four (4) UK nations take a consistent approach to study-wide reviews with one (1) application for all relevant UK sites. Each UK nation will take assurances from the study-wide review conducted by the lead nation (the nation conducting the initial review). The following outlines key differences in approvals from UK nations:

England and Wales – For any research taking place in England and/or Wales, the sponsor will receive an HRA and HCRW approval letter, which will detail any further requirements before beginning the research
Northern Ireland – Each participating Northern Ireland Health and Social Care body will confirm their capacity and capability after the relevant study-wide reviews and participating site assessments and arrangements are complete
Scotland – For any research taking place in Scotland, the sponsor will receive Research & Development permission after the relevant study-wide reviews and site assessments and arrangements are complete

Notification Scheme

Per the G-CTApp, MHRA’s notification scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications. The scheme only applies to clinical trial applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Interest in the notification scheme should be registered via the combined review process described above (GBR-125). MHRA acceptance of an application under the notification scheme will be confirmed within 14 calendar days from the application received effective date and authorization by the MHRA will be granted unless any criterion is not suitably met. If the MHRA determines the application does not meet the notification scheme criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under full clinical trial assessment with a decision communicated within the 30-day statutory timeframe.

As indicated in the G-CTApp, the notification scheme acceptance criteria are as follows:

Phase 4 trials must meet both of the following criteria:

All IPs are licensed and used according to the relevant UK, United States of America (USA), or European Union (EU) marketing authorization (except for placebo)
There are no ongoing safety concerns with the IP(s) that the sponsor is aware of, for example other trials on temporary halt/clinical hold, other trials with unresolved urgent safety measures or post-marketing regulatory restrictions

Phase 3 trials must meet at least one (1) of the following criteria:

The trial is already approved in the USA or EU based on the same protocol and Investigator’s Brochure (IB) versions submitted to MHRA, and for EU approvals, the same version of the IP dossier. For trials approved in the USA only, the IP dossier submitted to the MHRA must document the same IP manufacturing process
The MHRA has approved in the last two (2) years a previous Phase 3 clinical trial of the IP(s) at the same dose (or a higher dose), dosing frequency (or a higher frequency) and route of administration, and for the same indication (even if the trial was with a different sponsor) and utilizing the same manufacturing process
IPs are licensed and used according to the relevant UK, USA, or EU marketing authorization (except for placebo)

In addition, the G-CTApp states that to be eligible for the scheme, a Phase 3 trial must not include any of the following:

Complex, innovative trial design (e.g., basket, umbrella, and platform) that allows for prospective major adaptations such as the addition of indications or IPs via future amendments
Includes pediatric participants
Includes pregnant or breastfeeding participants
IP is first in class
IP is an advanced therapy medicinal product (ATMP)

Brexit Background

Per the G-MHRASubmiss, Brexit, the EUCouncil-Brexit, the WithdrlAgrmt, and the G-AfterTransition, the UK withdrew from the EU on January 31, 2020. The MHRA updated and published clinical trials guidance that became effective on January 1, 2021. G-AfterTransition summarizes the guidance to sponsors and researchers. Furthermore, the G-MHRASubmiss describes how to make certain regulatory submissions to the MHRA (substantial amendments, end-of-trial notifications, and developmental safety update reports (DSURs)). Per the MHCTR-EUExit and as explained in GBR-115, the new guidance went into force via the MHCTR-EUExit (also known as the “Exit Regulations”). The Exit Regulations also update existing UK legislation by, for example, replacing references to EU databases with newly established UK databases. The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119. For broader information and a comprehensive Brexit “checker” of new rules in the UK, see GBR-60.

To help ensure the continuity of supply of IPs for clinical trials the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain EU regulatory processes for a time-limited period. This recognition is known as “standstill.”

GBR-115 indicates that the UK is committed to being as aligned as possible with the EU Clinical Trials Regulation (GBR-21). The MMDAct grants authority for regulations to be made that correspond or are similar to GBR-21. For more information about GBR-21, see GBR-54.

6

10.9

Help (Preparing and Submitting Applications)

When a clinical trial authorization (CTA) is needed, Trial Sponsor and legal Representative, Registration of your clinical trial, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, Assessment of your submission, New notification scheme, Requesting approval of trials with complex innovative designs, and Applications that need expert advice

Part 4 (Article 126)

Part 2 (Chapter 1)

Introduction and Article 1

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (2), Part 2 (5, 6, and 7), Part 3 (12, 14, 15, 17, and 18), and Schedule 2

Approvals for project-based research in the National Health Service (NHS) and Northern Ireland’s Health and Social Care (HSC) Service

Regulatory Fees

Last content review/update: January 17, 2025

South African Health Products Regulatory Authority

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

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

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

For amendments to clinical trials:

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

For licenses:

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

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

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

Payment Instructions

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

Applicants should submit a cover page that identifies the services requested using the template provided in ZAF-37
Payments should be referenced in accordance with the SAHPRA Fee Categorization Guideline (Annexure A of G-SAHPRAFees)
If the applicable bank limits reference spacing, follow the sequence listed in Annexure A as far as the limitation allows; spacing and dashes (/) may be omitted
Fee payments may be transferred directly into the bank account of SAHPRA via an electronic or manual deposit process
No check payments will be accepted
For administrative control purposes, applicants should make one (1) payment per service
Payment should only be made once the application and required dossiers are ready for submission
Payments do not have to be made upon request of an application number; however, the applications and required dossiers should be submitted within a reasonable time upon receipt of an application number or as specified in the relevant application guidelines
As soon as the fee payment has been made, the proof of payment and cover page should be attached and sent via email to SAHPRA Finance at pop@sahpra.org.za, and the relevant unit(s) processing the application should be copied on the email.
If the proof of payment has not been submitted, or no details to identify the payment reference as per the G-SAHPRAFees have been provided, and any further attempts to clear these payments fail after 12 months, any liability for SAHPRA to refund these payments will be forfeited
If a payment has been received without an application, the applicant will be notified to submit the required application within 14 working days, failing which, the amount will be forfeited
Requests for refunds should be submitted in line with Annex B in the G-SAHPRAFees
Payment and pro forma invoice queries and requests can be directed to finance@sahpra.org.za or 012 501 0323
See the G-SAHPRAFees for details on special requests for extensions to the deadline

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

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

Fee payment questions can be directed to finance@sahpra.org.za or 012 501 0470.

Sections 1-3 and Annexure A

35

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

Last content review/update: May 16, 2024

Medicines and Healthcare Products Regulatory Agency

As per the MHCTR, the MHCTR2006, and the G-CTApp, the sponsor or the designated representative is responsible for paying a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) to submit a clinical trial application for authorization. According to the G-MHRAPaymt, applicants will receive an invoice to make a payment for the outstanding amount after validation of the application. Applicants must pay invoices upon receipt or they will incur penalty fees. Non-payment may also result in suspension of any license or authorization, followed by legal proceedings for any unpaid amounts.

As delineated in the G-MHRAFees, the MHRA levies the following clinical trial processing fees:

3,366 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier (higher fee for phase 1, full and simplified IMP dossier)
248 British Pounds – Applications without an IMP dossier (lower fee for phase IV, cross referral, additional protocol)
248 British Pounds – Clinical trial variation/amendment
No cost – Phase 4 notification
248 British Pounds – Assessment of annual safety reports

Note per the G-MHRAFees, there is no annual clinical trials fee and no fee for Phase IV notifications. For a cross-referral or additional protocol submission, no new IMP dossier or investigators brochure data should be provided; however, copies of the relevant manufacturer’s authorization(s) and qualified person declaration (if applicable) should be provided since these are study specific.

Per the G-CTAuth-GBR, the fees for the annual safety reports are applicable to annual progress reports and Development Safety Update Reports (DSURs). From June 1, 2024, MHRA will only accept online payment of this fee via MHRA’s payments service (GBR-26) prior to submission of an annual safety report. Receipts generated will be sent by email and must be included in the report submission as proof of payment. Failure to provide evidence of payment will result in the submission being made invalid.

The G-CTApp further indicates that no fees are required for applications submitted and authorized under the Notification Scheme.

Payment Instructions

According to the G-MHRAPaymt, the MHRA does not accept checks. Payments can be made electronically by bank transfer, credit card, or debit card. The relevant invoice and customer number should be quoted when making payments. Bank transfers should be sent to:

Account Name: MHRA
Account Number: 10004386
Sort code: 60-70-80
Swift code: NWBKGB2L
IBAN: GB68NWBK60708010004386
Bank: National Westminster Bank

Bank address:
National Westminster Bank RBS
London Corporate Service Centre, 2^nd Floor
280 Bishopsgate
London
EC2M 4RB
UK

As per G-MHRAPaymt, credit or debit card payments may be made securely online using GBR-26. Remittance advice notices can be sent to sales.invoices@mhra.gov.uk and should include the relevant invoice number on the remittance advice. MHRA cannot accept any documentation sent by postal mail service. Further information can be obtained by emailing sales.invoices@mhra.gov.uk. G-MHRAPaymt further provides that clinical trial application invoice disputes/queries should be emailed to ctdhelpline@mhra.gov.uk and cc: sales.invoices@mhra.gov.uk.

The G-CTApp indicates that invoices for clinical trial authorization applications and substantial amendment applications are sent directly to the applicant shortly after a valid submission has been established. The applicant’s cover letter should clearly highlight the purchase order (PO) number where available. It is the responsibility of the applicant to ensure timely payment of invoices for their submissions. Invoices must be settled on receipt of invoice. For additional information, applicants may contact the MHRA Finance Department at 020 3080 6533 or sales.invoices@mhra.gov.uk.

Fees

Development Safety Update Reports (DSURs)

8. Clinical trials - application fees

11, 13, and Explanatory Note

Part 3 (17)

Ethics Committee

Last content review/update: January 17, 2025

Overview

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

The NHA and the G-EthicsHR-ZAF require that every institution, health agency, and health establishment at which research is conducted establish an EC or have access to an independent EC that is registered with the NHREC. Per the G-EthicsHR-ZAF, researchers without affiliation to an institution or organization with an EC should approach a registered EC to request it to review their health research protocols.

Ethics Committee Composition

As delineated in the SA-GCPs and the G-EthicsHR-ZAF, an EC must consist of members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of all proposed research studies. Further, per the G-EthicsHR-ZAF, ECs should be independent, multidisciplinary, multi-sectoral, and pluralistic. In general terms, membership should include the following:

As many disciplines, sectors, and professions as possible, appropriate to the remit of the specific EC
Members from diverse age groups and academic or professional ranks
Ethnically and culturally diverse members and an appropriate mix of genders
Lay persons
Researchers who do not conduct human participant research or animal use research

The G-EthicsHR-ZAF states that subject to institutional requirements, a chairperson could be appointed or elected at the first meeting of a newly constituted EC. Alternatively, the chairperson could be appointed by the institutional leadership for a period of three (3) to five (5) years, renewable once, if so specified in the terms of reference. The chairperson must have experience in research methodology and research ethics, should have at least two (2) years’ experience as an EC member and should have leadership experience. If the chairperson is an external appointee, the institution must provide the chairperson with the necessary support and authority to perform the role. The chairperson should be assisted by at least one (1) deputy chairperson, who is elected by the EC members and assists the chairperson and serves as the role of chairperson when necessary.

As delineated in the G-EthicsHR-ZAF, the composition of ECs should promote optimal human participant welfare, research integrity (including data robustness and scientific validity), defendable significance of proposed research questions (including translatability of scientific findings into practice, where applicable), as well as legal, professional, and regulatory compliance. All EC members should have documented proof (i.e., evidence) of research ethics training, refreshed at least once. EC membership should consist of:

A minimum of nine (9) members with a quorum being a simple majority; where the number of members is more than 15, the quorum may be 33%
At least one (1) layperson
At least one (1) member with knowledge of, and current experience in, the professional care, counselling, or health-related treatment of people, (e.g., a social worker, nurse, psychologist, or medical practitioner)
At least one (1) member with professional training and experience in qualitative research methodologies
Members with professional training and experience in quantitative research methodologies
A member with expertise in biostatistics
A member with expertise in research ethics
At least one (1) member who is legally qualified and has extensive knowledge of family law, health law, and research ethics

Terms of Reference, Review Procedures, and Meeting Schedule

Per the G-EthicsHR-ZAF, when appointing EC members, institutions should be mindful of the need for ECs to develop institutional memory among the membership as well as to ensure succession planning. Members of ECs should be appointed formally for periods of three (3) to five (5) years, renewable once, after which the member should step down for at least one (1) term. Appointments should overlap so that no more than half the committee membership is new at any one appointment time. ECs should have standard operating procedures (SOP) that specify meeting attendance expectations, possible sanctions if attendance is poor, expectations for promptness of reviews, preparation for meetings, agenda, minutes, etc. ECs must define the review timelines in their SOPs. The appointment letter should describe the essential expectations of membership. ECs should provide induction training for new members that includes discussion of the role of EC members, the code of conduct, expectations of integrity, and confidentiality. Each EC should also have terms of reference that include the delegated and inherent authority as well as the scope of the EC's authority, its responsibilities, its relationship to non-affiliated researchers, its accountability responsibilities, and the mechanisms for reporting and remuneration, if any, for members. See the G-EthicsHR-ZAF for a sample terms of reference.

In addition, per the G-EthicsHR-ZAF, EC members are expected to familiarize themselves with the institutional documentation, as well as the national and relevant international research ethics guidelines, and should have documented proof of such familiarity, e.g., an assessment of training certificate, not a mere attendance certificate. See the G-EthicsHR-ZAF for additional training requirements. The SA-GCPs stipulate that EC members who review clinical trial proposals should have research ethics training and good clinical practice training, evidenced by certificates issued in the last three (3) years.

The G-EthicsHR-ZAF states that it is important for ECs to have clear SOPs that clarify the expectations about EC members’ review responsibilities. For EC meetings, the quorum should be a simple majority, and where the number of members is more than 15, the quorum may be 33%.

Per the G-EthicsHR-ZAF, institutions must have a Code of Conduct for EC members, which details the conduct and integrity expectations of members, including regular and punctual attendance at meetings, diligent performance of responsibilities, maintenance of confidentiality, and management of potential conflicts of interest. The induction process for new members should require that they sign the Code of Conduct to indicate they know and understand the expectations. (See A2.6 Code of Conduct for REC members sample.) Institutions must also ensure there is a formal appointment letter for EC members that sets out the term of office and the assurance that members are indemnified from personal liability against claims that may arise in the course of ordinary business of the EC.

Per the G-EthicsHR-ZAF, ECs should correspond primarily with the principal investigator (PI) or a delegated signatory, and not with the sponsor unless dictated by specific circumstances. EC members should disclose information that may lead to potential, actual, and perceptions of conflict of interest. EC members should not review or make decisions about research protocols in which they are involved personally (including as supervisor of a student) or financially. When such a protocol is to be discussed, the member concerned must declare the potential conflict and offer to recuse themselves from the meeting for that time. Should the member be permitted to remain for the discussion at the discretion of the chairperson (e.g., to facilitate clarifications), the member must leave the meeting for the duration of the final decision-making discussion concerning the application in question. EC members and ad hoc reviewers must not use the ethics review process to impose personal biases, professional jealousy, or territorial protection conduct about an applicant's protocol, including about research methods or the topic. If applicants pay fees for the ethics review service, this must not negatively affect the rigor of reviews, the integrity of the process, or the capacity to monitor the research that the EC approves. The EC should be alert to whether an advocate for special interest groups of participants proposed for specific research would add value to the review process for informed responsible decision-making in the context. The EC should be alert to the potential for poor consent processes in the absence of appropriately translated materials and the availability of interpreters.

Regarding archiving and record keeping, the G-EthicsHR-ZAF states that ECs should keep written records of all research protocols received for review, including information sheets, consent forms, and relevant correspondence, in the form in which they were approved. Electronic records are acceptable, provided the signatures, especially on the finally approved documentation, are properly documented and included in the record. EC records must provide a reliable and authoritative record of the business of the EC that will stand up to scrutiny in the event of queries, conflict, and audit. The record should include at least the following:

Name of PI
Protocol identification number
Title of the project
Date of approval or rejection
Duration of approval period (maximum 12 months, renewable)
Conditions of approval, if applicable
Whether approval was expedited
Copy of the signed final protocol or protocol approved
Whether and how consultation occurred
Records of adverse events
Records of amendments
Reports of adverse and serious adverse events and action taken
Other relevant information such as complaints from participants

Per the SA-GCPs, the EC should retain all relevant records for a period of at least three (3) years or as per institutional requirement, whichever period is longer, after completion of the trial and make them available upon request from the applicable regulatory authority.

1.2, 1.6, 5, Appendix A2.5 and A2.6

4.3 and 12

Chapter 9 (72 and 73)

Last content review/update: January 21, 2025

Overview

As set forth in GAfREC, the United Kingdom (UK) has a centralized recognition process for ethics committees (ECs), known as research ethics committees (RECs) in the UK. ECs are part of an accountable and independent Research Ethics Service (RES) (GBR-62).

As described in GBR-51 and GBR-62, the RES has a dual mission to protect the rights, safety, dignity, and well-being of research participants and to facilitate and promote ethical research that is of potential benefit to participants, science, and society. To achieve this, GBR-62 states that the RES works with the devolved administrations to conduct the following activities:

Provide robust, proportionate, and responsive ethical review of research through ECs
Provide ethical guidance to ECs
Provide and deliver a managed structure to support ECs
Deliver a quality assurance (QA) framework
Deliver a training program
Work with colleagues across the UK to maintain a UK-wide framework for ethical review
Work with colleagues in the wider regulatory environment to streamline the processes for approving research
Promote and support transparency in research

As stated in GAfREC, the RES encompasses England’s Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care, Finance, Digital and Governance Directorates, the Welsh Government’s Department of Health and Social Care as well as the ECs that are collectively recognized or established by these authorizing bodies. The UK Health Departments have authorized the head office of the RES in England, within the Health Research Authority (HRA), to perform some UK-wide functions on behalf of the other head offices, including performing some of the functions of the UK Ethics Committee Authority (UKECA), which is the statutory body that recognizes ECs for the review of clinical trials of investigational medicinal products (CTIMPs). (See Oversight of Ethics Committees section for more details on RES and UKECA functions.) In accordance with the MHCTR and the MHCTR2006, ECs recognized to conduct reviews of clinical trials for CTIMPs are authorized by the UKECA. The UKwide-Rsrch reaffirms that GAfREC is the UK policy document governing the RES function and EC reviews in each country.

All recognized RES ECs are required to comply with the provisions delineated in GAfREC, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9. However, specific ECs within the RES are recognized, or otherwise designated, to review certain types of research proposals. A list of recognized ECs within the RES is available through GBR-111. Also see GBR-64 for EC definitions.

Ethics Committee Composition

As delineated in the MHCTR and GAfREC, a RES-recognized EC, which includes those recognized by UKECA, may consist of up to 18 members. Collectively, members must encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. The ECs should include a diverse mixture of members in terms of age, disability, gender, race, religion, and sexual orientation. One third of the committee must also be lay members, and half of the lay members must be persons who are not and never have been health care professionals, clinical researchers, or managers of clinical research (also known as lay members). Additionally, GAfREC states that a quorate meeting must be attended by at least seven (7) members and include the chair, at least one (1) expert member, and one (1) lay member. GBR-9 mirrors this requirement, but adds that when investigational products are reviewed, a lay member must be present. See GBR-113 for additional recommendations for composition.

Per GBR-9, in order to accommodate the United States’ (US) quorum definition pursuant to regulations for the protection of human subjects in research (45 CFR 46) and the Common Rule (45 CFR 46 Subpart A), the RES also makes special arrangements to review UK-based research funded by US Federal Government departments and their agencies. In such cases, the quorum is a majority of the EC. See the ClinRegs United States page, Ethics Committee topic for more information on ethics review requirements in the US.

As indicated in GAfREC, committee member appointments are valid for up to five (5) years. Appointments may be renewed; however, members should not normally serve more than two (2) consecutive terms of five (5) years on the same EC, and members may resign at any time. Members must maintain confidentiality regarding all ethical review related matters and refuse any projects in which they have a conflict of interest. See the MHCTR and GAfREC for additional EC composition requirements.

Terms of Reference, Review Procedures, and Meeting Schedule

In addition to complying with composition requirements, GAfREC, GBR-113, and GBR-9 state that an EC must also adopt written standard operating procedures (SOPs). The SOPs should cover the entire review process from application submission to opinion and notification, amendments, and annual reporting.

Per GBR-9, applications that have been submitted via the CTIMP combined review service will be validated by the MHRA, and EC staff do not need to undertake a formal validation check. ECs should check the application against the validation checklist and request any missing information or clarifications from the applicant if required. All validated clinical trial applications for an ethical opinion should be reviewed at a full meeting of an EC. An EC should normally hold at least 10 scheduled full meetings in each year for the purpose of ethical review of applications. Additional meetings may be held where necessary to ensure that an ethical opinion on an application is given within the relevant time limit (or to discuss matters relating to the establishment or operating procedures of the EC or for training purposes). Meetings to review applications should normally be held at intervals of one (1) month unless there are holidays. The schedule of EC meetings for the financial year commencing on April 1^st should be agreed to by December 1^st in the previous financial year. The schedule should set out the dates, times, and venues of meetings, and the closing date for applications for each meeting. All members and deputy members of the EC should receive details of the schedule. The closing dates for full applications should normally be 14 calendar days prior to each EC meeting. In the case of applications for Phase 1 clinical trials in healthy volunteers, Type 1 ECs may adopt a later closing date for applications not less than seven (7) calendar days prior to the meeting and may accept applications booked in advance of the closing date which are submitted up to seven (7) days before the date of the meeting.

According to GBR-9, the EC Chair is responsible for ensuring that the EC reaches clearly agreed to decisions on all matters. If the Chair is unavailable, then the meeting should normally be chaired by the vice-Chair or, if the vice Chair is also unavailable, by the alternate vice-Chair. The EC meeting should reach unanimous decisions by consensus wherever possible. Where a consensus is not achievable, a formal vote should be taken by a counting of hands. The decision of the EC should be determined by a simple majority of those members present and entitled to vote. A record should be kept of the number of votes, including abstentions, in the minutes. Where the vote is tied, the Chair may give a casting vote, but should first consider any other options to arrive at a more consensual decision. Where any member wishes to record a formal dissent from the decision of the committee, this should be recorded in the minutes but should not be included in the opinion letter. An agenda should be prepared for an EC meeting and EC staff must prepare minutes of the EC meetings. See GBR-9 for additional requirements on the agenda, meeting conduct/decisions, and minutes during full EC meetings.

As per GBR-9, documents for EC meetings should be distributed as soon as possible after the agenda is finalized and applications have been validated, and in any case no later than 10 calendar days prior to the meeting (with the exception of expedited, proportionate review, and Phase 1 applications where there has been prior agreement). Under no circumstances should full applications be tabled at the meeting. Applications should be made available to members via the HRA Assessment and Review Portal (HARP) as soon as the application is validated, and an email sent to the EC members to inform them the application is now viewable.

GBR-9 requires ECs to retain all the documentation relating to a CTIMP on which it gives an opinion:

Where the trial proceeds, for at least three (3) years from the conclusion or early termination of the trial
Where the trial does not proceed (e.g., it is given an unfavorable opinion, or does not start following a favorable opinion), for at least three (3) years from the date of the opinion

In accordance with GBR-9, documentation should be retained on all invalid applications for at least one (1) year from the date of invalidation; and for three (3) years where the application is withdrawn by the EC, the chief investigator, or the sponsor after the EC review but before a final opinion is given. Signed final copies of the minutes of full EC meetings and sub-committee business should be retained electronically for at least 20 years. Where paper records are destroyed in accordance with this policy, they should be shredded and disposed of as confidential waste. Electronic records of studies will be retained indefinitely.

For detailed EC procedures and information on other administrative processes, see GAfREC, GBR-113, and GBR-9.

1-6, Glossary, Annex A, Annex C, Annex E, and Annex F

Part 2, Part 3 (11, 12, 14, 15, 17, and 18), and Schedule 2

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Introduction (Purpose and Scope, and Implementation), Terminology (Glossary), and Sections 1, 2, 3, and 15

Foreword, Introduction, 1.24, 1.27, 2.6, 3, and 5.11

Search Research Ethics Committee

Definitions of Authorised REC and Recognized REC

Research Ethics Committee (REC) Scope

Scope of Review

Last content review/update: January 17, 2025

Overview

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

Review protocols to ensure that research involving human participants has scientific merit and will promote health, and prevent or cure disability and disease; in addition, ensure the research has social merit in light of South Africa’s research priorities or is otherwise justified
Ensure clinical trials are governed by the ethical principles of beneficence and non-maleficence, distributive justice (equity), and respect for persons (dignity and autonomy)
Uphold the key norms for ethical research with human participants including relevance and value; scientific integrity; stakeholder engagement; fair selection of participants; informed consent; ongoing respect for enrolled participants; and researcher competence and expertise
Grant approval for research where the protocols meet the ethical standards of the institution, agency, or establishment
Determine whether and why randomization is relevant, and how this is addressed
Evaluate the appropriateness of the inclusion/exclusion criteria and the recruitment process in the South African context
Ensure the feasibility of obtaining meaningful results with the lowest possible risk of harm for participants and whether the risk of harm is appropriately weighed against anticipated benefits for participants or the class of persons from which they are drawn; high risk of harm may be justifiable where the anticipated benefit is of high importance to increase relevant knowledge and appropriate mitigating measures are in place to minimize harm to participants; and attention must be given to harms and benefits beyond the life of the trial itself, especially in respect to early phase studies and (pharmacovigilance) surveillance for chronic and life-threatening conditions
Protect the welfare of certain classes of participants deemed to be vulnerable (See the Informed Consent topic for additional information about these populations).

Role in Clinical Trial Approval Process

Per the G-EthicsHR-ZAF, the SA-GCPs, and the NHAParticipants, the principal investigator (PI) or the sponsor must submit a clinical trial application to both the South African Health Products Regulatory Authority (SAHPRA) and a registered EC for review and approval before a study may commence. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and a registered EC may be conducted in parallel. However, the G-EthicsHR-ZAF recommends that scientific review be completed prior to ethics review and, in cases where scientific review capacity is not available, the EC approval should be delayed until SAHPRA scientific approval has been provided. Further, where site permissions are required, e.g., from Provincial Health Research Committees (PHRCs) or superintendents, to conduct research in health care facilities, ECs must delay granting full approval until these permissions are received. This is to prevent research from beginning before the facility knows it will happen.

The G-EthicsHR-ZAF indicates that after the deliberative review process, the EC should approve, require amendment to, or reject a research protocol. In considering a research protocol, the EC may seek assistance from experts who have no conflicts of interest. EC decisions should be recorded in writing and appropriately documented in the minutes. A decision to approve should include the conditions (e.g., the duration of the approval, the reporting requirements, etc.). Reasons for a decision to require an amendment or to reject a research protocol should be recorded and provide sufficient feedback to the applicant. Outright rejection should be avoided if a researcher can be advised to improve the protocol. Researchers should be encouraged to address the concerns and improve their protocols. In addition, feedback should include the expected return date to minimize delays to finalize the approval process. The maximum time for a return date should not exceed six (6) months. Should the applicant exceed the stipulated return date without communication to the EC, the application should be removed from the agenda, and a new application must be submitted. ECs should require researchers to report immediately if a project is terminated or suspended before the anticipated date of completion. ECs should require researchers to report immediately anything that might warrant reconsideration of ethical approval of the protocol, including but not limited to:

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

Per the G-EthicsHR-ZAF, to prevent unnecessary duplication of work, ECs may, at their own discretion, recognize the review and approval of a research protocol granted by another registered South African EC. Reciprocal recognition means that two (2) or more registered ECs decide to recognize each other’s review. This arrangement may involve formal agreements between the ECs explaining how the workload and responsibilities are shared and the basis on which recognition occurs. Alternatively, the committee may decide to use reciprocity recognition on a case-by-case basis. ECs that recognize reciprocal review agree on the nature of the documents to be filed at each office. The expectation is that ECs should communicate with each other, through their chairpersons, and agree on a way forward regarding review of a multi-site protocol when it is desirable to avoid duplication of effort. The possibility of reciprocal recognition of reviews should occur in a collaborative, harmonious manner, bearing in mind that each EC retains the responsibility of protecting the safety, rights, and interests of participants enrolled in the studies it has approved. For more details on reciprocal review, see the G-EthicsHR-ZAF.

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

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

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

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

As delineated in the G-EthicsHR-ZAF, ECs have the right to monitor the research it approves. The frequency and type of monitoring should reflect the degree and extent of risk of harm to participants. Monitoring types include passive and active measures. Active monitoring requires a site visit. Passive monitoring is generally paper, using reports and other information. A site visit is expected for investigation of adverse events, serious adverse events for high-risk research, as well as other occurrences that prompt concerns for ECs. The EC should ensure that appropriate feedback is given to the PI, with an opportunity to address any identified gaps within a negotiated timeline. ECs may recommend and adopt any additional appropriate mechanism for monitoring, including random inspection of research sites, welfare monitoring sheets, data and signed consent forms, and records of interviews. ECs should ensure information and consent materials indicate that such monitoring may take place. Further, ECs should request regular, at least annual, reports from PIs. See the G-EthicsHR-ZAF for more details including the report requirements.

The G-EthicsHR-ZAF states that where circumstances indicate that a project is non-compliant with the approved protocol and the interests of participants are at risk of harm, the EC may withdraw approval, after due process has been followed. A clear process should be followed that permits swift but proper investigation and decision-making to ensure protection of participants. The investigation should include interaction with the researchers and other interested parties to ensure a fair and transparent process. If the decision is to withdraw approval, the EC should inform the PI and other interested parties, including the institutional authorities, and recommend suspension (temporary stoppage) or termination (permanent stoppage) of the project. It should also recommend remedial action where appropriate. In the case of suspension, the PI must comply with the recommendations and any special conditions imposed by the EC.

Expedited Review

Per the G-EthicsHR-ZAF, expedited review applies, in principle, only to research that poses no more than minimal risk of harm. Generally, expedited review means that no fewer than two (2) EC members review the protocol and that deliberation in the full committee meeting is foregone, unless the reviewers believe there are issues that the EC should discuss. The nature of research that may be expedited should be described in the procedures. The outcomes of the expedited review process must be reported to the full committee, at least by being noted on the agenda, so that the record is complete.

Rapid Review

As delineated in the G-EthicsHR-ZAF, rapid review process permits rapid but thorough processing of ethics review applications in circumstances that require accelerated preparation for a research study or project, for example when there is a national or localized emergency. The EC should carefully assess the nature of the research to determine the appropriate review process, bearing in mind that not all research during a major incident is necessarily urgent. Careful ethical reflection is essential, notwithstanding any perceived urgency. All the usual ethical norms and standards must be considered. The EC should have a review standard operating procedure (SOP) that allows a combination of rapid but thorough review and reciprocal recognition of review (see above) by other registered ECs. The SOP might stipulate that a small group of reviewers (3-5 persons) with appropriate expertise reviews the protocol. The deliberations and outcome of the process must be documented in minutes and reported to the full EC at its next meeting.

Joint Review

The G-EthicsHR-ZAF allows joint reviews wherein two (2) or more ECs review a multi-site research protocol together. The sites may be within South Africa or may include sites elsewhere on the African continent. A joint review is not the same as a reciprocally recognized review (described above). A joint review entails members of the ECs concerned communicating virtually or face-to-face to discuss their respective reviews and queries and come to conclusions. The joint review process permits efficiency of reviews, facilitation of capacity building, development of trust, and avoids unnecessary repetition of administrative work. When deliberations are completed and a decision to approve has been reached, each EC uses its own approval SOPs and processes. Joint review does not exempt any of the ECs involved from their responsibilities, including monitoring and looking after the interests of participants at their sites. The PIs concerned are responsible for informing their institutional EC of the fact of multi-site research, as well as the names of the other ECs with jurisdiction over other research sites. This information enables the chairs of the ECs to arrange a joint meeting of the ECs involved to review, deliberate on, and approve the protocol concerned simultaneously. Joint reviews involving South African and other African ECs can be used in a similar manner to facilitate the ethics review and approval processes. A memorandum of understanding is recommended between the ECs involved that outlines the process, the expectations, and the responsibilities.

Foreign Research Collaboration

The G-EthicsHR-ZAF indicates that where international research (multi-country studies) is conducted exclusively online or the online platform is used to recruit study participants, and the PI neither lives or works in South Africa, an exemption from ethics review and approval is possible. This is on the proviso that the PI can demonstrate to a local registered EC that permission has been obtained from the website owners and that a notice of research intent is posted on the relevant website. In addition, the PI must comply with the privacy policies and terms of website use, and with personal data protection requirements in the POPIA. (See the Personal Data Protection section for more information).

Artificial Intelligence

Per G-EthicsHR-ZAF, ECs must consider the following ethical considerations when reviewing protocols that involve the use of artificial intelligence (AI):

Transparency in the context of AI necessitates openness and clarity at every phase of the research
Researchers should explain how interpretable these models are, how this interpretation is communicated to a user, and to what extent interpretation is possible
Responsibility and accountability—Researchers should have a sufficient understanding of the AI model/technology and take responsibility for its use. Information on technical engineering perspectives should be made available for the ECs conducting the review. The ethical and responsible use and deployment of AI tools remain the responsibility of the PI to ensure the protection of research participants’ data
Equity and fairness—AI tools must be designed and implemented equitably and without unfair discrimination against any individual or group. Special attention should be given to vulnerable and historically underrepresented populations. Researchers should actively involve diverse participant groups in the design and testing phases to ensure fairness and representation. Additionally, algorithms should be assessed regularly for bias, and any discovered discrepancies should be promptly addressed and rectified
Benefit sharing, with particular attention to the needs and contributions of low-income communities, should be considered. Evidence of fostering equitable and collective sharing of the benefits and burdens of research must be presented to the EC
Safety risks and well as vulnerabilities to attack (security risks) should be addressed, prevented, and eliminated throughout the lifecycle of an AI system
Researchers must prioritize safety in the implementation of AI-enabled systems, with thorough assessments of the risk of harm and strategies for mitigation

See the G-EthicsHR-ZAF for detailed guidance on the above AI considerations.

3 (Part 4)

3.1 and Appendix

2.1-2.3, 3, 5.5, and 6.5

1.2, 2.1, 2.6, 4.3, and 9.2

3

Chapter 9, Sections 72 and 73

Last content review/update: May 16, 2024

Overview

According to GAfREC, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, the primary scope of information assessed by ethics committees (ECs) within the United Kingdom (UK) Health Departments’ Research Ethics Service (RES) (GBR-62) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. (Note: ECs are known as research ethics committees (RECs) in the UK). GAfREC specifies that ethical review is required for research proposals that involve investigational products (IPs), material consisting of human cells, and other situations that are described in GAfREC.

As per GAfREC, the MHCTR, the MHCTR2006, the MHCTR2006-No2, and GBR-113, ECs must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).

As indicated in GAfREC, the MHCTR, the MHCTR2006, GBR-113, and GBR-9, ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. See GAfREC, the MHCTR, the MHCTR2006, and GBR-9 for detailed ethics review guidelines.

GBR-112 indicates that certain ECs are flagged for special expertise including gene therapy or stem cell clinical trials; Phase 1 studies in healthy volunteers; Phase 1 studies in participants; research involving adults lacking capacity; research involving children; research involving prisoners or prisons; or fast-track ECs.

Role in Clinical Trial Approval Process

As described in GBR-9, GBR-66, and GBR-95, the type of EC responsible for approval (known as a “favorable opinion” in the UK) within the RES depends on the type of research being conducted. Per GAfREC and GBR-9, ECs are recognized or established by the United Kingdom Ethics Committee Authority (UKECA) to conduct reviews of clinical trials for IPs (known as clinical trials for investigational medicinal products (CTIMPs) in the UK). Per GAfREC, RES-recognized ECs established under Health Department policy within each of the four (4) UK nations (England, Northern Ireland, Scotland, and Wales) review research studies other than IP clinical trials. Also see GBR-64 for definitions of EC terminology and GBR-111 and GBR-112 to search for ECs within the RES.

As indicated in the MHCTR, the MHCTR2006, and GAfREC, IP applications require the favorable opinion of a UKECA-recognized EC, and approval by the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to the sponsor or the designated legal representative initiating the trial. The G-CTApp states that all new clinical trial applications must be prepared, submitted, and reviewed via the combined review process, wherein a single application route and coordinated review by MHRA and the EC leads to a single UK decision. New clinical trial applications for combined review are prepared and electronically submitted to the new combined review section of Integrated Research Application System (IRAS) (GBR-125). Per GBR-78, IRAS does not change the requirements for review, including authorizations or signatures, of any regulatory authority or National Health Service (NHS) body. Therefore, it requires different authorizations depending on the type of study and the applicable review bodies. According to GBR-9, submissions of the electronic application must be made to IRAS on the same day that a booking is made to schedule an EC review through the NHS REC’s Online Booking Service (GBR-95).

According to the MHCTR, GAfREC, and GBR-9, for all studies, only one (1) EC review (referred to as the “main EC”) is needed for a project taking place in the UK, regardless of the number of sites. Furthermore, GBR-9 states that the Chief Investigator (CI) should be based in the UK and that the REC may agree exceptionally to an application being submitted by a CI based outside the UK, but should consider as part of the ethical review whether adequate arrangements are in place for supervision of the study in the UK. The ethical review includes an assessment of the suitability of each site or sites at which the research is to be conducted in the UK. The site assessment is not a separate ethical review, but forms part of the single ethical review of the research. Management permission is still required from the organization responsible for hosting the research before it commences at any site. In the case of international studies, an application must be made to an EC in the UK, whether or not the study has a favorable ethical opinion from a committee outside the UK, and whether or not it has started outside the UK.

Per GBR-68, unless an application is being processed under the proportionate review service, the applicant should attend the EC meeting if possible. The EC will notify the sponsor of its decision, usually within 10 working days of the EC meeting. GBR-9 indicates that the EC should reach one (1) of the following decisions on any application reviewed at a full meeting or a proportionate review sub-committee meeting:

A final opinion, which may be either favorable with standard conditions, favorable with additional conditions, or unfavorable
Provisional opinion with request for further information, which means the EC may decide that a final opinion cannot be issued until further information or clarification has been received from the applicant

The MHCTR, GBR-9, and GBR-68 state that the EC must give its opinion within 60 calendar days of receipt of a valid application. When an EC requires further information before confirming its opinion, it may give a provisional opinion and may make one (1) written request for further information, clarification, or changes to documentation. The time required for the EC to receive a complete response to its request does not count against the 60-day timeline. Certain studies, including gene therapy studies, will take 90 days, or 180 days if a specialist group or committee is consulted. For other exceptions, see GAfREC and the MHCTR. (See the Submission Process and Timeline of Review sections for detailed submission process requirements.)

Per GBR-116, the Health Research Authority (HRA), on behalf of the UK, offers a fast-track research ethics review. Fast-track ethics review is open to global clinical trials and Phase 1 trials, whether the sponsor is commercial or non-commercial. This includes:

Any CTIMP led from the UK with at least one (1) other country participating
Any CTIMP led from outside the UK which could be placed in any country and the UK is competing for participation (including any only taking place in the UK)
Any Phase 1 or Phase 1/2 CTIMP in healthy volunteers or participants

Fast-track ethics review is not available for any CTIMP involving a gene therapy medicinal product, any CTIMP funded by the US Department of Health and Human Services, and any other type of clinical trial or research study.

Per GBR-9, the EC’s favorable ethical opinion applies for the stated duration of the study, except where action is taken to suspend or terminate the opinion. The MHCTR, GAfREC, and IRAS (GBR-78) require the applicant to identify an expected end date for the study. A change to the definition of the end of the study is a substantial amendment. Extension of the study beyond the period specified in the application form is a non-substantial amendment.

GBR-9 describes EC processes related to reviewing and approving clinical trial amendments and any related notifications. The sponsor of a CTIMP may make an amendment to a clinical trial authorization, other than a substantial amendment, at any time after the trial has started. These do not need to be notified. If the amendment is substantial, the sponsor is required to submit a valid amendment to the MHRA and/or the REC that gave the favorable opinion of the trial. Where the sponsor requests an ethical opinion on a CTIMP, the EC should provide this in all cases within 35 calendar days of receiving a valid amendment. If the opinion is unfavorable, the sponsor may then modify the proposed amendment. A written notice of the modification should be sent to the main EC at least 14 calendar days before it is due to be implemented. The EC may then give an unfavorable opinion on the modified amendment within 14 calendar days, otherwise it may be implemented. See GBR-9 and GBR-98 for guidance on what changes qualify as a substantial amendment, which requires notification to the EC and MHRA. GBR-9 states that while the EC is not responsible for proactive monitoring, it has a duty to keep the favorable ethical opinion under review in the light of progress reports and significant developments and may review the opinion at any time. If information raises concerns about the suitability of the site or investigator, the favorable opinion may be reviewed.

Introduction (Purpose and Scope), Terminology (Glossary), and Sections 1, 3, 5, 6, and 10.9

Foreword, 1.27, 2, and 3

Search Research Ethics Committee

2.3, 3, 4.3, and 5.4

Combined review of clinical trials of investigational medicinal products

Amendment of the Clinical Trials Regulations; Amendment of the Adults with Incapacity (Scotland) Act 2000

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (2 and 3), Part 3 (11, 12, 14, 15, 17, and 18), Schedule 2, and Schedule 3 (Part 1)

Ethics Committee Fees

Last content review/update: January 17, 2025

As indicated in the G-EthicsHR-ZAF, ethics committees (ECs) may independently decide whether to charge fees for a protocol review for external researchers. Researchers without affiliation to an institution or organization with an EC should approach a registered EC to request it to review their health research protocols. If the EC is willing to review external applications, a fee for service may be levied.

5.2 and 5.5

Last content review/update: May 16, 2024

As set forth in GAfREC, ethics committees (ECs) are not permitted to charge an application fee or seek any other financial contribution or donation for reviewing research proposals. Additionally, EC members receive no payment for contributing to the application review process at scheduled meetings or for attending these meetings.

4.3

Oversight of Ethics Committees

Last content review/update: January 17, 2025

Overview

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

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

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

Registration, Auditing, and Accreditation

As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCPs, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study. Registration information is available on the NHREC webpage (ZAF-12), and a list of ECs currently registered with NHREC is available at ZAF-13. The application to register an EC is at ZAF-53. ZAF-54 states that the EC registration is recorded and publicly listed by the NHREC.

Per the G-EthicsHR-ZAF, the criteria for the NHREC registration assessment and the eligibility audit for ECs are based on the G-EthicsHR-ZAF and other internationally recognized guidelines. Members of the NHREC undertake the assessment and auditing to ensure that ECs comply with capacity and operational requirements. After the first pre-registration audit, guidance and recommendations for improvement are provided with specific timelines for improvements. Before the registration is completed and a registration number is issued, NHREC conducts a follow-up audit to ensure that required revisions have been completed. Voluntary deregistration can occur when an EC is no longer active and closes. A critical part of the ongoing quality assurance review process is the EC annual report form (ZAF-54).

The G-EthicsHR-ZAF states that the NHREC conducts a comprehensive quality assurance assessment and administrative audit of ECs on a five (5)-year cycle to check compliance with the various administrative and record-keeping standards. When an EC persistently fails to comply with expected standards, the NHREC must enforce the standards, e.g., to suspend operations until compliance is achieved or, in extreme cases, to revoke registration of the committee. If an EC is suspended, the NHREC informs the EC of the suspended registration status and outlines the steps to be taken to rectify matters so that a registered status may be reinstated. Capacity evaluation and enhancement for ECs is also an important function of the NHREC. During the period of suspension, the EC concerned may not review new protocols for health research and may not permit another registered EC to review on their behalf. Instead, they should refer applicants to another registered EC. An assessment of the implications for harm to participants will determine whether ongoing monitoring of approved studies is acceptable to the NHREC. Failure by the EC to respond to the required measures to reverse the status of suspended registration can lead to registration being revoked. In this case, a new application for registration is required.

Use of Information

1.2 and 6.4

4.1 and 12.0 (National Health Research Ethics Council)

Chapter 9 (72 and 73)

Last content review/update: May 16, 2024

Overview

As stated in GAfREC and GBR-9, the United Kingdom (UK)-wide Research Ethics Service (RES) (GBR-62) provides proportionate and responsive ethical review of research through its “recognized” ethics committees (ECs), known as research ethics committees (RECs) in the UK. Per the MHCTR, the MHCTR2006, and GAfREC, the UK Ethics Committee Authority (UKECA) is the statutory body that recognizes ECs for the review of clinical trials of investigational products (CTIMPs). The UK Health Departments have authorized England’s Health Research Authority (HRA) to perform some of the RES functions (more details below).

As indicated in the MHCTR and GBR-9, the UKECA recognizes two (2) types of ECs for new CTIMPs:

Type 1: Reviews Phase 1 clinical trials of investigational products (IPs) taking place at any site in the UK, where the sponsor has no knowledge of any evidence that the product has effects likely to be beneficial to the participants of the trial, and the participants are healthy and not suffering from the disease or condition to which the trial relates.
Type 3: Reviews clinical trials of IPs taking place at any site in the UK, including first-in-person studies involving people with the target disease or condition to which the trial relates.

As stated in GAfREC, the HRA performs the following EC oversight activities on behalf of the UKECA:

Develops and manages a national training program for ECs
Develops, implements, and maintains standard operating procedures (SOPs) for ECs and provides advice and support to ECs on procedural issues
Develops a quality assurance program, including accreditation of ECs, based on regular monitoring and audit of their operation and performance
Provides guidance and advice to assist ECs in their work and encourage consistency of approach to common issues in research ethics
Acts for UKECA to provide a national mechanism for operational advice and assistance to ECs recognized to review and approve clinical trials
Acts for UKECA to handle appeals against the unfavorable opinions of ECs in respect of CTIMPs
Acts for UKECA to transfer to a successor EC the functions of an EC that has ceased to operate or that has been varied, abolished, or had its recognition revoked
Acts for UKECA to reallocate to ECs applications made to the Gene Therapy Advisory Committee which do not require its review

Further, per GAfREC, the following oversight functions are the responsibility of UKECA for the purposes of clinical trials:

Establishes or recognizes ECs
Establishes or recognizes ECs to act in relation to such descriptions or classes of research as it considers appropriate
Abolishes or revokes the recognition of ECs that it has established or recognized
Monitors the extent to which ECs adequately perform their functions, including through annual reports from ECs it has recognized
Approves standing orders and SOPs for EC business and operations, as well as variations and revocations to these orders and procedures

Registration, Auditing, and Accreditation

Per GAfREC, HRA, acting for UKECA, develops a quality assurance program to encourage a consistently high level of service to applicants, including accreditation of ECs, based on regular monitoring and audit of their operation and performance.

GBR-123 indicates that HRA implements a rolling accreditation program to audit UK ECs against standards as detailed in GAfREC and GBR-9. ECs are issued with an audit decision: full accreditation, accreditation with conditions (low-risk non-compliance identified requiring an action plan), or provisional accreditation (high- and low-risk issues requiring an action plan). Published bi-annually, HRA’s latest accreditation report is at GBR-124. In addition, quality control checks are undertaken, and results are shared with management teams. For example, operational managers observe EC meetings and provide a check against agreed-upon standards relating to meeting conduct and minute taking. Findings from the meeting observations are shared with the EC chair and staff and collated to identify common themes to inform improvements. For more information about quality assurance, contact quality.assurance@hra.nhs.uk.

Introduction (Purpose and Scope), Implementation, Terminology (Glossary), and Sections 1, 2, and 3

Accreditation Scheme for Research Ethics Committees and Quality Control

1.3, 2.1, 2.3, 3.3, 5.4, Glossary, Annex C, Annex D, Annex E, and Annex F

Part 2 (Conditions Based on Article 3 of the Directive)

Part 2, Part 3 (12), and Schedule 2

Submission Process

Last content review/update: January 17, 2025

Overview

As delineated in the SA-GCPs, the sponsor and the investigator must obtain approval from the South African Health Products Regulatory Authority (SAHPRA) and a registered ethics committee (EC) to begin a clinical trial in South Africa. Per ZAF-23, the review and approval of clinical trial applications by SAHPRA and an accredited EC may be conducted in parallel. As indicated in ZAF-20, the same process applies to the review and approval of an amendment to the protocol. However, note that the G-EthicsHR-ZAF recommends that scientific review be completed prior to ethics review and, in cases where scientific review capacity is not available, the EC approval should be delayed until SAHPRA scientific approval has been provided.

Regulatory Submission

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

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

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

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

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

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

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

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

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

Ethics Review Submission

Each EC has its own required submission procedures, which can differ significantly regarding the number of copies to be supplied and application format requirements. Refer to each EC’s website for specific submission procedures.

3-7

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

3.1

2.6 and 6.2

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

Last content review/update: January 21, 2025

Overview

In accordance with the MHCTR, the MHCTR2006, the G-CTApp, and GBR-9, the United Kingdom (UK) requires the sponsor or the designated legal representative to obtain clinical trial authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) prior to initiating the trial. Per G-CTApp and G-IRASCombRev, the UK’s combined review process offers a single application route and coordinated/parallel review from MHRA and the ethics committee (EC) leading to a single UK decision for clinical trials.

Note: G-CTApprovedCountries and the MHCTR-EUExit list the countries where a clinical trial sponsor or their legal representative may be established; these countries are initially European Union (EU) and European Economic Area (EEA) countries.

Combined Review Submission

Per G-CTApp and G-IRASCombRev, all new clinical trials applications of investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process using the Integrated Research Application System (IRAS) (GBR-125). For support and getting started, users should review GBR-72 and contact the combined review team at cwow@hra.nhs.uk. Step-by-step instructions are provided in G-IRASCombRev. As delineated in GBR-9, applications submitted via the combined review service are submitted jointly by the chief investigator and the sponsor. Per GBR-116, applicants seeking fast-track review of clinical trial applications must also apply via combined review on GBR-125. Per the G-CTApp, MHRA’s notification scheme enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications. The scheme only applies to clinical trial applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Interest in the notification scheme should be registered via the combined review process (GBR-125). Per G-ATMP, all advanced therapy medicinal products must submit clinical trial applications using the same processes as all other medicines. See Scope of Review section for fast-track eligibility criteria.

Per GBR-122, for studies that were submitted before combined review, these applicants should continue to submit amendments and reports for these studies at IRAS via GBR-78’s log-in. HRA will update sponsors and applicants with full instructions and plenty of notice for any planned changes in the future, such as the migration of existing, ongoing studies. See GBR-122, for additional details on the migration of existing materials in IRAS. GBR-72 includes learning resources and a video on the combined review process.

G-IRASCombRev contains a step-by-step guide to combined review submission. The following is an overview of the steps:

Finalize protocol and supporting documents
New users create IRAS account and create a new project and allocate roles
Complete project details, study information, and clinical trial dataset in IRAS and upload supporting documentation
Send application to the sponsor to review and authorize
Book an EC online and submit application

G-IRASCombRev indicates that when selecting an EC meeting that is not the first available meeting, the 60-day regulatory clock for both the EC and the MHRA will start on the cutoff date for the meeting that is chosen, which is 14 days before the meeting date. Once booked, the EC booking page will update to show the confirmed booking details. The applicant will then be able to scroll down the page to select the option to “submit to the regulators.” See G-IRASCombRev for detailed step-by-step instructions.

For overall help during the submission process, see the CTapp-Issues which identifies common issues with validation and assessment of clinical trial applications and how to avoid them.

Other regulatory information aside from new clinical trial applications are to be submitted pursuant to the G-MHRASubmiss. These submittals include substantial amendments for existing clinical trials, end-of-trial notifications, and developmental safety update reports (DSURs). The G-CTAuth-GBR also states that clinical trials not approved or yet transitioned over to the combined review process should continue to use the online MHRA Submissions portal (GBR-13). The steps for gaining access to GBR-13 are contained in the G-MHRASubmiss and GBR-11.

For overviews of submittals to MHRA, see GBR-18. Also see the Initiation, Agreements & Registration section for information on obtaining a trial identification number during trial registration.

The UKwide-Rsrch provides guidance and requirements for research in more than one (1) United Kingdom (UK) nation, and specifies that the four (4) nations of the UK take a consistent approach to study-wide reviews so that sponsors only need to submit one (1) application on GBR-125 in most circumstances. Each UK nation will take assurances from the site-wide review conducted by the lead nation (the nation conducting the initial review).

As described in GBR-78, other relevant approvals can be sought on the IRAS site. For example, applicants can request inclusion in the National Institute for Health and Care Research Clinical Research Network (NIHR CRN) Portfolio, which comprises high-quality clinical research studies that receive support services from the Clinical Research Network in England.

Per G-CTApp, MHRA supports the conduct of trials with complex innovative designs such as umbrella, basket, platform, and master protocol plus submodules. When submitting a clinical trial application for a trial with innovative designs that involve prospective major adaptations, the sponsor must justify the choice of a complex trial design, ensure that each adaptation as well as the entire trial are safe and scientifically sound, and describe how the integrity of trial results will be maintained throughout the conduct of the trial. See G-CTApp for example scenarios of when it is appropriate to propose major adaptations via submission of a substantial amendment request. Before submitting an application for authorization of a trial with a complex innovative design and/or an amendment requesting approval of major adaptations, sponsors are recommended to establish a dialogue with the MHRA and seek advice.

As delineated in the MHCTR, the clinical trial application and accompanying material must be provided in English.

Terminology (Glossary) and Sections 1.1-1.2 and 14

Combined Review - What will happen to ongoing CTIMP studies submitted in the standard system?

CI Checklist Before Seeking Approval, CTA Submission, and Ethics Submission

Help (Preparing and Submitting Applications)

Apply to conduct a clinical trial for an advanced therapy medicinal product

2

Trial Sponsor and legal Representative, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, New notification scheme, and Requesting approval of trials with complex innovative designs

Amending your trial protocol or other documentation

2

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (3) and Part 3 (12, 14, 17, and 18)

Approvals for project based research in the National Health Service (NHS) and Northern Ireland’s Health and Social Care (HSC) Service

Submission Content

Last content review/update: January 17, 2025

Regulatory Authority Requirements

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

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

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

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

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

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

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

Ethics Committee Requirements

Per the G-EthicsHR-ZAF, each EC has its own application form and clearance requirements that can differ, but ECs must ensure that the submission content includes the following:

A description of the essential ethical elements: an explanation of the proposed research in plain language, information about potential participants (age range, vulnerabilities, etc.), and ethical implications of the research
Indication of whether it is a sub-study or parent study; each sub-study must be reviewed
Adequate consideration of participants’ welfare, rights, beliefs, perceptions, customs, and cultural heritage
All documents and other material to be used to inform potential participants, such as information sheets, consent forms, questionnaires, advertisements, videos, dramatizations, and letters
A description of the readability level to ensure that plain language is adapted to the anticipated literacy levels in the participant documentation
Evidence of community engagement and plans for ongoing consultation, as appropriate
Plans to implement benefit sharing, as appropriate to the context
Monitoring schedules, the responsible persons, and their contact numbers
Disclosure of any researcher conflicts of interest, financial interests, or information that may result in perceptions of conflict of interest
A data management plan (See the Personal Data Protection section for more details)

See ZAF-22, ZAF-45, and ZAF-49 for example EC applications, which share some or all of following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

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

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

Clinical Protocol

Per the G-EthicsHR-ZAF, it is strongly recommended that a report on the scientific review should accompany the protocol in the EC application. If a separate scientific review capacity is not available, the EC must ensure that the science is satisfactorily explained in the protocol. As delineated in the G-EthicsHR-ZAF, the SA-GCPs, and ZAF-23 the clinical protocol should contain the following information (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

General information
Background information
Study rationale and motivation
Trial objectives, purpose, and endpoints (with justifications)
Scientific design and methodology
IP information
Participant eligibility, selection, and withdrawal; inclusion and exclusion criteria
Selection of study population and sampling
Community and stakeholder engagement
Recruitment and enrollment
Risk/benefit analysis
Reimbursements and inducements for participants
Informed consent
Participant treatment
Participants’ interests in privacy and confidentiality
Efficacy assessment
Safety assessment
Statistics
Direct access to source data/documents
Research procedures and quality control/quality assurance
Data and safety monitoring plan
Data handling/recordkeeping
Statistical measures
Financing/insurance
How data records (written, audio or visual) are to be secured, the length of time for which they will be retained, and who will be responsible for storage and/or final disposal
An explanation on why particular identifying information is required for the study that purports to collect data anonymously
Measures in place to assess whether notifiable activities might occur amongst participants, e.g., abuse of minors or notifiable diseases

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

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

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

Submission Documents

3.1 and 5.5

2.6, 6.2, 7.1-7.16

Cover page, 3, and Annexure A

Last content review/update: May 16, 2024

Regulatory Authority Requirements

As specified in the G-CTApp, a clinical trial submission package to the Medicines and Healthcare Products Regulatory Agency (MHRA) should contain the following documents:

Cover letter (when applicable, the subject line should state that the submission is for a Phase 1 trial and is eligible for a shortened assessment time, or if it is submitted as part of the notification scheme); this letter should clearly highlight the Purchase Order (PO) number to help the MHRA invoice and allocate payments promptly and efficiently
Clinical trial application form in PDF and XML versions
Protocol document
Investigator’s brochure (IB)
Investigational medical product dossier (IMPD) or a simplified IMPD
Summary of scientific advice obtained from the MHRA or any other regulatory authority, if available
Manufacturer’s authorization, including the importer’s authorization and Qualified Person declaration on good manufacturing practice for each manufacturing site if the product is manufactured outside the European Union (EU) (See G-ImportIMPs and the Manufacturing & Import section for more information)
Copy of the United Kingdom (UK) or the European Medicines Agency’s decision on the pediatric investigation plan and the opinion of the pediatric committee, if applicable
Content of the labelling of the investigational product (IP) (known as investigational medicinal product (IMP) in the UK) (or justification for its absence)

Ethics Committee Requirements

As per the MHCTR, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), ECs require the chief investigator (CI) to submit the following documentation for ethics approval:

Application for an EC opinion
A summary of the trial, including justification, relevance, and methodology to be used
Research hypothesis
Statistical analysis and justification for the numbers of participants to be recruited
Protocol
IB
Peer review process details
Sponsor name and contact information
Financial arrangements for the trial (e.g., funding sources, participant reimbursement, compensation provisions in the event of trial-related injury or death, and insurance or indemnity coverage for sponsor and investigator(s)) (See the Insurance & Compensation section for additional information)
Terms of agreement between sponsor and participating institution(s)
Material to be used (including advertisements) to recruit potential research participants (See the Initiation, Agreements & Registration section for additional information on participant recruitment)
Informed consent form and copies of materials to be provided to participants (See the Required Elements section for additional information)
Participant treatment plans
Benefit/risk assessment for participants
Investigator(s) Curriculum Vitaes (CVs)
Trial design and suitability of facilities

Further, to help with planning before seeking EC approval, GBR-18 provides a checklist for CIs.

Clinical Protocol

Per GBR-9, the protocol describes the objectives, design, methodology, statistical considerations and organization of a clinical trial. According to GBR-113, the clinical protocol should contain the following elements:

Protocol summary
Sponsor or designated representative name and contact information
Investigator(s) CV(s) and contact information
IP description (See the Investigational Products topic for detailed coverage of this subject)
Form, dosage, route, method, and frequency of administration; treatment period
Trial objectives and purpose
Trial design, random selection method, and blinding level
Participant selection/withdrawal
Participant treatment
Summary of potential risks and known benefits to research participants
Safety and efficacy assessments
Adverse event reporting requirements (See the Safety Reporting section for additional information)
Statistics and methods to track trial data
Sponsor specifications for direct access to source data/documents
Quality control/quality assurance procedures and practices
Ethical considerations
Data management and recordkeeping
Financing and insurance details
Publication policy

For complete protocol requirements, refer to GBR-113.

Terminology (Statutory Definitions Relating to CTIMPs)

3.1 and 6

CI Checklist Before Seeking Approval

Documents to send with your application

Part 3 (12, 14, 15, 17, and 18) and Schedule 3 (Parts 1 and 2)

Timeline of Review

Last content review/update: January 17, 2025

Overview

Based on ZAF-23 and the SA-GCPs, the review and approval of clinical trial applications by the South African Health Products Regulatory Authority (SAHPRA) and an accredited ethics committee (EC) may be conducted in parallel. The applicant must notify each regulatory body of the other’s approval once it has been received. However, note that the G-EthicsHR-ZAF recommends that scientific review be completed prior to ethics review and, in cases where scientific review capacity is not available, the EC approval should be delayed until SAHPRA scientific approval has been provided. Also, where site permissions are required, e.g., from Provincial Health Research Committees (PHRCs) or superintendents, to conduct research in health care facilities, ECs must delay granting full approval until these permissions are received to prevent research from beginning before the facility knows it will happen.

Regulatory Authority Approval

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

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

Next, the CTC reviews the proposed clinical trials. ZAF-11 provides the dates of the 2025 CTC meetings and the SAHPRA submission due dates. It is advisable to submit clinical trial applications before these due dates. Once the reviewer approves the application, the CTC presents the committee’s/reviewer’s recommendations to the SAHPRA. ZAF-1 states that applicants receive a response within 10 working days from the CTC meeting, and they must send an answer within seven (7) working days after receipt of comments. If an applicant would like to request a meeting with the CTC, the request should be submitted through the SAHPRA Chief Executive Office pursuant to the procedures in the G-ConsultMtg.

Ethics Committee Approval

Review timelines vary per each EC’s procedures. The G-EthicsHR-ZAF states that ECs must define the review timelines in their standard operating procedures.

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

3.1 and 5.5

4.4

Last content review/update: May 16, 2024

Overview

Per G-CTApp and G-IRASCombRev, all new clinical trials applications for investigational products (CTIMPs) must be prepared, submitted, and reviewed via the combined review process. Combined review offers a single application route and coordinated/parallel review from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC) leading to a single United Kingdom (UK) decision for clinical trials.

Combined Review

Per the G-CTApp and GBR-72, the initial combined review assessment will be completed within 30 days of being submitted. The G-CTApp indicates that applications for healthy volunteer trials and sponsor-determined phase 1 trials in non-oncology participants may qualify for a shortened assessment time and MHRA will work with the EC to expedite these applications. The MHRA and the EC will inform applicants of the outcome of a submission. If there are grounds for non-acceptance of the application, the applicant will have the opportunity to respond, usually within 14 days, though this may be extended on request. Communication informing the applicant of the MHRA and EC decisions following receipt of the responses will usually be sent within 60 days of receiving the original valid application. If an extension to the response date has been agreed to, then this will impact the final decision timeline. Notification of the decision relating to a gene therapy, somatic cell therapy (including xenogenic cell therapy) product, tissue engineered product, or products containing genetically modified organisms will be sent within 90 days of receiving the original application unless otherwise advised.

The G-CTApp states that the MHRA uses automated electronic communication. To ensure receipt of MHRA correspondence, applicants should add MHRA_CT_Ecomms@mhra.gov.uk to their safe sender email list. MHRA will only send official correspondence to the named applicant email address. According to the MHCTR, if the sponsor or the designated representative does not receive a request for additional information from the MHRA within 30 days, the clinical trial application is treated as authorized.

Regarding the new notification scheme, the G-CTApp states that this pathway enables a more streamlined and risk-proportionate approach to processing clinical trial authorization for “initial” applications for Phase 4 and certain Phase 3 clinical trials deemed to be of lower risk. Applications submitted under this scheme will be processed by the MHRA within 14 calendar days from the application received effective date, provided the sponsor can demonstrate the trial meets the inclusion criteria. Authorization by the MHRA will be granted unless any criterion is not suitably met. If the MHRA determines the application does not meet the criteria, an objection decision will be communicated within 14 calendar days from the application received effective date, and the application will continue under the full authorization assessment with a decision communicated within the 30-day statutory timeframe.

In addition, as stated in the G-CTApp, certain first-in-human (Phase 1) trials of investigational products with higher risk or greater elements of uncertainty require the MHRA to seek advice from the Clinical Trials, Biologicals, and Vaccines Expert Advisory Group (CTBV EAG) of the Commission on Human Medicines (CHM) before approval for the trial can be given. See the G-CTApp for detailed requirements.

Initial Process Review and Timelines

Combined review of clinical trials of investigational medicinal products, New notification scheme, Assessment of your submission, and Applications that need expert advice

Initiation, Agreements & Registration

Last content review/update: January 17, 2025

Overview

In accordance with the GRMRSA, the SA-GCPs, the G-EthicsHR-ZAF, and the NHAParticipants, a clinical trial can only commence in South Africa once an applicant receives approval from the South African Health Products Regulatory Authority (SAHPRA) and from a registered ethics committee (EC). There is no waiting period required following the applicant’s receipt of these approvals. Note that the G-EthicsHR-ZAF recommends that scientific review be completed prior to ethics review and, in cases where scientific review capacity is not available, the EC approval should be delayed until SAHPRA scientific approval has been provided. Also, where site permissions are required, e.g., from Provincial Health Research Committees (PHRCs) or superintendents, to conduct research in health care facilities, ECs must delay granting full approval until these permissions are received to prevent research from beginning before the facility knows it will happen.

The trial must be conducted in compliance with the SA-GCPs, the G-EthicsHR-ZAF, and the GRMRSA. Also, per the SA-GCPs, all clinical trials must be conducted in a laboratory complying with Good Laboratory Practices (GLP). See ZAF-2 for the World Health Organization (WHO)’s handbook on GLPs.

Per the SA-GPPs, pharmacists must be involved in clinical trials, including for example, assisting in the development of protocols, overseeing medicine supplies, monitoring administration protocols, and maintaining registries. According to the SA-GCPs, the sponsor must also define and allocate all study related duties and responsibilities to the investigator prior to initiating the study.

Clinical Trial Agreement

According to the SA-GCPs, all parties involved in the conduct of a trial should be familiar with guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines. All clinical trials should be conducted in accordance with all ethical principles outlined in the Declaration of Helsinki (ZAF-44). Before the trial begins, a sponsor must prepare a written agreement. The agreement must be signed by the sponsor and the PI, and any other parties involved (e.g., institutions and contract research organizations) with the trial to confirm the contract terms. Both the sponsor and the PI must commit to providing safety information between each other. The sponsor should also obtain the investigator's agreement to:

Conduct the trial in compliance with the SA-GCPs, the SAHPRA requirements, ZAF-27, and the EC approved protocol
Comply with data recording/reporting procedures
Permit monitoring, auditing, and inspection
Retain the trial-related essential documents until the sponsor informs the investigator(s) and institution(s) that these documents are no longer needed

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

Clinical Trial Registration

According to the SA-GCPs, NHAParticipants, and ZAF-32, the PI or the sponsor must enter the trial information in the South African National Clinical Trials Register (SANCTR) (ZAF-48). The G-EthicsHR-ZAF states that solely the sponsor must register all South Africa-based trials on SANCTR, and if the trial has no commercial sponsor, the PI must register the trial. According to the SA-GCPs, the National Department of Health (NDOH) then issues a unique SANCTR National Register Number. ZAF-32 has instructions for registering either online or via email.

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

Governance

The G-EthicsHR-ZAF explains that research, especially that using state or provincial facilities and resources, should link to health care system priorities, and findings should be integrated into policy planning and management of health programs. PHRCs were established to liaise with researchers to ensure that the greatest health needs of each province are being addressed. As such, they perform a gate-keeping role by managing access to health facilities. While they accept ethics approval granted by a registered EC, they need to consider applications to use their facilities to manage potential interference with or interruption of services. It is thus important that PIs respect this role of the PHRCs. Some provinces have also registered provincial ECs, and these committees are important in areas of the country where other ECs are not active.

Part 2 (General Objectives and Requirements of Pharmaceutical Services)

3.1, 5.3, and 6.5

1.2, 2.1, 2.6, 4.4, 6.1-6.2, 6.4, 6.9, 7.11, and 9.2

3

Part 30 (2)

Last content review/update: January 21, 2025

Overview

In accordance with the MHCTR, the MHCTR2006, and GAfREC, a clinical trial can only commence after the sponsor or the designated representative receives authorization from the Medicines and Healthcare Products Regulatory Agency (MHRA) and the chief investigator (CI) receives an approval from a recognized ethics committee (EC). In addition, GBR-9 clarifies that a favorable EC opinion does not imply that research activity at sites can begin. Confirmation of management permission or approval from relevant care organization(s) to proceed with the research also needs to be in place. In addition, if the EC issued a favorable opinion with additional conditions, the clinical trial cannot start until these conditions are met. GBR-18 indicates that once all the relevant approvals are in place, all documentation has been finalized, and all participating sites have the information they need, the trial can begin. This process is often achieved by holding a start-up meeting at each site so that the CI ensures all technical aspects of a trial and protocol requirements are fully understood by relevant site staff. Trial-specific training (protocol and procedures) and review of trial conduct (e.g., safety reporting) is often undertaken at this stage. For clinical trials of an investigational product (IP), this communication should also include pharmacy staff, if applicable, so that they can confirm all requirements are in place before dispensing IPs to participants.

See GBR-40 for information about DigiTrials, which supports clinical trials in England to provide safe, authorized access to patient data to help set up trials. DigiTrials includes recruitment and feasibility services to identify whether there are enough suitable participants, as well as participant communication and outcomes services.

Per the MHCTR and GBR-18, specific documentation, including MHRA licensing, must be in place before an IP can be released for a clinical trial.

As stated in the MHCTR, clinical trials should be conducted in compliance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), and laboratory practices for IPs must comply with the UK-GLPs. Per the CTIMP-Condtns, MHRA assumes that the trial will commence within 12 months of the date of the favorable ethical opinion. The EC must be notified of the trial start date with evidence of the authorization. Further, the trial should not commence at any site until management permission has been obtained from the organization responsible for the care of the participants at the site. If the trial does not commence within 12 months of the favorable opinion being issued, the sponsor should send the EC a written explanation for the delay. A further written explanation should be sent after 24 months if the research has still not commenced. If the trial does not commence within 24 months of the favorable opinion being issued, the EC may recommend to the MHRA that the clinical trial authorization should be suspended or terminated. See CTIMP-Condtns for additional information on standard conditions for clinical trials.

Per GBR-78, all project-based research must also have governance and legal compliance approvals from the appropriate lead United Kingdom (UK) Health Department. The Integrated Research Application System (IRAS) (GBR-78) facilitates this process. As described in GBR-67, approval from the Health Research Authority (HRA) is required for all National Health Service (NHS) project-based research led from England or Wales. HRA and Health and Care Research Wales (HCRW) approval brings together the assessment of governance and legal compliance. For any new studies that are led from Scotland or Northern Ireland but have English and/or Welsh NHS sites, the national research and development coordinating function of the lead nation will share information with the HRA and HCRW assessment teams, who can issue HRA and HCRW approval for English and Welsh sites and thereby retain existing compatibility arrangements. Studies led from England or Wales with sites in Northern Ireland or Scotland will be supported through existing UK-wide compatibility systems, by which each country accepts the centralized assurances, as far as they apply, from national coordinating functions without unnecessary duplication. For more information on HRA’s assessment criteria and standards for approval, see GBR-29.

Clinical Trial Agreement

According to GBR-107 and GBR-70, contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates for industry-sponsored clinical trials with the NHS/Department of Health and Social Care (DHSC) participants in hospitals throughout the UK Health Services, which encompasses England, Northern Ireland, Scotland, and Wales. Applicants are advised to use the templates without modification. Any proposed modifications will not be accepted unless first agreed to by the UK Contracting Leads. Proposing modifications to the templates is likely to result in significant delay.

GBR-107 also provides the model non-commercial agreement (mNCA) template to meet the requirements of non-commercial sponsors and the NHS/DHSC bodies undertaking the research. This agreement has been developed as a single, UK-wide agreement template, meaning that it can be used irrespective of where the sponsor and research site are established. It is designed to be used without modification or negotiation. The mNCA has been developed for a range of interventional research scenarios, including clinical trials, medical device studies, research using participant data, and research using human tissue. The terms and conditions are suitable for all such scenarios and only the completion of highlighted sections, including the schedules of the agreement, will differ depending on the study involved.

The UKwide-Rsrch reiterates that national model contracts are available and, as such, contracting expectations and arrangements across the four (4) UK nations are broadly similar. For all four (4) nations:

In commercially sponsored research, it is mandatory to use the unmodified contract templates appropriate to the study type
In non-commercially sponsored research, it is expected that the unmodified contract appropriate to the study type is used; use of bespoke or modified agreements, where an appropriate template exists, is likely to result in significant delay and costly review; any modifications must be highlighted in the application

The UKwide-Rsrch also highlights national differences relating to the way contractual agreements are reviewed and agreed. In England and Wales, sponsors must obtain a waiver from HRA and HCRW to use a modified or bespoke agreement (an agreement that differs from a published UK-wide model agreement template). This waiver allows NHS sites to freely negotiate all the contractual terms of the agreement; in Wales, this negotiation is carried out with a central team. In Northern Ireland, to modify the UK-wide model agreement template, a waiver is needed from the Health and Social Care R&D Approvals Service, which allows sites to freely negotiate all the contractual terms of the agreement. In Scotland, sponsors can expect to carry out a single contract negotiation for all Scottish sites, which will be negotiated with a nominated lead site or central team. If the study is single center, it will be negotiated at the relevant site.

Additional details and templates are available in GBR-107 and GBR-70.

Clinical Trial Registration

As per the GBR-102 and the G-CTApp, the sponsor or investigator is required to register the clinical trial in a publicly accessible database as a condition of a favorable ethical opinion. Registration should occur before the first participant is recruited and no later than six (6) weeks after recruitment of the first participant. To help researchers meet the UK’s transparency requirements, GBR-102 indicates that the HRA will automatically register approved clinical trials with the International Standard Randomised Controlled Trial Number (ISRCTN) Registry (GBR-47) to ensure that information is publicly available. ISRCTN is the UK’s preferred clinical trials registry. HRA’s commitment to register clinical trials on behalf of sponsors and researchers is in line with the “Make It Public” research transparency strategy (see GBR-55).

Per GBR-18, each clinical trial must have a unique trial number. Clinical trials with sites in the European Union (EU), the European Economic Area (EEA), or Northern Ireland should also apply for a European number. Per GBR-87, as of January 31, 2023, all new clinical trials with sites in Europe should register on the new Clinical Trials Information System (CTIS) (GBR-39). GBR-39 specifies that by January 31, 2025, any ongoing trials must be transitioned from EudraCT (GBR-87) to GBR-39. For more information, see the EudraCT transition fact sheet (GBR-16). CTIMP-Condtns indicates that for clinical trials involving sites in both the UK and the EU, a record in EU’s GBR-39 does not satisfy the public registry condition because the UK component of the trial will not be visible in CTIS (GBR-39). Failure to register is a breach of the clinical trial conditions unless a deferral has been agreed to.

Per GBR-102, HRA also recognizes any registry covered by the World Health Organization (WHO) or the International Committee of Medical Journal Editors (ICMJE), such as clinicaltrials.gov (GBR-49). For any submissions prior to December 31, 2021, the applicant should have registered their clinical trial on an established international register.

6

Terminology (Glossary) and Sections 1, 3, and 14

1.17, 5.1.2, and 8.2.6

About NHS DigiTrials and NHS DigiTrials - our services

CI Checklist Before Seeking Approval, CTA Submission, Final Trial Management Documentation, Trial Registration, and Trial Begins

Help (Preparing and Submitting Applications)

2-3

3.2

Registration of your clinical trial, Combined review of clinical trials of investigational medicinal products, Documents to send with your application, and Assessment of your submission

7

Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 3 (12, 13, and 18)

Contracting Arrangements

Safety Reporting

Last content review/update: January 17, 2025

Safety Reporting Definitions

In accordance with the SA-GCPs 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)

The G-EthicsHR-ZAF defines SAE as an unforeseen harmful event related to the study (e.g., injury/death due to an experimental intervention), thereby negatively affecting the research participants and requiring an intervention.

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

Safety Reporting Requirements

Investigator Responsibilities

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

Per the G-EthicsHR-ZAF, researchers are expected to provide appropriate information to the EC to facilitate monitoring, including alerts. If an EC conducts a site visit, the evaluation should include inspecting documentation of AEs and SAEs. In addition, ECs should request regular, at least annual, reports from PIs on matters including a list of all AEs in the past 12 months.

Sponsor Responsibilities

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

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

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

The G-SafetyRpt delineates the following reporting timeframes:

The sponsor should initially report all fatal or life-threatening SAEs in local reports within seven (7) calendar days after first knowledge, using CIOMS format (ZAF-15)/SAHPRA SAE form (ZAF-19). The follow-up report should be submitted within an additional eight (8) calendar days.
All fatal or life-threatening SAEs in foreign reports should initially be reported within 30 calendar days after first knowledge by the sponsor. The follow-up report should be submitted within an additional six (6) months as part of the progress report. If the SAEs result in premature study closure, the reporting times are shorter—seven (7) days for the initial report and within an additional eight (8) days for the follow-up report. These reports should be in a line listing format. Note that these reporting requirements also cover foreign reports of “special concern,” which is a significant safety issue defined for each clinical trial that requires urgent attention from the regulatory authority. An adverse reaction of special concern from a foreign jurisdiction should be based on the decision of its regulatory authority. A safety issue leading to international regulatory action is considered to be significant at all times and hence reportable.
Local reports of other serious events (unexpected, not fatal or life threatening) within 15 calendar days of the event and every six (6) months in the CIOMS format (ZAF-15)/SAHPRA SAE form (ZAF-19)
A line listing of all local reports—serious (unexpected and expected) AEs—and any other issues of special concern outside South Africa should be submitted every six (6) months (using the progress report form in ZAF-18).
An initial detailed report of new information impacting the risk-benefit profile of the IP or conduct of trial should be submitted within three (3) calendar days; a follow-up report should be submitted within an additional six (6) months.
An initial detailed report of other major safety concerns (e.g., changes in nature, severity, or frequency of risk factors) should be submitted within 15 days of knowledge of the concern; a follow-up report should be submitted within an additional six (6) months.
DSURs should be submitted within one (1) year from approval of the study and annually thereafter.

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

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

Form Completion & Delivery Requirements

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

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

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

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

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

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

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

Part B

Clinical Evaluation and Management (Pharmacovigilance)

1, 2, and 6

8

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

5.5 and Appendix 1 (A1.1)

5.12, 6.4, 6.9, and 12

1 and 30(7)

Last content review/update: October 25, 2024

Safety Reporting Definitions

According to GBR-1 and GBR-64, the following definitions provide a basis for a common understanding of the United Kingdom’s (UK’s) safety reporting requirements:

Adverse Event or Adverse Experience (AE) – Any untoward medical occurrence in a participant, including occurrences which are not necessarily caused by or related to that product
Adverse Drug Reaction (ADR) – Any untoward and unintended response in a participant to an investigational medicinal product which is related to any dose administered to that participant
Serious Adverse Event (SAE), Serious Adverse Drug Reaction (SADR), or Unexpected SADR – Any AE, ADR, or unexpected ADR that results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or a congenital anomaly/birth defect
Unexpected Adverse Drug Reaction (ADR) – An adverse reaction where the nature or severity is inconsistent with the applicable product information
Suspected Unexpected Serious Adverse Reaction (SUSAR) – A suspected serious adverse reaction, which is also “unexpected,” meaning that its nature and severity are not consistent with the information about the medicinal product in question

Per the G-CTAuth-GBR, the Medicines and Healthcare Products Regulatory Agency (MHRA) advises that the guidance on reference safety information (RSI) contained in GBR-30 (developed by the Clinical Trials Facilitation Group of the Heads of Medicines Agencies (HMA)) remains applicable. For clinical trials that are being conducted in the UK, an RSI cannot be used for expectedness until the RSI has been approved by the MHRA. Additional SUSARs that occur before the new RSI is approved should be reported in the usual expedited manner. If sponsors wish to harmonize the implementation date of an RSI in a trial that includes European Union (EU) and UK sites, then they can use the date when approval is granted in all member states and the UK. In the interest of efficiency and harmonization for multinational trials, the MHRA recommends that amendments including changes to the RSI are submitted to the UK and EU at the same time. The RSI in place at the time the SUSAR occurred should be used to assess expectedness for follow-up reports.

Safety Reporting Requirements

Per GBR-99, a sponsor or investigator may take appropriate urgent safety measures (USMs) to protect research participants against any immediate hazard to their health or safety, without prior authorization from a regulatory body. The main ethics committee (EC), and the MHRA for clinical trials for investigational medicinal products (CTIMPs), must be notified immediately (no later than three (3) days) in the form of a substantial amendment that such measures have been taken and the reasons why. GBR-9 states that for trials which have been submitted via the combined review service, one USM notification is made via the combined review part of the Integrated Research Application System (IRAS) (GBR-125) and received by the MHRA. No additional notification is required directly to the EC. GBR-32 reaffirms this stating that SUSARs and safety reports for CTIMPs that were approved by combined review should be submitted to the MHRA only. If the safety report requires action, the MHRA will instruct the study team to submit a substantial amendment. Any other SUSARs or annual safety report submitted UK wide will be acknowledged by email by the EC. The submitted cover report for the SUSAR or annual safety report will not be signed and returned, and the email will act as the formal acknowledgement.

In addition, the G-CTAuth-GBR states that the sponsor should call the MHRA’s Clinical Trials Unit at 020 3080 6456 to discuss the issue with a safety scientist, ideally within 24 hours of measures being taken, but no later than three (3) days. If key details are not available during the initial call, then the sponsor should inform the MHRA no later than three (3) days from the date the measures are taken by email to clintrialhelpline@mhra.gov.uk. Written notification in the form of a substantial amendment is also required. The substantial amendment covering the changes made as part of the USM is anticipated within approximately two (2) weeks of notification to the MHRA. Any potential reason for delay of substantial amendment submission should be discussed and agreed upon with the MHRA at the time of initial notification or through a follow-up call. Submission of the substantial amendment must not be delayed by additional changes outside of those taken and required as an urgent safety measure. Unrelated and unacceptable changes may result in rejection. For more details on how submissions should be made using MHRA Submissions, see G-CTAuth-GBR.

Investigator Responsibilities

As specified in the MHCTR, GBR-1, and GBR-30, the investigator is responsible for reporting all SAEs/SADRs immediately to the sponsor. The report may be made orally or in writing and followed by a detailed report no later than 24 hours after the event. When the reported event results in a participant’s death, the investigator must provide the sponsor with any requested information. According to the MHCTR, in cases where reporting is not immediately required according to the protocol or the Investigator’s Brochure (IB), the investigator should report an SAE/SADR within the appropriate timeframe based on the trial requirements, the seriousness of the SAE/SADR, and protocol or IB guidelines. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness.

See GBR-18 for a safety reporting flowchart that gives an overview of the investigator’s expedited safety reporting requirements to the sponsor for a clinical trial in the UK.

Sponsor Responsibilities

According to the MHCTR, the G-CTAuth-GBR, and the MHCTR-EUExit, the sponsor is required to record and report all relevant information about fatal or life-threatening SUSARs as soon as possible, but no later than seven (7) calendar days to the MHRA, to the institution in which the trial is being conducted, and to the EC. Any additional relevant information should be sent within eight (8) days of the initial report. The sponsor must also report any non-fatal or non-life threatening SUSARs no later than 15 calendar days following first awareness of the event. Per GBR-1, the investigator and the sponsor share responsibility for the assessment and evaluation of adverse events with regard to seriousness, causality, and expectedness. Per the G-CTAuth-GBR, sponsors must report all UK-relevant SUSARs to the MHRA. The agency’s definition of ‘UK-relevant’ includes:

SUSARs originating in the UK for a trial
SUSARs originating outside the UK for a trial
If the sponsor is serving as a sponsor of another ongoing trial outside the UK involving the same medicinal product
SUSARs involving the same medicinal product if the sponsor of the trial outside the UK is either part of the same mother company or develops the medicinal product jointly, on the basis of a formal agreement, with the UK sponsor

Per GBR-18, sponsors should develop formal, written processes for the management of adverse events and safety reports, including the handling of both expedited reports and annual safety reporting.

Other Safety Reports

Per the G-CTAuth-GBR, sponsors must submit Development Safety Update Reports (DSURs) to the MHRA. The DSUR should consider all new available safety information received during the reporting period. The DSUR should include:

A cover letter listing all relevant clinical trial numbers of trials covered by the DSUR and an email address for correspondence (Note: per GBR-18, every clinical trial with a European site must include a European number. GBR-87 indicates that as of January 31, 2023, all new clinical trials with sites in Europe should use the Clinical Trials Information System (CTIS) (GBR-39)
An analysis of the participant’s safety in the concerned clinical trial(s) with an appraisal of its ongoing risk/benefit
A listing of all suspected serious adverse reactions (including all SUSARs) that occurred in the trial(s)
An aggregate summary tabulation of SUSARs that occurred in the concerned trial(s)

As stated in the G-CTAuth-GBR, at the end of the DSUR reporting period, the sponsor may assess the new safety information that has been generated and submit any proposed safety changes to the IB as a substantial amendment. This amendment must be supported by the DSUR and approved before the RSI is changed. A shortened DSUR is available for approved trials under MHRA’s notification scheme that are not part of a multi-study development program. Phase 4 national (UK only) trials of licensed products, which commanded a low fee from the MHRA, and where all participants have completed treatment and are only in the follow-up stage will also be suitable for submission of a short format DSUR. As an alternative to producing a full DSUR for these trials, the Health Research Authority Annual Progress Report (GBR-27) may be used.

The MHRA and Health Canada jointly released DSUR-UK_Canada to strengthen participant safety in clinical trials by improving the quality of DSURs. To increase the transparency of the data included in DSURs, the MHRA and Health Canada are requiring that the region-specific section of the DSUR explain how safety data were reviewed during the reporting period. Specifically, the region-specific section of the DSUR should include a summary description of the processes used by the sponsor to review the worldwide safety data of the investigational product (IP) (e.g., regular analyses of accumulating data, in-house safety review meetings, proposal of specific pharmacovigilance activities, or substantial modifications of the protocol). In addition, the region-specific section must describe how each safety signal (i.e., an event with an unknown causal relationship to the IP) identified during the reporting period was evaluated, as well as how a decision was made regarding the signal itself.

See the G-CTAuth-GBR, the MHCTR, GBR-1, GBR-18, GBR-30, and GBR-99 for detailed reporting requirements for the investigator and sponsor.

Form Completion & Delivery Requirements

Per the G-CTAuth-GBR, SUSARs during clinical trials should be reported to the MHRA in one (1) of the following ways:

Individual Case Safety Reports (ICSR) Submissions (GBR-126) (which replaces the EudraVigilance website (EVWEB)) – The ICSR Submissions route is used to submit single reports. (Note that per GBR-127, MHRA also decommissioned the eSUSAR reporting platform.)
MHRA Gateway (which replaces the EudraVigilance Gateway) – To gain access to the MHRA Gateway, which is used to submit bulk reports, users must first register via MHRA Submissions (GBR-13). The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11.

See the Regulatory Fees section for information on fees for annual safety reporting and DSURs. See the G-CTAuth-GBR and GBR-99 for more details on submittal and delivery requirements.

4 and 5

10

Changes to SUSARs and annual safety reports

CI Checklist Before Seeking Approval, Trial Registration, Safety Reporting, and Urgent Safety Measures

SUSAR

Reference Safety Information – updated guidance, Suspected Unexpected Serious Adverse Reactions (SUSARs), Development Safety Update Reports (DSURs), and Urgent Safety Measures

14

Part 5

Progress Reporting

Last content review/update: January 17, 2025

Interim and Annual Progress Reports

In accordance with the GRMRSA, the person authorized by the South African Health Products Regulatory Authority (SAHPRA) to conduct a clinical trial (i.e., the sponsor) must submit progress reports to the SAHPRA every six (6) months from the application approval date. The SA-GCPs requires the investigator to submit written progress reports to the ethics committee (EC) annually and to the SAHPRA every six (6) months. ECs and the SAHPRA may request reports more frequently. The G-EthicsHR-ZAF states that ECs should request regular, at least annual, reports from principal investigators (PIs) on matters including: progress; current enrolment status; whether participant follow-up is still active or completed; record maintenance and security; evidence of compliance with the approved protocol and any conditions of approval; negative reports from monitors or good clinical practice (GCP) inspectors; all adverse events in the past 12 months; and all amendments made in the past 12 months.

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

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

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

Final Report

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

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

The G-EthicsHR-ZAF states PIs or research leaders must disseminate research results or findings, whether positive or negative, in a timely, accessible, responsible, and competent manner. This includes reporting back to participant communities where appropriate.

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

6.1-6.2 and 7.3.1

2.3 and 5.5

5.5, 5.11, 5.14, and 6.15

Part 30 (6)

Last content review/update: October 25, 2024

Interim and Annual Progress Reports

As indicated in the G-CTAuth-GBR and GBR-9, the investigator and the sponsor share responsibility for submitting progress reports to the ethics committee (EC), as required, on the status of a clinical trial and for submitting a final study report upon the trial’s completion. These requirements comply with the progress and final reporting requirements delineated in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113).

In accordance with GBR-32 and GBR-65, it is no longer a requirement to submit annual progress reports to the EC. However, GBR-65 states that depending on the type of approval, a progress report may be requested to track progress.

In addition, GBR-65 states that if the study was reviewed by an EC in Scotland or Northern Ireland, an annual progress report should be submitted 12 months after the date on which the favorable ethics opinion was given, except in the following instances:

If the study is expected to run for less than two (2) years in duration
If the study received a proportionate review
If the study received a favorable ethics opinion from an EC in England or Wales

Furthermore, GBR-65, states that if a study was given a favorable ethics opinion by an EC in Scotland or Northern Ireland, there are separate forms for submitting progress reports, depending on the type of research. The form for clinical trials of investigational medicinal products (GBR-27) should be completed in typescript and authorized by the Chief Investigator (CI) or the sponsor/sponsor representative. An electronic copy should be emailed to the EC within 30 days of the end of the reporting period.

See the Regulatory Fees section for information on fees for annual progress reports.

Final Report

As per the MHCTR and the G-CTAuth-GBR, the sponsor must notify the Medicines and Healthcare Products Regulatory Agency (MHRA) and the EC in writing that a clinical trial has ended within 90 days of the conclusion of the trial. As indicated in GBR-128, all project-based research (not research tissue banks or research databases) that has been reviewed by an EC needs to submit a final report within 12 months of the end of the study. The final report should be completed and submitted in the combined review part of Integrated Research Application System (IRAS) (GBR-125). When completing the final report form, IRAS guides the user with instructions next to each question.

The G-CTAuth-GBR further specifies that a declaration of the end of a clinical trial should be sent to the MHRA within 90 days of the global end of the trial and within 15 days of the global premature end of the trial. The submission must include an end of trial form (GBR-133) and a cover letter. Note that only the global end-of-trial notification is required to be submitted. However, a facility may inform the MHRA of the local (UK) end of trial via the end-of-trial notification form, but these local notifications will not be officially acknowledged and the MHRA Submissions automatic email confirmation should be considered as evidence of submission. If a local end of trial is submitted, the MHRA would still expect to receive relevant safety updates and substantial amendments for the ongoing trial until the global end of trial notification is received. An exemption to this requirement must be requested via a substantial amendment for approval. The amendment must clearly state to what documents the proposal relates and provide a robust rationale for the request. All safety documentation must be submitted unless there are no other trials ongoing with the same product in the UK. Any trial activities (such as follow-ups, visits) must be completed before the submission of the global end-of-trial declaration form. It is not possible to submit amendments to the trial or the Development Safety Update Report (DSUR) once the global end-of-trial declaration form has been received by the MHRA. If the end-of-trial declaration has been received within a reporting period, or within 60 days following the data lock point, the corresponding DSUR will not be required.

Per the G-CTAuth-GBR, the timeframe for publishing the summary of results is within one (1) year of the end of trial. Sponsors should publish summary results within this timeframe in the public register(s) where they registered the clinical trial. While it is not required to submit this clinical trial summary report to the MHRA, sponsors must send a short confirmation email to CT.Submission@mhra.gov.uk once the results-related information has been uploaded to the public register and provide the relevant link.

As per GBR-9, the investigator is also required to submit a summary of the final study report to the main EC within one (1) year of the trial’s conclusion. GBR-20 clarifies that the form in GBR-20 should be used for this submittal, which includes submitting a lay summary of results. This is a UK-wide final report for all project-based research studies that have been reviewed by an EC within the UK Health Departments’ Research Ethics Service (GBR-62). The information contained in this final report helps the Research Ethics Service to monitor whether the research was conducted in accordance with the EC’s favorable opinion and applicable transparency requirements. Per the GBR-120, sponsors should include a plain language summary of their findings in the final report, which will be published on HRA’s website alongside the study research summaries. See GBR-120 for guidance on writing a good plain language summary for a general audience.

Per the G-PIPs, UK marketing authorization holders who sponsor a study that involves the use of the authorized medicinal product in the pediatric population, must submit to the MHRA results of the study within six (6) months after the trial ended. Additional requirements and submittal details are in the G-PIPs and the G-PIPsProcess.

Terminology (Glossary), and Sections 1 and 14

4.10 and 4.13

Final report on the research

End of Trial

Legal Background and Scope

Part 3 (Section 27)

Definition of Sponsor

Last content review/update: January 17, 2025

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

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

1

6

Last content review/update: May 16, 2024

As per the MHCTR, the MHCTR2006, the G-CTApp, GBR-103, GBR-9, GBR-2, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is defined as an individual, company, institution, or organization who takes ultimate responsibility for the initiation, management, and financing (or arranging the financing) of a trial. The sponsor must ensure that the trial design meets appropriate standards and arrange for the trial to be properly conducted and reported. In addition, per GBR-101, the sponsor is the individual, organization, or partnership that takes on overall responsibility for proportionate, effective arrangements being in place to set up, run, and report a research project.

In accordance with GBR-113, the United Kingdom (UK) also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Per the G-CTApp, G-SubtlAmndmt, and the GBR-103, the clinical trial sponsor or legal representative needs to be established in the UK or a country on an approved country list which initially includes the European Union (EU)/European Economic Area (EEA) countries per G-CTApprovedCountries. A change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the MHRA and the ethics committee. GBR-103 specifies that the legal representative:

May be an individual person or a representative of a corporate entity
Does not have to be a legally qualified person
Should be willing to act as the agent of the sponsor in the event of any legal proceedings instituted (e.g., for service of legal documents)
Should be established at an address in the UK or a country on the approved country list
Does not assume any of the legal liabilities of the sponsor(s) for the trial by virtue of the role of legal representative and does not therefore require insurance or indemnity to meet such liabilities; but may, in some cases, enter into specific contractual arrangements to undertake some or all of the statutory duties of the sponsor in relation to the trial, in which case the legal representative would also be regarded as a co-sponsor and would then require insurance or indemnity cover

The MHCTR also permits two (2) or more parties to take responsibility for the sponsor’s functions. When this applies, the MHCTR requires one (1) of the parties to submit the clinical trial application for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA), and to specify who is responsible for carrying out the following functions:

Communications relating to substantial amendments, modified amendments, and trial conclusion
Communications relating to urgent safety measures
Pharmacovigilance reporting

Basic Principles

Terminology (Statutory Definitions Relating to CTIMPs)

5.1 and 5.2

Responsibilities (9.10)

Changes to the trial sponsor/legal representative

2

Trial Sponsor and legal Representative

Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (3)

Site/Investigator Selection

Last content review/update: January 17, 2025

Overview

As set forth in the SA-GCPs, the sponsor is responsible for using qualified individuals (e.g., biostatisticians, clinical pharmacologists, and physicians), as appropriate, throughout all stages of the trial process. Sponsors should select investigator(s) who are qualified by training and experience and have adequate resources to conduct the proposed clinical trial.

Per the SA-GCPs, all parties involved in the conduct of a trial should be familiar with the guidance in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27) and other international guidelines.

Capacity Building & Training

As described in 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.

The G-EthicsHR-ZAF states that researchers must be suitably qualified and technically competent (trained and supervised, in the case of student researchers) to carry out the proposed research. The principal investigator (PI) has primary responsibility to ensure the safety and wellbeing of participants, the scientific integrity of the protocol, research data management, and responsible implementation of that protocol. Competence is demonstrated mainly by academic qualifications, credentials, and scientific and technical competence, as evidenced in previous publications or testimonials. Competence includes research competence, which is assessed in terms of education, knowledge, certification, and experience. In addition, researchers must produce evidence of appropriate research ethics training within the previous three (3) years.

The SA-GCPs prescribes mandatory GCP training with evidence of current (i.e., within three (3) years) GCP training and general research ethics training. To meet the required GCP training, the GCP-Trning indicates that virtual methods are acceptable (Zoom, Teams, etc.) for both basic and refresher training. Virtual training must be done properly, which includes monitoring interactive and active engagement of participants, and using a full-time facilitator (qualified to conduct training) available for the entire duration including questions and answers. To ensure inclusivity and fairness, consideration should be given to those who are unable to attend virtual training, especially in remote areas where internet accessibility remains a challenge. A hybrid model could be considered in this case. The duration of basic GCP training should be in alignment with the prescribed outcomes or unit standards (approximately two (2) days). The training content should be accredited by the Health Professions Council of South Africa (HPCSA).

Management of Investigators

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

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

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

Foreign Sponsor Responsibilities

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

Per the G-EthicsHR-ZAF, all international collaborative health research conducted in South Africa must undergo ethics review and approval by a South African registered EC and comply with the SA-GCPs. In addition, if international collaborators are affiliated with a foreign research institution or university, they must provide evidence of ethics review and approval from their home institution. International researchers are expected to demonstrate sensitivity to and understanding of the local socio-economic and political conditions of the research context, as these may indicate vulnerabilities of potential participants. It is advisable to create appropriate memoranda of understanding (MOUs) and agreements to establish the expectations, roles, and contributions of the various parties, as well as the limitations of the collaborative relationship. An agreement should exist between the host research institution and the collaborating institution(s) regarding all aspects of the research, including management of the research itself; research data management that includes the fate of the data and samples after completion of the study; financial arrangements; approach to research output publications; infrastructure development; allocation of intellectual property rights; and dispute resolution mechanisms. Selection of study participants is expected to be based on distributive justice and fairness. Risk/benefit assessments must be properly conducted to ensure that foreseeable risks of harm are mitigated and that anticipated benefits of participation are distributed fairly.

Data and Safety Monitoring Board

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

Multicenter Studies

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

The G-EthicsHR-ZAF states that for international multi-site research, at least one (1) PI or co-PI must be physically in South Africa.

1.25, 5.5, and 5.6

5

3 and 4

2.3 and 3.3

1.2, 4.3, 5.9, 6.2, 6.4, and 7.12

Last content review/update: January 21, 2025

Overview

As set forth in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The MHCTR2006 indicates that the sponsor must also ensure that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. GBR-9 states that the chief investigator (CI) should be based in the United Kingdom (UK). In rare cases when this is not required, adequate arrangements must be in place for supervision of the study in the UK.

As delineated in the MHCTR, the MHCTR2006, and GBR-113, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Per GBR-113, if a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. Per GBR-18, for clinical trials of investigational products (CTIMPs) conducted at National Health Service (NHS) sites, the addition of a new site and/or addition or change of a principal investigator (PI) is no longer considered a substantial amendment. No changes have been made to the classification of amendments relating to new sites/change of PI at non-NHS sites. If a site is added in a nation not previously involved in a study, this should be indicated in the combined review section (GBR-125) of the Integrated Research Application System (IRAS) for CTIMPs, and made clear in a cover letter when submitting the amendment to the lead nation.

UK Local Information Pack

GBR-113 recommends establishing a Data Monitoring Committee (DMC) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Per GBR-63, researchers working with NHS/Health and Social Care in Northern Ireland (HSC) organizations across England, Northern Ireland, Scotland, and Wales should use the UK Local Information Pack (LIP), which provides one (1) consistent package to support study setup and delivery across the UK.

The UKwide-Rsrch explains the LIP ensures that consistent information is given to all UK research sites and indicates that there are national differences in the LIP. In England and Wales, the LIP should include the Initial Assessment Letter, which may be shared with sites. Additionally, the sponsor should send the LIP directly to the site’s Research and Development (R&D) department, delivery team, and local clinical research network (if a National Institute for Health and Care Research Clinical Research Network (NIHR CRN) Portfolio) using the England and Wales non-commercial email template or commercial email template, as appropriate. For Welsh sites, it is expected that the sponsor has a process to translate patient-facing documents into the Welsh language if requested by sites or participants. In Northern Ireland, the sponsor may send the LIP to each participating site’s R&D department and delivery team once the application has been validated and once instructed to do so by the Health and Social Care R&D Approvals Service. The LIP should be shared using the Northern Ireland non-commercial email template or commercial email template, as appropriate. In Scotland, the NHS Research Scotland Permissions Coordinating Centre makes the LIP available to participating R&D departments and the appropriate Network or Portfolio Manager. The sponsor is responsible for making the information available to the research teams using the Scotland email template, which covers both non-commercial and commercial studies.

For help with LIP packages, email templates and other requirements, see GBR-106.

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list (which initially includes European Union (EU)/European Economic Area (EEA) countries), it is a statutory requirement to appoint a legal representative based in the UK or a country on the approved country list for the purposes of the trial. Per the G-CTApprovedCountries, the UK published a list of countries where a sponsor of a clinical trial, or their legal representative, may be established; currently listed countries are those in the EU and EEA. The G-SubtlAmndmt delineates that a change in sponsor or legal representative for a UK trial is a substantial amendment requiring submission to both the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC), pursuant to the guidelines in the G-CTAuth-GBR. Where the sponsor is from the rest of the world, and the legal representative is established in the UK, and there are sites in the EU/EEA, the sponsor will need to assign an EU/EEA legal representative for these sites via a substantial amendment to the relevant EU/EEA competent authorities. No amendment submission to the MHRA is required where the sponsor or legal representative for an ongoing trial is established in the EU/EEA as the UK will continue to accept this approval. Further, no amendment will need to be submitted in the UK if the sponsor retains the UK legal representative for the UK study. Similarly, no amendment will need to be submitted in the UK if a sponsor remains in the UK and a legal representative is added to cover EU/EEA sites.

Additional foreign sponsor requirements are listed in Section 5.2 of GBR-113.

Data Safety and Monitoring Board

Per GBR-18, the chief investigator should ensure that arrangements are made for a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK). GBR-113 recommends establishing a DMC to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.

Multicenter Studies

Per GBR-18, for multicenter trials, the careful selection and evaluation of investigator sites is critical for the successful completion of a trial within budget, timelines, and to ensure the generation of high-quality data. When undertaking site selection, the preparation of ‘reserve’ investigator sites (so that the trial may be extended to these sites if recruitment issues arise) should be considered as part of proactive trial planning. Factors that should influence investigator site selection include:

Interest in the research question
Experience and qualifications of the investigator
Sufficient staff to conduct the study and their experience and qualifications
Availability of a suitable patient population
Adequate time to conduct and oversee the trial
Adequate facilities
Previous track record with similar trials
Geographic location
Contractual and budgetary negotiations and arrangements

Per GBR-18, for multicenter trials, the CI must ensure that each PI is provided with all relevant, version-controlled documents before commencing recruitment. Further, it is good practice to ensure the PI signs a protocol signature page to confirm receipt and their agreement to comply with the current version of the protocol. The trial master file should be held at the coordinating site and copies of relevant documents should be kept at each participating site in an investigator site file.

Further, as delineated in GBR-113, in the event of a multicenter clinical trial, the sponsor must ensure that:

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

1.1

5.23, 5.5, 5.6, 6, and 7

CI Checklist Before Seeking Approval, Addition of New Sites & Investigators, Final Trial Management Documentation, Feasibility & Investigator Selection, Final Protocol, and Trial Master File

Preparing and Submitting Application (Site-specific information)

Changes to the trial sponsor/legal representative

2

Amending your trial protocol or other documentation

Insertion of Regulation 3A of the Principal Regulations, Insertion of Regulation 29A of the Principal Regulations, and Part 2 (Principles based on Articles 2 to 5 of the GCP Directive)

Part 1 (3) and Part 3 (15)

Providing the UK Local Information Pack

Insurance & Compensation

Last content review/update: January 17, 2025

Insurance

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

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

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

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

Compensation

Injury or Death

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

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

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

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

The seriousness of the disease being treated
The degree of probability that adverse reactions will occur and any warning given
The risks and benefits of the established treatments relative to those known or suspected of the trial medicines

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

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

Trial Participation

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

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.

The G-EthicsHR-ZAF explains that inducements (also known as incentives) may be offered in justified circumstances (e.g., where recruitment is anticipated to be difficult) to encourage participation and to express appreciation by offering gifts over and above reimbursement of expenses and compensation for time and inconvenience. Inducements are not necessarily cash but may take other forms like data or airtime vouchers, food vouchers, etc. Importantly, an inducement should not unfairly influence an informed choice about whether to participate or undermine a potential participant’s ability to assess the risk of harm. This is especially important for Phase I and First in Humans clinical trials where the circumstances may involve healthy people being offered significant payments over and above those outlined in the TIE method. All inducements should be clearly explained and justified to the EC. If there are community members on the EC, their input may be constructive regarding appropriate inducements.

Post-Trial Access

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

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

3 and 4

Cover, 1 and 2

1-5 and 7

3.1, 3.3, 3.4, and Appendix 2 (A2.2)

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

Last content review/update: May 16, 2024

Insurance

As set forth in the MHCTR and the MHCTR2006, it is a legal requirement for an insurance and indemnity provision to be made to cover the liability of the investigator and sponsor for trial-related injuries. The MHCTR does not ascribe responsibility to the sponsor or the designated representative to obtain insurance and indemnity. However, GBR-2, GBR-103, GBR-101, and GBR-18 state that the sponsor or the designated representative is responsible for ensuring adequate insurance and indemnity arrangements are in place to cover the sponsor’s and the investigator’s potential liability, and for providing a copy of this coverage in the clinical trial application submission.

In addition, according to GBR-2, the sponsor or the designated representative must ensure that the research covered by the National Health Service (NHS)’s indemnity policy is in place for each publicly funded participating study site. See GBR-33 for detailed information on the NHS indemnity responsibilities for clinical negligence involving investigators and participants. GBR-33, specifically addresses the sponsor’s or the designated representative’s requirement to insure or indemnify the investigator participating in industry-sponsored Phase 1 clinical trials.

The International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113) also guides sponsors on providing insurance.

Compensation

Injury or Death

As specified in the MHCTR, the sponsor or the designated representative is responsible for providing compensation to research participants and/or their legal heirs in the event of Phase 1 trial-related injuries or death. According to GBR-33, the sponsor must have agreed with the research participant to provide compensation for injury whenever a causal relationship with participation is demonstrated. This undertaking can be provided directly by the sponsor through the consent process, or through authorizing the contract research organization (CRO) or investigator on behalf of the sponsor. In addition, the sponsor should follow these practices:

If the health or wellbeing of the participant deteriorates significantly as a result of taking part in the study, the sponsor will compensate the volunteer, irrespective of the ability of the participant to prove fault on the part of the sponsor or anyone else connected with the study.
The amount of compensation should be calculated by reference to the amount of damages that would commonly have been awarded for similar injuries by an English court had liability been proven. The amount of compensation may be reduced if the volunteer is partly responsible for the injury or if the volunteer is separately compensated under any other insurance policy.
The sponsor and participant agree to refer any dispute about whether compensation is payable or the amount of such compensation to an arbitrator with power to consult a barrister of 10 years’ standing on any issue of law, including the amount of damages to be paid.
Participants should be given a copy of the relevant Association of the British Pharmaceutical Industry (ABPI) guidelines and should be invited to seek clarification of any aspect of the undertaking that is not clear to them.
Participants may make a claim through the investigator, and the sponsor should aim to respond sympathetically and promptly.

GBR-113 also provides guidance for sponsors on providing compensation to research participants in the event of trial-related injuries or death. The sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

3, 4, and 6

Introduction and Basic Principles

5.8

CI Checklist Before Seeking Approval (Trial Planning Phase) and Final Trial Management Documentation

Responsibilities

Part 2 (Conditions Based on Article 3 of the Directive)

Part 3 (15), Part 4 (8), and Schedule 1 (Part 1 (1) and (16))

Risk & Quality Management

Last content review/update: January 17, 2025

Quality Assurance/Quality Control

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

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

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

Monitoring Requirements

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

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

As delineated in the G-EthicsHR-ZAF, researchers are expected to provide appropriate information to the EC to facilitate monitoring, including alerts and investigator brochures.

Premature Study Termination/Suspension

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

The G-EthicsHR-ZAF reiterates that if a project is terminated or suspended before the anticipated date of completion, then the researchers must report this immediately to the EC.

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

1 and 4

5.5

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

Last content review/update: October 25, 2024

Quality Assurance/Quality Control

As stated in the MHCTR, the MHCTR2006, and GBR-92, the sponsor is responsible for maintaining 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 International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113). The sponsor is required to obtain agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

Conduct the trial in compliance with GBR-113 and the protocol agreed to by the sponsor and approved by the ethics committee (EC)
Comply with data recording and reporting procedures
Permit monitoring, auditing, and inspection
Retain essential documents until the sponsor informs them that they are no longer needed

MHCTR2006 requires the sponsor to notify the Medicines and Healthcare Products Regulatory Agency (MHRA) of serious breaches of good clinical practice (GCP) or the trial protocol. A serious breach is defined as one that is likely to affect to a significant degree: the safety or physical or mental integrity of the trial participants; or the scientific value of the trial. Per G-MHRA-SeriousBreaches, the sponsor or delegated party should notify the MHRA GCP Inspectorate within seven (7) days of becoming aware of a serious breach. Further, the sponsor should investigate and take action simultaneously after the MHRA notification. Notifications should primarily be sent to the following email address: GCP.SeriousBreaches@mhra.gov.uk.

Per the G-RiskAssmt, MHRA recommends that a risk assessment is undertaken for all clinical trials. Phase 1 trials are required to have a documented risk assessment process and to produce a risk assessment for all proposed trials. The risk assessment should be done as early as possible to help the sponsor identify whether the sponsor wishes to proceed with sponsorship and the potential category of IP for eventual marketing authorization. An early risk assessment will also identify the study management requirements, which can assist in the planning and resourcing aspects of the trial (e.g., identification of trial monitoring requirements so that these can be budgeted for in any funding application). There is no requirement to submit risk assessments to the MHRA or the ethics committee (EC). However, any safety monitoring produced because of the risk assessment must be described in the protocol. Finally, information contained in the risk assessment may prove useful in completing the application form for approvals, particularly for the EC application. See the G-RiskAssmt for details on how to conduct the risk assessment.

See GBR-10 for best practices in improving clinical trial setup to reduce timelines and increase citizens’ access to research. Also see GBR-34 for investigator training and guidance on implementing people-centered research.

Monitoring Requirements

Per GBR-18, the sponsor must develop an audit plan to assess and assure the reliability and integrity of the clinical trial systems against all relevant written standards. The following activities and checks could include the following:

Interview staff to assess whether they are appropriately trained; understand their role(s); and are working to all relevant standards, the protocol, and SOPs.
Tour the facility to assess if there are adequate resources and if the equipment is fit for its intended use.
Review documents to evaluate whether data reported is verifiable from source data and that written records confirm that the trial was conducted appropriately.

Auditors must be independent of the trial team and appropriately trained for their role. Their findings and observations must be documented in a formal audit report. Any deficiencies identified during an audit must be followed up with appropriate corrective and preventive actions wherever possible.

Per GBR-18, the MHRA may conduct inspections to ensure the clinical trial is being conducted in compliance with good clinical practice (GCP) as prescribed in GBR-92 and GBR-113. The MHRA takes a risk-based approach to inspections depending on the type of trials and risk rating. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization. A response to this report (describing any corrective and preventive actions) must be produced. See GBR-92 for pre-inspection checklists and other resources. Per G-RiskAssmt, GCP Inspectors will review risk assessments. The risk assessment should provide the rationale behind trial management/monitoring and GCP activities applied, or not, to the trial.

Finally, the sponsor’s audits and inspections should be conducted in compliance with GBR-113, which calls for a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan). The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials.

Premature Study Termination/Suspension

The G-CTAuth-GBR states that the MHRA has the authority to suspend or terminate a trial. In addition, the sponsor can contact the MHRA to put a trial on temporary halt or terminate a trial. If a sponsor suspends a trial temporarily, the MHRA must be notified. Sponsors of clinical trials of investigational products (CTIMPs) must use the combined review part of the Integrated Research Application System (IRAS) (GBR-125) to submit this notification as a substantial amendment. Per GBR-122, for studies that were submitted before combined review, these applicants should continue to submit this notification at IRAS via GBR-78. The G-CTAuth-GBR indicates the notification should be made as a substantial amendment using the amendment tool, clearly explaining what has been stopped and the reasons for the suspension. To restart a trial that has been temporarily suspended, you must make the request as a substantial amendment using the notification of amendment form, providing evidence that it is safe to restart the trial.

Per the G-CTAuth-GBR and GBR-18, to terminate a CTIMP, the sponsor must notify (as a substantial amendment) the MHRA and the EC via the combined review part of IRAS (GBR-125). For studies that were submitted before combined review, the submission should be made at GBR-78, using the end-of-trial form (GBR-133). GBR-128 specifies that for CTIMPs, the declaration of end of trial must be sent to the MHRA within 15 days of the global premature end of trial. Before declaring an end of the study, sponsors should review the plans that were approved by the EC for use of tissue and data collected in the course of the study, providing information to participants, and dissemination of results. If changes need to be made to these agreed upon arrangements, the sponsor should consider whether an amendment is required before submitting the end of study notification. GBR-65 also states that if research is terminated early or is temporarily suspended, then all relevant review bodies should be notified within 15 days.

According to GBR-113, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the sponsor should also inform the EC promptly and provide the reason(s) for the termination or suspension.

5.0, 5.1, 5.2, 5.18, 5.19, 5.21, and 6.10

Ongoing Management & Monitoring, MHRA Inspection, Audit, Temporary Halt, Early Termination, and End of Trial Declaration

Early termination or temporary halt of research

Suspend or Terminate a Trial and End of Trial

Amendment of Regulation 31 of the Principal Regulations and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive)

Part 3 (15), Part 4 (28), Part 6 (36 and 38), and Schedule 7 (Parts 2 and 3)

Data & Records Management

Last content review/update: January 17, 2025

Electronic Data Processing System

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

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

See the G-EthicsHR-ZAF for detailed ethical, legal, and security considerations for database storage and access.

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

Records Management

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

4

4.2

Introduction, 1.2, 5.10, 6.4

Last content review/update: May 16, 2024

Electronic Data Processing System

To safeguard personal data within electronic health record (EHR) systems, G-EHRAccess provides guidance on updating these systems to ensure access by sponsors and their representatives (e.g., monitors and investigators) is limited to only the records of clinical trial participants and that this access is auditable. See G-EHRAccess for details on system security, remote access, document sharing, consent, and other considerations.

According to GBR-113, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human participant protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training.

Records Management

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the Chief Investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the Medicines and Healthcare Products Regulatory Agency (MHRA) upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

In addition, GBR-113 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

1.65, 5.18, and 8

Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive)

Personal Data Protection

Last content review/update: January 17, 2025

Responsible Parties

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

Data Protection

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

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

Accountability – The responsible party must ensure that the conditions and all the measures in the POPIA are complied with at the time 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 G-EthicsHR-ZAF reaffirms that data protection measures should be aligned with the requirements of the POPIA, including the conditions for cross-border transfer and sharing of health data. To ensure data processing is lawful, fair, and transparent, researchers should submit a data management plan to the ethics committee (EC), which covers how data will be collected, stored, accessed, shared, and disposed of or retained. The data management plan should indicate how it complies with the POPIA, how data security will be maintained and the processes for possible data breaches. If data-sharing options include the use of open-access databases, the selected databases must meet the minimum legal, ethical, and security requirements. See the G-EthicsHR-ZAF for additional guidance and analysis. Also see the Specimen Import & Export section for details on sharing human biological material (HBM) and HBM data.

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

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

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

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

Consent for Processing Personal Data

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

As delineated in the G-EthicsHR-ZAF, consent to processing of personal information in terms of the POPIA requires a voluntary, specific, and informed expression of will, separate from the consent to participate in research. Special attention should be given to ensuring that computers and electronically stored data are protected from unauthorized access, inadvertent or accidental dissemination in the form of a ‘data dump’, etc. In general terms, a participant should know what personal information is being collected; why it is being collected; what will happen to it; how long it will be retained; whether it will identify the participant; whether it will be shared with others and why; whether it will be shared with third parties inside South Africa and why; and whether it will be sent outside South Africa and why. The participant should agree to these terms. Note that when processing some types of personal information, consent alone is insufficient as stipulated in the POPIA. Necessity must be evident too with special personal information, such as information about a person’s race or ethnic origin, a person’s health or sex life, a person’s inherited characteristics (genetic makeup), biometric information, or children’s personal information.

Consent for Processing Personal Data of Minors

Per the POPIA, there is a general prohibition on the processing of personal information of a minor. However, a responsible party may process personal information concerning a minor if the processing meets one (1) of the following conditions:

It is carried out with the prior consent of a competent person
It is necessary for the establishment, exercise, or defense of a right or obligation in law
It is necessary to comply with an obligation of international public law
It is for historical, statistical, or research purposes to the extent that the purpose serves a public interest and the processing is necessary for the purpose concerned; or it appears to be impossible or would involve a disproportionate effort to ask for consent and the processing does not adversely affect the individual privacy of the child to a disproportionate extent
It is of personal information which has deliberately been made public by the minor with the consent of a competent person

As required in the G-EthicsHR-ZAF, when personal information about a minor (under 18 years) is to be processed, permission of a parent/legal guardian is required before data collection, even when permission is not required for the specific activity that gives rise to the information (e.g., donating blood). A minor aged 16 years or more may donate blood without parent/legal guardian permission, but the POPIA requires parent/legal guardian permission to process the information.

3.3 and 3.4.3

Preamble, Chapter 1 (1-2), Chapter 2 (4-5), Chapter 3, Chapter 5 (55-56), and Chapter 9 (72)

Schedule (2-4) and Forms 1 and 2

Last content review/update: January 21, 2025

Responsible Parties

For purposes of data protection requirements, the UK-GDPR, the UK-DPAct, and the G-GDPR delineate that the sponsor acts as the “controller” in relation to research data. This is because the sponsor determines what data is collected for the research study through the protocol, case report form, and/or structured data fields in a database. GBR-7 provides guidance on key data protection requirements to consider in the post-Brexit environment. Among other things, it describes how data can continue to flow to and from the United Kingdom (UK), as well as controller responsibilities.

Data Protection

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the sponsor (known as the “controller” in data protection legislation) must comply with the following principles of the data protection legislation:

Lawfulness, fairness, and transparency
Purpose limitation
Data minimization
Accuracy
Storage limitation
Integrity and confidentiality (security)
Accountability

The sponsor must show that each data processing activity has a lawful basis under this legislation, in addition to the common law basis. For health and social care research, the lawful basis is determined by the data controller’s organization type:

For universities, National Health Service (NHS) organizations, Research Council institutes, or other public authority, the processing of personal data for research should be a “task in the public interest.”
For commercial companies and charitable research organizations, the processing of personal data for research should be undertaken within “legitimate interests.”

As described in the G-GDPR, with regard to transparency, the sponsor should understand whether personal data is collected indirectly from a third party or directly, as these determine the actions to take to comply with data protection requirements. In most cases, the sponsor will need to provide transparency information about the legal basis and other details of processing personal data. See the table in G-GDPR, which sets out the specific transparency requirements for personal data. In addition, GBR-100 contains a series of templates by the Health Research Authority (HRA) with suggested transparency language. Further, the sponsor should take measures to ensure data is processed securely, giving consideration to security, storage, and pseudonymization/anonymization when possible. For details on complying with security and storage requirements, see GBR-100.

Per the UK-GDPR and the UK-DPAct, the data protection legislation introduces a duty requiring public authorities or bodies to appoint a data protection officer (DPO); a DPO may be required for non-public entities if they carry out certain types of processing activities. The DPO assists the sponsor with monitoring internal compliance, informs and advises on data protection obligations, provides advice regarding Data Protection Impact Assessments (DPIAs), and is a point of contact for participants and the supervisory authority. See G-GDPR for guidance related to DPIAs.

For more information on data protection requirements following the UK’s transition out of the European Union (EU), see GBR-7.

Consent for Processing Personal Data

Per the UK-GDPR, UK-DPAct, and G-GDPR, consent to participate in research is not the same as consent as the legal basis for processing personal data under the data protection legislation. Per the G-GDPR, for the purposes of the UK-GDPR, the legal basis for processing data for health and social care research should not be consent. This means that requirements in the UK-GDPR relating to consent do not apply to health and care research. Per the G-GDPR, even though consent is not the legal basis for processing personal data for research, the common law duty of confidentiality still applies, so consent is still needed for people outside the care team to access and use confidential information for research.

As delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, participants have the right to be informed about the collection and use of their personal data. This is a key transparency requirement under the data protection legislation. The UK-GDPR specifies what data individuals have the right to be informed about (i.e., privacy information). In addition, as delineated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the participant has certain data rights, which are limited by a range of exemptions. These exemptions must be balanced with what is fair to participants. As indicated in the G-GDPR, exemptions to data subject rights are not automatic, but must be considered on a study-by-study basis. It is important, therefore, to take into account the relevance of data rights to a particular study in the Participant Information Sheet (PIS) when offering or limiting the rights available to research participants. If data rights have been previously offered or limited to participants that are not appropriate under UK-GDPR, then the PIS may need to be revised as a non-substantial amendment.

As indicated in the G-GDPR and GBR-100, the HRA has developed a series of templates with transparency language to help organizations comply with the data protection legislation. The requirements vary depending on the point of collection of personal data (directly or indirectly) and the timing of the study. Also see GBR-129 for guidance from the UK Information Commissioner’s Office.

The UKwide-Rsrch describes the following differences among the UK nations regarding accessing identifiable data without consent, including for potential participants:

England and Wales – If the project involves access to identifiable patient data relating to people living or receiving care and treatment in England and Wales without consent, the sponsor may need to apply to the HRA via the Confidentiality Advisory Group (CAG) (GBR-38). The CAG provides advice to the HRA on the use of confidential patient information for research uses. See GBR-41 for details and resources on the CAG.
Northern Ireland – There is currently no legal basis for those outside of the direct care team to process identifiable data without consent. The Health and Social Care Privacy Advisory Committee can provide advice on any options available in Northern Ireland. The Health and Social Care Honest Broker Service does not provide identifiable data for consented studies or trials but may be able to offer advice on options to access anonymized data to support research
Scotland – If a project is multi-center, a sponsor will need to obtain permissions through the Public Benefit and Privacy Panel for Health and Social Care. For single center studies, applicants should contact the Caldicott Guardian at the research site to discuss the requirements for accessing the data

UK-US Data Bridge

As explained in GBR-22, under the “UK Extension to the EU-US Data Privacy Framework” (GBR-23), businesses in the UK can transfer personal data to certified U.S. organizations without further safeguards as defined in the GBR-23. US organizations that have been certified can opt in to receive data from the UK through the UK-US data bridge. Per GBR-19, before transferring personal data, UK organizations must verify that the receiving US organization is certified pursuant to GBR-23. Sensitive personal data must be appropriately identified as sensitive when transferred under the UK-US data bridge to ensure it receives appropriate protections under the framework. Under the UK extension, sensitive personal information includes genetic data, biometric data for the purpose of uniquely identifying a natural person, and data concerning sexual orientation. See GBR-22, GBR-23, and GBR-19 for additional information about the UK Extension to the Data Privacy Framework.

Principles, Lawful Basis for Processing, Individual Rights, Accountability and Governance

Part 1, Part 2 (Chapter 2), and Schedules 2-4

Will identifiable, confidential patient data be accessed outside the care team without prior consent at any stage of the project (including identification of potential participants)?

Documentation Requirements

Last content review/update: January 17, 2025

Obtaining Consent

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

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

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

G-EthicsHR-ZAF explains that an important element of enabling an informed choice is the nature and quality of information made available to the potential participant, such as reading the information sheet and/or dialoguing with the participants, allowing for verbal consent, which is then recorded and transcribed or documented manually in the researchers’ notes. The process should permit sufficient time for consultation between the recruitment step and the time of deciding whether to participate. No person should be required to make an immediate decision. ECs should assess the proposed process for informed consent as well as the information that potential participants will be given and the measures to facilitate understanding. Considerations for assessment include whether:

The informed consent setting is sufficiently private and appropriate to minimize the possibility of undue influence
The person conducting the informed consent process is appropriately trained, independent, and bias-free
The text is in plain language and appropriate to the participants’ level of understanding with translations, as needed

Re-Consent

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

Per the G-EthicsHR-ZAF, the informed consent should be a trust-based process and relationship between the researcher and the participants, groups, and communities that extends over time. Consent must be negotiated and renegotiated as the research continues and develops.

Language Requirements

According to the SA-GCPs, the ICF should be provided in a participant’s preferred written language. 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.

The G-EthicsHR-ZAF states that informed consent material must be translated into the language(s) best suited for the population and context of the study. If appropriate, the consent documents can be translated. However, merely translating documents is insufficient to ensure that consent is informed because illiteracy is prevalent in some contexts, language dialects vary substantially across regions, some words and terminology are not easily translated, translated written materials may not be helpful to some participants, and/or professional translators are not content experts so mistranslation may occur. Therefore, it may be more useful to train a research assistant/interpreter who can explain information about the study verbally to potential participants in their language of choice and answer any questions they may have about the study.

Regarding the plain language text, the G-EthicsHR-ZAF indicates that the text should be appropriate to the participants’ level of understanding, which means:

Translated into the language(s) best suited for the population and context of the study
Has content, language(s), and procedures that are simplified and modified to accommodate any written or verbal language differences or impairments with which the participant may present
Free of jargon and unexplained acronyms
Clear and explains technical terminology

Documenting Consent

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

The G-EthicsHR-ZAF indicates that there may be circumstances where alternative forms of obtaining consent are allowed when it is not possible to have written consent. If it is ethically justifiable for the specific circumstances, then verbal consent may be approved. Usually, if verbal consent is permitted, a witness attests that the person did consent to participation after indicating understanding of the information provided. In addition, sometimes the nature of the research requires electronic data collection, or the potential participants may have an impairment that prevents a personal face-to-face consent process with written consent. Alternatives to face-to-face personal consent may not occur without sound justification approved by a registered EC. The justification for an alternate format of consent process must be evidenced by clear descriptions of why an alternative is justified in the circumstances and how the interests of the potential participant are properly protected.

Per the G-EthicsHR-ZAF, where electronic consent is proposed, the research protocol must describe in detail the method and process for obtaining consent. Electronic signatures are a functional equivalent of a paper-based signature with the same legal authority if it meets legal requirements including:

A typed name at the end of an email
A scanned image of a handwritten signature embedded into a document
A digital signature

Further, the G-EthicsHR-ZAF states that in regards to telephonic (verbal) and electronic informed consent, EC reviewers of research protocols must insist on a proper decisive description of how informed consent will be regarded as authentic. The following electronic methods of obtaining informed consent are recommended:

Telephonic recruitment for research that poses more than minimal risk of harm should be limited to screening for eligibility, followed by face-to-face informed consent, or virtual informed consent via an electronic platform
Telephonic research surveys are possible for minimal risk studies, and verbal agreement to participate serves as informed consent
For research that poses more than minimal risk of harm, different electronic platforms could be used for different purposes: a technology (e.g., email) to screen and obtain informed consent and another system to collect data

Waiver of Consent

Per the G-EthicsHR-ZAF, any decision by the EC to grant a waiver of participant or legal representative/guardian consent must be documented and must include the justification for the decision. A waiver of consent to conduct the research can be justified on two (2) grounds: if the waiver will not infringe upon any right of a participant, and obtaining consent is impracticable; or if the rights infringement is minimal and is outweighed by the expected social value of the research, and obtaining consent is impracticable. Any decision by the EC to grant a waiver of participant or legal representative/guardian consent must be documented and must include the justification for the decision. A waiver of consent is not automatic and requires a researcher to apply to the EC for approval to use someone's personal information or personal health information without obtaining consent from the individual. The application must explain why a waiver is requested and how one of the justification criteria above applies. The EC must assess the level of risk of harm associated with a waiver, which refers to the risk of harm flowing from researchers accessing identifiable private information and not to risk of harm concerning the whole research project. An alteration of requirements for informed consent (as opposed to a full waiver) is possible, e.g., when existence of a signed consent form might pose a risk of harm (breach of confidentiality) to the participant in studies involving illegal behavior. The alteration may take the form of permitting unsigned informed consent documentation.

3, 4.4, 4.8, and 6

3.4 and 6.3

11, 12.3, and 15.1.3

3.1

2.5 and 5.9

Chapter 9 (71)

Last content review/update: May 16, 2024

Obtaining Consent

In all United Kingdom (UK) clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the MHCTR, the MHCTR2006, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). As per the MHCTR, the MHCTR2006, and GBR-9, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) recognized by the United Kingdom Ethics Committee Authority (UKECA) (henceforth referred to as a “recognized EC”) and operating according to standard operating procedures (GBR-9) issued by England’s Health Research Authority (HRA).) Refer to GBR-18 and GBR-69 for more on informed consent in the UK.

The MHCTR and G-ConsentPIS, state that the investigator(s) must provide detailed research study information to the participant or legal representative/guardian. The MHCTR and G-ConsentPIS also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and the legal representative/guardian, should also be given adequate time to consider whether to participate. Per G-ConsentPIS, the Participant Information Sheet (PIS) supports the consent process to help ensure participants have been adequately informed. In addition, the PIS forms part of the transparency information that must be provided to participants under the data protection legislation for the use and processing of personal data. (See the Personal Data Protection section for more information on data protection requirements.) For more guidance on the PIS, see the PrtInfoQty-Stds, the PrtInfo-DesignPrin, and GBR-14, which include FAQs, information principles, and standards.

Per GBR-31, the HRA guides researchers and ECs in taking a proportionate approach to seeking consent. A proportionate approach adopts procedures commensurate with the balance of risk and benefits so that potential participants are not overwhelmed by unnecessarily lengthy, complex, and inaccessible information sheets. Participants should be provided with succinct, relevant, truthful information in a user-friendly manner that promotes their autonomy. Specifically, the methods and procedures used to seek informed consent and the level of information provided should be proportionate to:

The nature and the complexity of the research
The risks, burdens, and potential benefits (to the participants and/or society)
The ethical issues at stake

Per GBR-113, none of the oral and written information concerning the clinical trial, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive any legal rights, or that releases or appears to release the investigator, the institution, the sponsor, or their agents from liability for negligence.

Re-Consent

According to GBR-113, the EC should approve any change in the ICF due to a protocol modification before such changes are implemented. The participant or legal representative/guardian will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

Per GBR-18, during a clinical trial, researchers should periodically reaffirm the willingness of participants to continue. If significant new information becomes available, participants should be reconsented using revised (and re-approved) consent documents so that their continued consent is confirmed.

Language Requirements

As stated in the MHCTR, applications to the EC and the Medicines and Healthcare Products Regulatory Agency (MHRA) and any accompanying material, such as the ICF content, should be presented in English.

Documenting Consent

The MHCTR states that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. Where the participant is illiterate, or the legal representative/guardian is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness. As provided in G-ConsentPIS, consent can be documented electronically or in writing. A physical or electronic copy of the signed consent form will still need to be provided to the participant. To record consent electronically, electronic signatures will be needed. Because there are different forms and classifications of electronic signatures, the researcher should determine what is appropriate for the particular study. GBR-6 sets out the legal and ethical requirements for seeking and documenting consent using electronic methods (also known as eConsent in the UK), as well as expectations regarding the use of electronic signatures. eConsent enables potential research participants to be provided with the information they need to make a decision via a tablet, smartphone, or digital multimedia. It also enables their informed consent to be documented using electronic signatures. This approach can supplement the traditional paper-based approach or, where appropriate, replace it.

Waiver of Consent

No information is currently available.

1 and 2

2, 4.4, 4.8, 8.2, and 8.3

Informed Consent

Principles of consent - General principals and Role of Participant Information Sheets; Content - Participant Information Sheet and Consent Form; and Examples and Templates

Amendment of Regulation 3 of the Principal Regulations; Amendment of Regulation 12 of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; Amendment of Schedule 1 to the Principal Regulations; Amendment of Schedule 3 to the Principal Regulations; and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive and Conditions Based on Article 3 of the Directive)

Part 1 (3), Part 3 (12, 15, 17, and 18), Schedule 1 (Part 1 (3) and Part 2), and Schedule 3 (Parts 1 and 3)

Required Elements

Last content review/update: January 17, 2025

Based on the informed consent essential elements in the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, G-PostCTAccess, and the NHAParticipants, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

The study involves research and an explanation of its nature and purpose, including that it conforms to the protocol
The procedures to be followed and their purpose and nature
Why the potential participant has been approached, their responsibilities, and the research-related activities and procedures that the participant is being asked to consent to
Who the researchers are, the nature of their expertise, and their responsibilities
The aspects of the clinical trial that are experimental
Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant; information should include the probability and magnitude of the foreseeable risks of harm
The measures to be taken to minimize risk of harm
Any benefits to the participant or to others that may reasonably be expected from the research both during and after 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 without explanation or prejudice, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
Compensation and/or medical treatment available to the participant in the event of a trial-related injury
The planned incentives, if any, to attract the participant and the planned reimbursements, if any, for time, inconvenience, and expenses
The extent to which confidentiality of records identifying the participant will be maintained, the possibility of record access by the sponsor, the ethics committee (EC), or the South African Health Products Regulatory Authority (SAHPRA)
How the personal information of participants, including confidentiality of data collected during the research, will be protected
Who will have access to participants' information, biological samples and associated data, including whether samples will be shared with other researchers
That participants may request that corrections to their information be made or that their information or samples be deleted or destroyed; in cases where withdrawal of samples and information is not possible, the potential limitations and consequences of not withdrawing samples and data from research should be explained
Instances where a legal obligation to disclose information may arise
Statement that participants may contact the EC at the contact details provided if they have questions or complaints about their rights and welfare
The sponsor’s identity
Potential conflicts of interest of the principal investigator (PI)
The consequences of a participant's decision to withdraw from the study
Information about approval from a registered EC and SAHPRA
Information about the EC monitoring the clinical trial
The approximate number of participants in the research study, locally and globally
The expected duration of participation
Whether feedback about the study will be provided and, if so, how it will be provided
Whether biological samples will be used for commercial benefit
Where relevant, whether incidental findings will be shared with participants
An explanation of whom to contact in the event of research-related injury
A statement that participants may contact the researcher at the contact details provided if they have questions about the research project
Foreseeable circumstances under which the investigator(s) may remove the participant without consent
The research may be terminated early in particular circumstances
The participant or legal representative/guardian will be notified if significant new findings developed during the study which may affect the participant's willingness to continue
Information on post-trial or continued access (PTA/CA)
Whether data and/or samples can be used after the person’s death, especially if it is possible that the person may die during the study
Description of a measure to probe understanding and comprehension of the information is planned (e.g., a teach-back method), and how it proposes to do so especially for very vulnerable potential participants.

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

6.3

3.1 and 5.5

1.2, 2.5, 5.9, and 6.2

5

Last content review/update: May 16, 2024

Based on the MHCTR, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

The study purpose, procedures, and duration
Study title and the study Integrated Research Application System (IRAS) ID are clearly displayed
Approximate number of participants involved in the trial
The participant’s responsibilities in participating in the trial
Trial treatment schedule and the probability for random assignment to each treatment
Experimental aspects of the study
Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
Any benefits or prorated payment 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
Compensation and/or medical treatment available to the participant in the event of a trial-related injury
Any additional costs to the participant that may result from participation in the research
That 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
The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Medicines and Healthcare Products Regulatory Agency (MHRA), the ethics committees (ECs), the auditor(s), and the monitor(s)
That the participant or legal representative/guardian will be notified if significant new findings developed during the study may affect the participant's willingness to continue
Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury
Foreseeable circumstances under which the investigator(s) may remove the participant without consent

ICF examples and templates are provided in the G-ConsentPIS.

For more information about informed consent required elements, see GBR-18, GBR-113, GBR-100, GBR-31, and GBR-69.

1 and 2

4.4 and 4.8

Informed Consent

Principles of consent - General principles and Role of Participant Information Sheets; Content - Participant Information Sheet and Consent Form

Part 1 (3), Part 3 (12 and 15), and Schedule 3 (Parts 1 and 3)

Participant Rights

Last content review/update: January 17, 2025

Overview

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

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

The Right to Privacy and Confidentiality

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

2-4, and 6

1-3

1.1, 2.1, 2.3, and 3.1

2.4-2.5 and 4.3

2 and 5

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

Act, Preamble, and Chapter 2

Last content review/update: May 16, 2024

Overview

In accordance with the MHCTR, the MHCTR2006, the G-ConsentPIS, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the United Kingdom’s (UK’s) ethical standards promote respect for all human beings and safeguard the rights of research participants. The MHCTR states that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR, the G-ConsentPIS, and GBR-113, the participant or legal representative/guardian should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the MHCTR, the G-ConsentPIS, and GBR-113, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

Also see GBR-117 for an interactive web-based communications toolkit to help researchers and participants keep in touch after participation in a research study.

The Right to Privacy and Confidentiality

As per the MHCTR and GBR-113, the arrangements to protect participants’ privacy should be provided in the application to the ethics committee, and the ICF should inform potential participants of any potential risk to their confidentiality.

The Right of Inquiry/Appeal

The MHCTR and GBR-113 state that the research participant or legal representative/guardian should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

The MHCTR, the MHCTR2006, and GBR-113 state that a research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

4.8

Principles and Content

Amendment of Regulation 3 of the Principal Regulations; Amendment of Schedule 1 to the Principal Regulations; and Part 2 (Principles Based on Articles 2 to 5 of the GCP Directive and Conditions Based on Article 3 of the Directive)

Part 1 (3 and 15), Schedule 1 (Parts 1, 2, and 5)

Emergencies

Last content review/update: January 17, 2025

The NHA and the G-EthicsHR-ZAF make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies. As per the G-EthicsHR-ZAF, there are emergency situations that merit use of deferred consent (also called delayed consent). Usually, the circumstances entail a temporary loss of decision-making capacity and a reasonably held prognosis that the person will regain the capacity within a predictable period (e.g., an unconscious patient in the Emergency Unit who is predicted to regain consciousness within hours). Deferred consent should be used only where the likelihood of obtaining personal informed consent after the research has begun is likely. The ethics committee (EC) may approve use of deferred consent if the following conditions are met:

The proposed research is based on valid scientific hypotheses that support a reasonable possibility of more benefit than that offered by standard care
The individual has a temporary loss of decision-making capacity
There is a reasonably held prognosis that they will regain the capacity within a predictable period
Participation is not contrary to the medical interests of the patient
When the individual regains capacity to make decisions, they must be informed that they have been enrolled in a research study (i.e., deferred consent must be obtained); if they object to having been enrolled in the study, this counts as a refusal to participate, and they should be asked whether their data already collected must be withdrawn

If death of the participant occurs before deferred consent can be obtained, it should not be assumed that continued use of the data and/or samples is ethical. The deceased’s wishes or those of their proxy or mandate holder should be ascertained.

Per the G-EthicsHR-ZAF, during disease outbreaks, potential participants must be assisted to understand the research proposed and the implications of enrollment, despite the situational duress and anxiety. The notion that informed consent is a process does not change because the research is being conducted in pandemic circumstances. Research during a public health emergency must adhere to standard research ethics principles including informed consent.

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

11.5-11.6 and Annex 1

3.1 and 3.3

Chapter 2 (7, 8, and 9)

Last content review/update: May 16, 2024

The MHCTR, the MHCTR2006-No2, the MHCTR-BSQ, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113) make provisions to protect the rights of a research participant during the informed consent process when a clinical trial of an investigational product (IP) is complicated by medical emergencies. As delineated in the G-ConsentPIS and GBR-18, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If the prior consent of the participant or legal representative/guardian cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and the ethics committee (EC) must provide documented approval in order to protect the participant’s rights, safety, and well-being. The participant or legal representative/guardian should provide consent as soon as possible.

The MHCTR-BSQ amends the MHCTR and creates an exception for minors participating in a trial where urgent treatment is required and prior consent cannot be obtained. This situation also requires the EC to issue its approval beforehand.

The MHCTR2006-No2 amends the MHCTR and creates an exception to the general rule in England, Northern Ireland, and Wales that incapacitated adults cannot be included in a clinical trial under medical emergencies. If the treatment to be provided is a matter of urgency and obtaining prior consent is not possible, incapacitated adult participants may be included in the trial once EC approval has been obtained. In Scotland, the provisions of Section 51 of the AIA2000 govern the inclusion of adults lacking capacity in research.

The G-ConsentPIS states that the United Kingdom allows adults not able to consent for themselves to be recruited into clinical trials without prior consent in emergency situations if the following conditions exist:

Treatment needs to be given urgently
It is also necessary to take urgent action to administer the drug (IP) for the purposes of the trial
It is not reasonably practicable to obtain consent from a legal representative
The procedure is approved by an EC
Consent is sought from a legal representative as soon as possible

4.8.15

Informed Consent

Principles of Consent - Emergency Research

Section 51

4 and Explanatory Note

2 and Explanatory Note

Schedule 1 (Parts 4 and 5)

Vulnerable Populations

Last content review/update: January 17, 2025

Overview

The NHA, the SA-GCPs, the G-EthicsHR-ZAF, the G-GPHlthCare, and the NHAParticipants require special considerations for vulnerable populations, and characterize them by limited education, limited economic resources, inadequate protection of human rights, discrimination due to health status, limited ability to provide informed consent, limited availability of health care and treatment options, or an inadequate understanding of scientific research. Vulnerable populations include children/minors, mentally and physically disabled, pregnant women, substance abusers, prisoners, armed forces, the homeless, the elderly, members of a group with a hierarchical structure, patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, nomads, refugees, and other vulnerable groups such as persons in dependent relationships. (Note: Each of the items listed above will not necessarily be found in all sources, which provide overlapping and unique elements).

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

Involve vulnerable persons only when non-vulnerable persons are not appropriate for inclusion
Not systematically avoid inclusion of vulnerable participants because it is unfairly discriminatory, and would prevent this population from benefiting from relevant research
Be responsive to health needs and priorities of vulnerable persons, and
Provide special attention in the ethical review to ensure research-related risks are assessed and minimized, and appropriate consent procedures are followed

Per the G-EthicsHR-ZAF, where factors usually associated with vulnerability are integral to the research, the protocol should demonstrate how vulnerability will be managed. In cases where the researcher is known to the community and speaks the local language and/or is accepted as part of that community, this may be seen as a positive element for the research context. Special care should be exercised before undertaking research involving participants in such communities, and ECs should ensure that:

Persons in these communities are not being involved in the research merely because they are expediently accessible, while the research is feasible to undertake in a less vulnerable community
Research is relevant to the needs and priorities of the targeted community
Research participants know they will take part in research and that the research will be carried out only with appropriate consent

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

Persons in Dependent Relationships or Hierarchical Situations

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

Persons Highly Dependent on Medical Care

Per G-EthicsHR-ZAF, individuals who are highly dependent on medical care deserve special attention when considering research participation. The gravity of their medical condition may require invasive measures that carry increased risk of harm. The quality of informed consent may be compromised by the effect the medical condition has on the participant’s decision-making or communication abilities. A patient may be reluctant to refuse consent for fear that this may compromise their medical treatment. Adequate provision must be made for informing patients and their relatives about the research to ensure that stress and other emotional factors do not impair their understanding. Their dependency on caregivers should not unfairly affect research participation decisions.

Persons with Physical Disabilities

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

Elderly Persons

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

Research Involving Collectivities

Per the G-EthicsHR-ZAF, a collectivity is a term used to distinguish some distinct groups from informal communities, commercial, or social groups. Collectivities are persons who participate in research in groups distinguished by common beliefs, values, social structures, and other features that identify them as a separate group; customary collective decision-making according to tradition and beliefs; the custom that leaders express a collective view; and members of the collectivity being aware of common activities and common interests. Research involves a collectivity when property or information private to the group as a whole is studied or used; permission of people occupying positions of authority is required; and participation of members acknowledged as representatives is involved. Among other requirements, research involving collectivities should include measures to ensure an informed consent process for individual participants.

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

3.2

1.2, 3.1, 3.4, 6.2, and 12

1 and 4

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

Last content review/update: May 16, 2024

Overview

As per the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), in all United Kingdom (UK) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

Per GBR-131, vulnerability may be defined in different ways and may arise as a result of being in an abusive relationship, vulnerability due to age, potential marginalization, disability, and due to disadvantageous power relationships within personal and professional roles. Participants may not be conventionally vulnerable but may be in a dependent relationship that means they can feel coerced or pressured into taking part.

As stated in GBR-131, researchers must assess potential vulnerability within the context of the research, in terms of potential consequences from their participation (immediate and long-term) or lack of positive impact where this is immediately needed or expected. Further, researchers should make the participants aware of the limits to confidentiality and decide whether verbal or written consent will be more appropriate and protective of the participants’ interests. In addition, researchers should consider the following:

Participants’ vulnerability
Potential negative consequences or lack of personal benefits from their involvement in research where these are expected
Providing appropriate information to elicit freely-given informed consent for participation as well as information regarding data deposit and data re-use (where deposit is possible)
Limits to confidentiality and occasions where this may occur
Legal requirements of working with the specific population
Incentives and compensation for participation

In addition, GBR-131 states that when working with participants who are considered vulnerable, researchers may find themselves in a position of increased responsibilities or expectations. Researchers should endeavor to assess the likelihood of additional ethics issues and develop strategies and a framework of clear responsibilities they can refer to should such issues arise. They should also use their research ethics committee as a resource for advice and guidance. Researchers should be able to justify the approach they take in dealing with unforeseen ethics issues and maintain the integrity of the research.

As per GBR-131, in cases where research involves potentially vulnerable groups, every effort should be made to secure freely given informed consent that participants have actively provided. Every effort should be made to ensure that they have the time and opportunity to access support in their decision-making, for example by discussing their choice with a trusted adult or relative. Passive assent, including group assent (with consent given by a gatekeeper) should be avoided wherever possible, and every effort should be made to develop methods of seeking consent that are appropriate to the groups studied, using expert advice, support, and training, where necessary. Vulnerability should be considered on a case-by-case basis; many groups or individuals not traditionally considered as vulnerable could be exposed to issues from participating in research that make them vulnerable. See GBR-131 for additional resources and case studies.

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

1.61, 3.1, and 4.8

Schedule 1 (Parts 1, 4, and 5)

Children/Minors

Last content review/update: January 17, 2025

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

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

The parent/legal guardian in all but exceptional circumstances (such as emergencies)
The minor/child who is competent to make the decision
Any organization or person required by law (defined in the NHA)
Where the minor/child is not competent, assent from the minor/child and consent from the parent/legal guardian

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
It is carried out in such manner and on such conditions as may be prescribed
The consent of the minor’s parent/legal guardian is provided

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

It is carried out in such manner and on such conditions as may be prescribed
The consent of the Minister of Health is provided, or, where appropriate, consent from a delegated authority
The consent of the minor’s parent/legal guardian is provided
The consent of the minor is provided when the minor is capable of understanding

The G-EthicsHR-ZAF further indicates that the following are minimum conditions for an ethics committee (EC) to approve research with minors:

Their participation is scientifically essential to the research and investigate a problem of relevance to minors, and the protocol should provide sufficient information to justify why minors should be included as participants
Minors should only participate in research where such research poses acceptable risks of harm
Research involving minors must be reviewed appropriately, including pediatric or child research specialists as reviewers
Registered ECs’ deliberations are properly documented in minutes and recorded and include EC members with appropriate minor research experience
Minors should participate in research only when the required written permissions from the parent/legal guardian have been obtained
When a parent/legal guardian gives permission for their minor to choose whether to participate in research, this permission is given based on a detailed description of all diagnostic and therapeutic interventions that will affect the minor in the study
The informed consent documentation must explain whether results of tests will be made known to minor participants and their parents
The minor’s interest in confidentiality must be respected
The minor’s privacy interests are considered
Research involving minors must respect their evolving capacity to give consent
Researchers must familiarize themselves with the legal obligations to report minor abuse and neglect

See the NHAParticipants and G-EthicsHR-ZAF for detailed application requirements.

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

The study objective(s) can also be achieved if conducted on an adult
The research is unlikely to significantly improve scientific understanding of the minor’s condition, disease, or disorder to such an extent that it will result in significant benefit to the minor(s)
The reasons for the consent to the research by the parent/legal guardian and, if applicable, the minor, 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.

Assent Requirements

The SA-GCPs requires the 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 assent should not be assumed simply because of failure to object during the informed consent process. It is necessary for the minor and the parent/legal guardian to be in agreement on participation. The minor’s refusal to participate is final.

Per the G-EthicsHR-ZAF, the parent/legal guardian does not choose for the minor who has factual capacity to choose, rather, the parent/guardian gives permission for the minor to choose (i.e., to assent to participation). Where a minor is very young (less than seven (7) years old) or is factually incapable of exercising a choice, then the parent/legal guardian chooses whether the minor should participate. When ECs review protocols that involve minors, it is critical to consider whether the required written permissions have been obtained, including assent from the minor in writing preferably (i.e., agreement to participate) if they choose to participate.

See the Personal Data Protection section for requirements on processing personal data of minors.

5, 6.3, and 8.5

8.5

1-6 and Appendices 1-3

3.2 and 3.3

1.2, 2.5, 3.2, and 6.2

4 and 7

Chapter 9 (71)

Last content review/update: May 16, 2024

According to the MHCTR and GBR-4, a minor in the United Kingdom (UK) is an individual under 16 years of age.

As set forth in the MHCTR, the MHCTR2006, the G-ConsentPIS, GBR-4, GBR-9, and the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (GBR-113), when the research participant is a minor, informed consent should be obtained from a parent/legal guardian. As per GBR-4, the researcher needs only to obtain consent from one (1) person with parental responsibility. GBR-130 further indicates that the parent/legal guardian must not be connected with the conduct of the trial, is suitable to act by virtue of their relationship with the child/young person, and is available and willing to do so. A legal representative should only ever be approached if someone with parental responsibility cannot be contacted prior to the proposed inclusion of the child/young person due to the urgent nature of the treatment provided as part of the trial. In this situation, a professional legal representative (e.g., a doctor) can be responsible for the medical treatment of the child/young person if they are independent of the study, or a person nominated by the healthcare provider.

Additionally, GBR-130 states that researchers must ensure that the parent/legal guardian:

Understand that they are being asked to give consent on behalf of the child/young person
Understand the objectives, risks, and inconveniences of the trial and the conditions under which it is to be conducted
Have been informed of the right to withdraw the child/young person from the trial at any time
Have a contact point where further information about the trial can be obtained

The MHCTR, the MHCTR2006, and GBR-4, state that a study may only be conducted on minors if several conditions are fulfilled including:

An ethics committee (EC), following consultation with pediatric experts, has endorsed the protocol
The parent/guardian has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the minor from the trial at any time
No incentives or financial inducements are given to the minor or the parent/guardian except in the event of trial-related injury or loss
The trial relates directly to a condition from which the minor suffers, or is of such a nature that it can only be carried out on minors
The participant(s) will derive some direct benefit from their participation in the trial
The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the minor’s stage of development

GBR-4 provides additional best practices:

Children and their parents (or those with parental responsibility) should be involved in the decision-making process around consent to take part in research, regardless of whether the child or young person is legally competent to give consent. This includes involving children or young people who are not considered competent to give consent.
Assent should be sought from a child who is not considered competent as long as this is practicable and the child is not too young.
In some situations, a young person who is competent may object to the involvement of their parents and their confidentiality should be respected.
Before giving consent, children and young people should be provided with age-appropriate information that enables them to understand participation in research. Information may be provided using a layered or staged approach so that it is more easily understood.
Children and young people should be given the opportunity to ask questions and to get support in their decision-making, such as talking to a trusted adult.
Good records should be kept of any discussions about consent and of the final decision.
Inducements and coercion must be avoided.
Seeking consent is a process and it is good practice to engage regularly with the child and family over the course of research to confirm they are willing to continue. In studies in which children who are not competent will become competent during the study period, then consent from young people should be sought as soon as possible after competency is reached. A decision about how this will be managed should be made at the start of the study and included in the protocol.

See the MHCTR, the MHCTR2006, GBR-4, and GBR-9 for detailed requirements. The G-ConsentPIS provides style guidance and suggestions for presenting age-appropriate information in the participant information sheet.

Assent Requirements

As indicated in GBR-4, whenever practical and appropriate, a child's assent should be sought before including them in research. Even when a child or young person is competent, it is still normally good practice to involve the family in the decision-making process; however, if the young person objects, researchers should respect their privacy.

As per GBR-4, for clinical trials of investigational products (IPs), it is usually inappropriate to ask very young children (e.g., under five (5) years old) to sign an assent form; however, their views should be considered. Researchers must make an informed judgment to determine when seeking assent is appropriate; the age of a child can only be taken as a guide. The child's developmental stage, knowledge of illness and experience of health care should also be considered. Although there is a danger that children can be asked to exercise greater autonomy than normal, this must be balanced with the potential loss of trust associated with denying their assent. Such judgment needs a framework of considerations for analysis, a record of observations, and discussions and a documented decision. In circumstances where seeking assent at the outset is not appropriate, the researcher could provide the child with information as and when required.

Guidance (Consent)

2.51-2.58

4.8.12

Clinical Trial of an Investigational Medicinal Product (Consent for under 16)

Style and Examples & Templates

Amendment of Schedule 1 to the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; and Part 2 (Conditions Based on Article 3 of the Directive)

Part 1 (2) and Schedule 1 (Part 4)

Pregnant Women, Fetuses & Neonates

Last content review/update: January 17, 2025

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

The G-EthicsHR-ZAF states that any proposed exclusion of women participants must be justifiable in light of research priorities as well as the specific research question under consideration. Systematic class exclusion must be guarded against to avoid unfair participant selection. Additional health concerns arise during pregnancy, including the need to avoid unnecessary risk to the embryo, fetus, or infant; however, automatic exclusion of pregnant women should be avoided to prevent data inequities for pregnant and nursing women. Researchers and ECs should exercise extra caution when women participants are or may become pregnant. Exclusion of women from research may be justifiable to protect the health of the embryo, fetus, or infant and if exclusion is scientifically supportable. The informed consent documents must explain carefully and fully what the effects of the research activities on the embryo, fetus, or infant might be. Usually, research involving pregnant women should be undertaken when:

The purpose of the proposed research is to meet the health needs of the mother of the embryos, fetuses, or infants
Appropriate studies on animals and nonpregnant women have been completed
The risk of harm to the embryo, fetus, or infant is minimal, when procedures or interventions have no potential individual benefit for the women or embryo, fetus, or infant
The risk of harm is outweighed by the prospect of potential individual benefit, when procedures or interventions have potential individual benefit for the women or embryo, fetus, or infant
In all cases, inclusion poses the least risk of harm possible for achieving the objectives of the research

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

3.2

1.2, 6.2, and 10.7

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

Last content review/update: May 16, 2024

The G-ConsentPIS states that researchers must give a clear warning to potential participants when there is a risk of harm to an unborn child and/or risk when breastfeeding. The Participant Information Sheet (PIS) should provide specific advice to potential participants about the risks of becoming pregnant, of fathering a child, or of breastfeeding while taking part in the research including the need for pregnancy testing, contraceptive requirements, and how to report a pregnancy during the study. The PIS should also provide information about what will happen if a participant becomes pregnant, including whether and how the researcher will monitor the pregnancy. This would include access to the mother's and/or child's notes, and any possible follow up of the child including post-natal examinations. For men, researchers must provide clear warnings and advice if the research treatment could damage sperm and consequently pose a risk to possible pregnancies. Specific advice for pregnant partners may be needed, including information on any compensation arrangements.

Further, the G-ConsentPIS finds that the risk of harm caused during pregnancy is most likely when recruiting young people to a clinical trial for an investigational medicinal product (CTIMP). In this case, there should be consent from someone over the age of 16, and the following should be done:

Discuss the risk of pregnancy, pregnancy testing, and the use of appropriate contraception with their parents (or their legal guardian) during the consent process and with young potential participants as part of the assent process
Consider local social beliefs
Involve pediatricians and the ethics committee in preliminary discussions if this is a concern
Consult young people when designing consent and writing information
Respect the young person's autonomy but encourage involvement of the parents
Be aware that in CTIMPs, it is the parents of children under 16 who legally provide consent, and this will include consent to pregnancy testing and discussion of contraception
Information needs to go beyond "We will do a pregnancy test…" to include what will happen in broad terms

In accordance with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.

As set forth in GBR-35, any research studies involving women capable of becoming pregnant and breastfeeding women require additional safeguards to ensure the research conforms to appropriate ethical standards and upholds societal values. According to GBR-35, the following conditions are required for research to be conducted with this population:

Reproductive toxicology studies have been completed and the results support conducting a trial, or there is a good reason not to conduct the reproductive toxicology studies and/or the risk of pregnancy is minimized (e.g., because she agrees to adhere to a highly effective method of contraception); Women using a hormonal contraceptive, such as “the pill,” should use an alternative method of contraception until the possibility of an interaction with the investigational product has been excluded
The female participant is not pregnant according to her menstrual history and a pregnancy test, and is not at risk of becoming pregnant during, and for a specified interval, after the trial
The female participant is warned about the potential risks to the developing child should she become pregnant, and she is tested for pregnancy during the trial, as appropriate
The female is tested for pregnancy before dosing starts and possibly during the trial, as appropriate

Content - Participant Information Sheet

Prisoners

Last content review/update: January 17, 2025

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

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

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

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

3.2

4

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

Last content review/update: January 21, 2025

Per the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority. The ethics committee must also ensure that the study will be independently monitored to assure the dignity and rights of the prisoners involved in the research.

Per the UKwide-Rsrch, a prisoner or young offender is defined as any inmate of the prison systems of England and Wales, Scotland, or Northern Ireland. It does not include patients detained under the MHAct at special hospitals or other psychiatric secure units, or juvenile offenders detained in local authority secure accommodation or secure training centers. Health research involving prisoners or young offenders should relate directly to their health care and be of such a nature that it could only be conducted in this population. See the UKwide-Rsrch for details on differences between the four (4) United Kingdom nations with regard to research on prisoners.

1.61

Do you plan to include any participants who are prisoners, young offenders or on probation?

Mentally Impaired

Last content review/update: January 17, 2025

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

Per the G-EthicsHR-ZAF, research involving adults with incapacity should be approved only if:

The research, including observational research, is not contrary to the best interest of the individual
The risk of harm assessment shows that the research, including observational research, places the incapacitated adult at no more than minimal risk
The research involves greater than minimal risk but provides the prospect of direct benefit for the incapacitated adult; the degree of risk must be justified by the potential benefit
The research, including observational research, involves greater than minimal risk, with no prospect of direct benefit for the incapacitated adult, but has a high probability of providing generalizable knowledge (i.e., the risk should be justified by the risk-knowledge ratio)
Greater than minimal risk must represent no more than a minor increase over minimal risk
Where appropriate, the person assents to participation (Note that the incapacitated person’s refusal or resistance to participate, as indicated by words or behavior, takes precedence over permission by a proxy)

As delineated in the G-EthicsHR-ZAF, proxy decision-makers for incapacitated adults are not permitted in South African law unless the proxy is a court appointed curator or holds a statutory mandate to make health care decisions for the now incapacitated person pursuant to the NHA. Incapacity may not be assumed but requires independent and objective assessment by appropriately trained persons. If the research participant regains capacity to make decisions, they must be informed that they have been enrolled in a research study. If they object to having been enrolled in the research study, this counts as a refusal to participate, and their data must be withdrawn. If the participant does not object, personal consent may be desirable depending on the length and complexity of the study.

4 and 6.3

3.1 and 3.2

1.2, 3.3, and 6.2

4

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

Last content review/update: May 16, 2024

As per the MHCTR and GBR-9, a recognized ethics committee (EC) within the Health Research Authority (HRA), must approve the participation of adult research participants who are incapable by reason of physical and mental capacity to give consent, and must obtain advice from professionals with expertise in handling this population.

The MHCTR and the G-ConsentPIS, specify that when a study involves adult participants with mental incapacities, informed consent should be obtained from the legal representative/guardian. This consent should only be provided once the legal representative/guardian has had an interview with the investigator(s) to understand the trial objectives and risks, been provided with a point of contact for further information, and been informed of the right to withdraw the participant from the trial at any time. The G-ConsentPIS provides additional country-specific information on legal representative requirements.

As delineated in the MHCTR, a clinical trial of an investigational product may involve participants with mental incapacities under the following conditions:

The participant has received information according to the participant’s capacity of understanding regarding the trial, its risks, and its benefits
No incentives or financial inducements are given to the participant or legal representative/guardian except in the event of trial-related injury or loss
The trial relates directly to a condition from which the participant suffers, or is of such a nature that it can only be carried out on participants with mental incapacities
The participant(s) will derive some direct benefit from their participation in the trial, or produce no risk at all
The trial is necessary to validate data obtained in other trials involving persons able to give informed consent, or by other research methods
The trial has been designed to minimize pain, discomfort, fear, and any other foreseeable risk in relation to the disease and the participant’s stage of development

See the MHCTR, G-ConsentPIS, and GBR-3 for detailed requirements.

2.51-2.58

Principles of Consent - Adults Who Are Not Able to Consent for Themselves

Part 1 (15), Schedule 1 (Parts 1 and 5)

Definition of Investigational Product

Last content review/update: January 17, 2025

As delineated in the SA-GCPs and the PIC-S-GMP-Guide (which South Africa adopted pursuant to the SA-GMPs), an investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes:

A product with a marketing authorization when used or assembled (formulated or packaged) in a different way from the approved form
When used for an unapproved indication
When used to gain further information about an approved use

2

Annex 13

1.2, 6.2, and 12

Last content review/update: May 16, 2024

As delineated in the MHCTR, the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), and GBR-9, an investigational product (IP), referred to as an investigational medicinal product (IMP) in the United Kingdom (UK), is defined as a pharmaceutical form of an active substance or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

Terminology (Statutory Definitions Relating to CTIMPs)

1.3

Part 1 (2)

Manufacturing & Import

Last content review/update: January 17, 2025

Manufacturing

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

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

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

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

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

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

Import

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

The CTA-Import indicates that there have been delays in the release of IPs at the SAHPRA border control because the import licenses (clinical trial approval letters) have not specified the quantities of study medication authorized for importation. To address this problem, a protocol amendment application (ZAF-20) is required to request the approval of the remaining study medication to be imported for these specific trials. Applicants will be allowed six (6) months from the date of the CTA-Import (i.e., from September 19, 2024) to obtain the necessary approvals.

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

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

1.1, 3.1.2, and Appendices 1-2

3

Annex 13

1.2, 5.7, 6.2, and 6.6

21 and 22C

23

Last content review/update: May 16, 2024

According to the MHCTR, the MHCTR2006, the G-CTApp, and the G-GMP-GDP, the Medicines and Healthcare Products Regulatory Agency (MHRA) is responsible for authorizing the manufacture of investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) to be used in a trial. A Manufacturer’s Authorization for Investigational Medicinal Products (MIA(IMP)) must be obtained by the person responsible for the manufacture of any IP to be used in the trial. The sponsor or the designated representative must include a copy of the MIA(IMP) in the clinical trial application submission to the MHRA. The applicant must complete the form listed in GBR-28 to obtain an MIA(IMP) from the MHRA. The MHCTR defines “manufacturing authorization” to include importing and assembly authorizations, as applicable. The G-CTApp states that if an IP is manufactured outside the European Union (EU), the clinical trial application should include an MIA(IMP), importer authorization, and qualified person (QP) declaration on good manufacturing practice (GMP) for each site. The MHRA will approve the manufacture or import of an IP after the clinical trial application has been approved.

Per G-ATMP, a manufacturer’s license from MHRA is needed to manufacture unlicensed advanced therapy medicinal products (ATMPs) in the UK. See G-ATMP for guidance on the two (2) ATMP manufacturer license pathways: the hospital exemption or the “specials” scheme.

As per the MHCTR, the MHCTR2006, the G-GMP-GDP, and GBR-15, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the MIA(IMP) holder must also comply with the GMP guidelines and provide an IMP Certificate of Analysis. In addition, the MHCTR and the MHCTR2006 specify that the holder of an MIA(IMP) must always have the services of at least one (1) QP at their disposal. The QP must satisfy the qualification and experience requirements delineated in the aforementioned sources. The QP’s primary legal responsibility is to certify batches of IPs prior to use in a clinical trial, or prior to release for sale and placement in the market. See Part 6 and Schedule 6 of the MHCTR for detailed applicant requirements.

In accordance with the G-ImportIMPs, IPs that have been QP-certified in countries on the list of approved countries (initially, EU and European Economic Area (EEA) countries per G-CTApprovedCountries) do not need to be re-certified when importing to the UK. However, the sponsor must require the MIA(IMP) holder to put in place an assurance system to check these IMPs have been certified by a QP in a listed country before release to the trial. A sponsor may perform verification of QP certification in a listed country themselves if they are the holder of a UK MIA(IMP). Alternatively, they may outsource this verification to a third party who holds a UK MIA(IMP). IPs coming to Great Britain from Northern Ireland do not require this additional oversight. IPs coming directly to the UK from third-party countries that are not on the list of approved countries will continue to require import and QP certification in the UK by the MIA(IMP) holder as per the existing requirements. See the G-ImportIMPsAuth, for additional details on the authorizations and procedures. For additional details on what is new from Brexit, see the Scope of Assessment section.

The G-IPsNIreland delineates that the supply and use of IPs in Northern Ireland must follow EU laws as per the Northern Ireland Protocol. For policy papers and details on the Northern Ireland Protocol, see GBR-119.

Per the G-SubtlAmndmt, for any change to IP manufacturing, importation, or certification relevant to the supply of IPs in an ongoing UK trial, a substantial amendment must be submitted to the MHRA. However, if the sponsor chooses to retain an existing UK release site for the ongoing UK trial but includes an additional EU/EEA site for trials in the EU/EEA only, then no substantial amendment to the MHRA will be required.

Please note: The UK is party to the Nagoya Protocol on Access and Benefit-sharing (GBR-5), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see GBR-48.

Application for New Manufacturer’s Authorization for Investigational Medicinal Products MIA (IMP) (Human Use)

Annex 2

Manufacture of unlicensed ATMPs in the UK

Documents to send with your application

Overview

Amendment of Regulation 13 of the Principal Regulations; Amendment of Regulation 42 of the Principal Regulations; Amendment of Regulation 44 of the Principal Regulations; and Part 2 (Principles based on Articles 2 to 5 of the GCP Directive, Conditions Based on Article 3 of the Directive and Amendment of Schedule 6 to the Principal Regulations)

Part 1 (2), Part 3 (13), Part 6, Schedule 1 (Part 2), Schedule 3 (Part 2), Schedule 6, and Schedule 7

Quality Requirements

Last content review/update: January 17, 2025

Investigator’s Brochure

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

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

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

Quality Management

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

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

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

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

2

Part II (11.4) and Annex 13

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

Last content review/update: May 16, 2024

Investigator’s Brochure

In accordance with the MHCTR, the MHCTR2006, and GBR-92, the sponsor or the designated representative is responsible for providing investigators with an Investigator’s Brochure (IB), which must contain all of the relevant information on the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor or the designated representative should also update the IB as significant new information becomes available.

As specified in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the IB must 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 IPs in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post marketing experiences)
Summary of data and guidance for the investigator(s)
Bibliography

See Section 7 of GBR-113 for detailed content guidelines.

Quality Management

Per GBR-113, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

5.12 and 7

Overview

Insertion of Regulation 3A of the Principal Regulations; Amendment of Regulation 13 of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; Amendment of Regulation 42 of the Principal Regulations, Amendment of Regulation 44 of the Principal Regulations; and Part 2 Principles based on Articles 2 to 5 of the GCP Directive

Part 1 (2), Part 3 (13), Part 6, Schedule 6, and Schedule 7

Labeling

Last content review/update: January 17, 2025

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

The name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator
The pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/potency
The batch and/or code number to identify the contents and packaging operation
A trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)
The trial participant identification number/treatment number and where relevant, the visit number
The investigator name (if not already included above)
Directions for use (reference may be made to a leaflet or other explanatory document intended for the trial participant or person administering the product)
“For clinical trial use only” or similar wording
The storage conditions
The period of use (use-by date, expiration date, or re-test date as applicable), in month/year format and in a manner that avoids any ambiguity
“Keep out of reach of children” except when the product is for use in trials where the product is not taken home by the participant

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

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

2

Annex 13

1.2 and 6.6

35

10 and 30 (9)

Last content review/update: May 16, 2024

Labeling for investigational products (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)) must comply with the requirements set forth in the MHCTR, the MHCTR2006, GBR-15, the EU Good Manufacturing Practice Directive (GBR-12), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113). Per GBR-12, labeling for IPs must ensure protection of the participant and traceability, to enable identification of the product and trial, and to facilitate proper use of the IP. As specified in GBR-15, for an IP to be used in a clinical trial, it must be properly labeled in the official language of the country where the trial is being conducted.

As set forth in GBR-15, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

Name, address, and telephone number of the sponsor, contract research organization (CRO), or investigator
Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the case of open trials, the name/identifier and strength/concentration
Batch and/or code number to identify the contents and packaging operation
Trial reference code allowing identification of the trial, site, investigator, and sponsor (if not given elsewhere)
Trial participant identification number/treatment number and where relevant, the visit number
Investigator name (if not already included above)
Instructions 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 indicating the IP is clinical trial material
Storage conditions
Expiration date (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 not going to be taken home by participants

As per the MHCTR, a sample of the labeling is required as part of the clinical trial application submission. (See the Submission Content section for detailed clinical trial application submission requirements). Furthermore, according to GBR-15, the IP must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.

Article 15

Annex 1-3 - Investigational Medicinal Products - Packaging, Labelling, and Table 1

5.13

Amendment of Regulation 46 of the Principal Regulations

Part 1 (2) and Part 7, and Schedule 3, Part 2 (12)

Product Management

Last content review/update: January 17, 2025

Supply, Storage, and Handling Requirements

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

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

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

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

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

Record Requirements

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

Annex 13

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

Last content review/update: May 16, 2024

Supply, Storage, and Handling Requirements

As defined in the MHCTR and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (GBR-113), the sponsor must supply the investigator(s)/institution(s) with the investigational product(s) (IPs) (known as investigational medicinal products (IMPs) in the United Kingdom (UK)), including the comparator(s) and placebo, if applicable. The sponsor should not supply either party with the IP(s) until obtaining Medicines and Healthcare Products Regulatory Agency (MHRA) approval and a favorable opinion from a recognized ethics committee (EC).

Per the MHCTR and GBR-113, the sponsor must ensure the following (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

IP product quality and stability over the period of use
IP manufactured according to good manufacturing practice guidance (G-GMP-GDP and GBR-15)
Proper coding, packaging, and labeling of the IP(s)
IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP
Acceptable storage temperatures, conditions, and times for the IP
Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
Timely delivery of the IP(s)
Establishment of management and filing systems for the IPs
Sufficient quantities of the IP for the trial

As delineated in GBR-15, IPs should remain under the control of the sponsor until after completion of a two-step procedure: certification by the Qualified Person (QP) and release by the sponsor for use in a clinical trial. Both steps should be recorded and retained in the relevant trial files held by or on behalf of the sponsor. Shipping of IPs should be conducted according to instructions given by or on behalf of the sponsor in the shipping order. De-coding arrangements should be available to the appropriate responsible personnel before IPs are shipped to the investigator site. A detailed inventory of the shipments made by the manufacturer or importer should be maintained and include the addressees’ identification.

Refer to the MHCTR and GBR-113 for detailed, sponsor-related IP requirements.

To help ensure the continuity of supply of medicines for clinical trials from January 1, 2021, the BrexitLtr-IPs indicates that the UK will unilaterally recognize certain European Union (EU) regulatory processes for a time-limited period. This recognition is known as “standstill.”

Record Requirements

As per GBR-113, 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 pharmacy records are no longer needed. Additionally, the sponsor must ensure sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and should maintain records of batch sample analyses and characteristics.

As set forth in GBR-113, sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

However, per the MHCTR2006, the sponsor and the chief investigator must ensure that the documents contained in the trial master file are retained for at least five (5) years following the trial’s completion. The documents must be readily available to the MHRA upon request and be complete and legible. The sponsor should ensure that trial participant medical files are also retained for at least five (5) years after the trial’s conclusion.

Annex 13 – Investigational Medicinal Products – Packaging, Labelling

5.12-5.15, 5.5, and 7

Insertion of Regulation 3A of the Principal Regulations; Amendment of Regulation 15 of the Principal Regulations; and Amendment of Regulation 31 of the Principal Regulations

Part 3 (13 and 15), Part 4 (28), Part 6 (36 and 38), and Schedule 7 (Parts 2 and 3)

Definition of Specimen

Last content review/update: January 17, 2025

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 NHABiol and the G-EthicsHR-ZAF define “human biological materials (HBM)” as material from a human being, including DNA, RNA, blastomeres, polar bodies, cultured cells, embryos, gametes, progenitor stem cells, small tissue biopsies, and growth factors from the same. The G-EthicsHR-ZAF states that blood and blood products are also included pursuant to NHASpecAmend. The NHABloodCells generally refers to substances of human origin as biological substances.

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

Appendix 1 (A1.1)

1

Last content review/update: May 16, 2024

The term “specimen” is not referenced within the United Kingdom (UK). However, the following terms are used relating to specimens:

Relevant material: As per the UK-HTA, Code-E, GBR-73, and GBR-76, “relevant material” or “human tissue” is any material from a human body, other than gametes, that consists of, or includes, cells. This also includes blood (except where held for transplantation). Hair and nails from living persons are specifically excluded from this definition, as are gametes and embryos outside the body.
Bodily material: UK-HTA and GBR-64 defines “bodily material” as material from a human body that consists of, or includes, human cells. Unlike relevant material, this includes gametes, embryos outside the human body, and hair and nails from the body.
Tissue: GBR-64 defines “tissue” as any human material (e.g., blood, biopsies, urine) and includes relevant and bodily material.

Bodily Material and Tissues

Definition of Relevant Material

Glossary

Part 3 (45 and 53)

Specimen Import & Export

Last content review/update: January 17, 2025

Import/Export

Per the NHA, the MTA-Human, the NHABloodCells, the NHARegMicroLabs, the NHATissue, and the NHAStemCell, a permit must be obtained from the National Department of Health (NDOH) Director General to import or export human biological material (HBM). Both the South African Health Products Regulatory Authority (SAHPRA) approval letter and the NDOH import/export permit must be included with each HBM shipment. See also the Submission Content section for information on completing a clinical trial application. (Note that HBM is referred to as a “biological substance” in the older South African regulations (e.g., the NHABloodCells); this summary will hereinafter use HBM to refer to human biological material, specimens, and biological substances.)

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

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

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

Per the G-EthicsHR-ZAF, sharing HBM and data about HBM must comply with the POPIA and may not occur unless:

The recipient is in a country that has similar legal protections for processing of personal information
For situations where the recipient is in a country that does not have an adequate level of protection, prior authorization has been obtained or there is a code of conduct in place
The data subject has consented specifically to the intended transborder data sharing
The transfer is necessary in terms of a contract or for the benefit of the data subject

In addition, per the G-EthicsHR-ZAF, ethics committees (ECs) should consider the following during the review process for proposed HBM and HBM data sharing:

The recipient of such data should have the necessary research approvals to use the data for research purposes
The recipient should comply with the POPIA requirements, have clear processes to deal with possible data breaches, and must inform the provider and EC should a breach occur
The recipient must specify the timeframe for storage of the data and its destruction, where relevant
Any proposed re-use of the data not specified in the protocols should be subject to EC review and approval, as well as approval from the provider
Intellectual property rights must be specified
If the HBM and data are shared only for research purposes, such HBM and data cannot be used for commercialization
The researchers involved in HBM and data sharing must ensure that proper updated records are kept
Where data alone is shared, a Data Transfer Agreement (DTA) or Data Sharing Agreement (DSA) is necessary

General Import/Export Requirements for HBM

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

As per the NHABloodCells and ZAF-7, export permits for HBM 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 HBM. The applicant must also provide the Director-General with written information on stock levels for this substance along with the export application.

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

Import/Export Requirements for Specific HBM Categories

The NHABloodCells provides details on unique application requirements for specific types of HBM 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 HBM complies with the NHA requirements
Import or export of placenta tissue, embryonic or fetal tissue, embryonic, fetal or umbilical stem cells: applications will only be approved with the Minister’s written consent
Import or export of blood or blood products: applications must be accompanied by a national blood transfusion service certificate and test results. If no documentation is included, the applicant must submit a letter to the Director-General explaining the reason. The Director-General will decide whether tests must be conducted, and the Minister is authorized to determine whether the applicant’s institution can be exempted from these requirements.

Material Transfer Agreement

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

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

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

The G-EthicsHR-ZAF indicates that the MTA covers the transport of HBM between institutions/organizations within the country and cross-border transfers to provide access by the recipient to that material. The MTA should provide guidance on key issues, such as:

Purpose of the transfer of the HBM
Obligations of the parties
Terms and conditions under which HBM may be used
Whether modifications to the HBM are permissible
Whether third-party transfers may happen
What the benefit-sharing arrangements are
The relevant intellectual property rights
The indemnity arrangements

Research institutions may tailor the content to suit their individual contexts. Although some MTAs may include clauses governing sharing of data, it is advisable, as part of data management, to enter into separate data sharing agreements to regulate sharing of one (1) or more data sets from the custodian/provider to a third party.

4.2

2-13 and Forms 1 and 2

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

Chapter 9 (72)

2-5, 7, and Annexures 1-6

Cover page, 3, 4.1, and Annexure A

1 and 2

1, 3, and 16

Last content review/update: May 16, 2024

Import/Export

As specified in the UK-HTA, the Human Tissue Authority (HTA) has jurisdiction regarding the import and export of specimens (known as “relevant materials” or “human tissue” in the United Kingdom (UK)) and complies with the Code of Practice on import and export set forth in Code-E. According to the UK-HTA, Code-E, GBR-56, GBR-73, and GBR-52, the import and export of relevant material/human tissue is not in itself a licensable activity under the UK-HTA. However, once the material is imported, storage of this material may be licensable unless it is for a specific research project with ethical approval from an ethics committee (EC). GBR-73 explains that it is preferable for imported human tissue to be stored in a licensed establishment where possible, and if so, there is no requirement for EC approval to undertake research. However, if the premises where the human tissue will be held are not covered by a HTA license, each research project using the human tissue will require EC approval.

If relevant material/human tissue is being imported or exported for an application, the HTRegs specify that this must be carried out under the authority of a license or third-party agreement with an establishment licensed by the HTA to store material for human application. See G-Tissues-Brexit for guidance on Brexit-related regulatory changes that apply to the movement of human tissues and cells between Great Britain, Northern Ireland, and Europe. Establishments importing or exporting human tissues and cells intended for human application may require an HTA license covering these activities. For additional help, clinical trial staff should contact the HTA at enquiries@hta.gov.uk. For more information about Brexit, see the Scope of Assessment section.

Code-E requires imported and exported material to be procured, used, handled, stored, transported, and disposed of in accordance with the donor’s consent. In addition, due regard should be given to safety considerations, and with the dignity and respect accorded to human bodies, body parts, and tissue as delineated in Code-E. Any individual or organization wishing to import human bodies, body parts, and tissue into England, Wales, or Northern Ireland must comply with the guidelines set forth in Code-E. For exports, donors should be provided with adequate information upon providing consent, that their samples may be transported as exported samples for use abroad. It is the responsibility of the recipient country to ensure that, prior to export, the material is handled appropriately and that the required country standards have been met.

In addition, the G-QualityBlood lists the quality and safety standards when importing or exporting blood into or from the EU/European Economic Area (EEA). The UK maintains the existing quality and safety standards for the collection, testing, processing, storage, and distribution of human blood and blood components. The Medicines and Healthcare Products Regulatory Agency (MHRA) should be consulted before importing or exporting blood or blood components. See the G-QualityBlood for relevant EU quality and safety directives.

Human Tissues, Cells, and Blood as Starting Material

Per G-ATMP, if tissues and cells are being used as starting materials in a medicinal product, the donation, procurement, and testing of the cells are covered by the HTRegs under the authority of the Human Fertilisation and Embryology Authority (HFEA) for the use of gametes and embryos, which may be used in the derivation (development) of cells in the manufacture of advanced therapy medicinal products (ATMPs), and under HTA for the licensing and inspection for all other tissues and cells. Once the starting materials have been made available, medicines legislation applies to and is regulated by the MHRA.

Per G-ATMP, the HTA and the MHRA have agreed that the collection of blood as a starting material for an ATMP can be carried out under either a tissues and cells license or a blood establishment license.

Other Considerations

As set forth in the UK-HTA, the HTRegs, and GBR-9, the HTA also regulates the storage and use of specimens from the living, and the removal, storage, use, and licensing of relevant materials/human tissue from the deceased for specified health-related purposes in the UK. The UK-HTA refers to specified purposes as “scheduled purposes.” Per GBR-9, the HTA and the Health Research Authority (HRA) have agreed to collaborative arrangements in a Memorandum of Understanding.

Note that per GBR-9 and GBR-105, an HTA license is not needed for the storage of specimens for certain research projects that have been approved by an ethics committee (EC). The HTA and the UK Health Departments’ Research Ethics Service (RES) (GBR-62) have agreed that an EC can give generic ethical approval for a research tissue bank’s arrangements for collection, storage, and release of specimens, provided the specimens in the bank are stored on HTA-licensed premises. This approval can extend to specific projects receiving non-identifiable tissue from the bank. The specimens do not then need to be stored on HTA-licensed premises, nor do they need project-specific ethical approval. However, a license is required for specimens stored for which there is no ethical approval (e.g., in large biobanks).

Per the UK-HTA, the G-QAHumTissue, and Code-E, the scope of the UK-HTA provisions specifically cover England, Northern Ireland, and Wales. The UK-HTA licensing requirements do not apply in Scotland, with the exception of those provisions relating to the use of DNA. Scotland complies with the Scotland-AnatAct and the Scotland-HTA for the removal, retention, use, licensing, and import of human organs, tissue, and tissue samples specifically removed post mortem, and subsequently used for research. Per GBR-52, the Scotland-HTA does not regulate the use of tissue from the living for research.

Section 12 and Annex H

1 and 3

Import and Export of Tissue

Human tissues and cells in ATMPs and Blood and blood components in medicinal products

Introduction to the Human Tissue Authority Codes of Practice, Licensing – Import and Export, Licensing – HTA Licensing Standards, and Annex A

Glossary/Definitions, Import and Export

Part 5 (53 (6))

Section 3 - Licenses and Section 7 - Licenses - general provisions

Part 2 (13, 14, 16, 26, and 41)

Part 1 (6), and Part 2 (7), and Part 3

Consent for Specimen