South African Health Products Regulatory Authority

As stated in the MRSA, the South African Health Products Regulatory Authority (SAHPRA) is the regulatory authority overseeing medicines and clinical research, as well as medical devices and radiation safety. As stated in the MRSA and GRMRSA, SAHPRA is responsible for clinical trial oversight, approval, and inspections in South Africa. The agency grants permission for clinical trials to be conducted in South Africa in accordance with the provisions of the GRMRSA.

Per the MRSA and ZAF-39, SAHPRA is an independent, state-owned entity established to oversee the regulation of medicines in South Africa. According to ZAF-39, this agency is responsible for:

• The regulation of health products intended for human and animal use
• The licensing of manufacturers, wholesalers, and distributors of medicines and medical devices; radiation emitting devices; and radioactive nuclides
• The conduct of clinical trials in a manner that is compatible with national medicines policy

Per the MRSA, SAHPRA is a state-owned entity within the public administration but outside the public service. It acts through a Board appointed by South Africa’s Minister of the National Department of Health (NDOH). For details on the Board appointments, see ZAF-39 and ZAF-38.

As described in ZAF-39 and the SA-GCP, SAHPRA is tasked with regulating (monitoring, evaluating, investigating, inspecting, and registering) all health products. This includes clinical trials, complementary medicines, medical devices, and in vitro diagnostics (IVDs). Its mission is to promote access to health products and protect human and animal health in South Africa through science-based regulatory decisions. Per ZAF-36, SAHPRA’s Clinical Trial Committee (CTC), within the Clinical Trials Unit, reviews clinical trial applications and bioequivalence studies for human participants and recommends approval of the conduct of clinical trials. SAHPRA also authorizes the importation of unregistered medicine for the purpose of conducting clinical trials. The SA-GCP also states that SAHPRA is responsible for the following: ensuring efficient, effective, and ethical evaluation or assessment of health products that meet defined standards of quality, safety, efficacy, and performance; ensuring that the process of evaluating or assessing and registering health products is transparent, fair, objective, and concluded in a timely fashion; ensuring periodic re-evaluation and monitoring of health products; and conducting announced and unannounced inspections.

Other Considerations

Per ZAF-29, SAHPRA is an official member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH).

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

Contact Information

Per ZAF-35, SAHPRA’s postal address is:

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

SAHPRA’s physical address is:

Building A
Loftus Park
402 Kirkness Street
Arcadia, Pretoria
South Africa

Telephone: (012) 501 0300
Email: enquiries@sahpra.org.za

As per ZAF-47 and ZAF-36, the following are the SAHPRA Clinical Trials Unit emails:

New clinical trials application alert, responses to new clinical trial applications and related queries: ctcresponses@sahpra.org.za
Protocol amendments, responses to amendments and related queries: ctcamendments@sahpra.org.za
Additional investigators and sites, responses to additional and related queries: ctcinvestigators@sahpra.org.za
Bioequivalence (BE) studies, BE amendments, responses to BE studies and related queries: ctcbeprotocols@sahpra.org.za
Notifications and related queries: ctcnotifications@sahpra.org.za
Individual patient serious adverse events and related queries: ctcsaes@sahpra.org.za
Guidelines, forms, and related queries: ctcguidelines@sahpra.org.za

See EsclatProc for SAHPRA’s core business escalation procedures when contacting the relevant Clinical Trials Unit.

Medicines and Healthcare Products Regulatory Agency

As per the MHCTR, the “licensing authority” is responsible for clinical trial authorization. Pursuant to the MMDAct, the Secretary of State for the Department of Health and Social Care (DHSC) is authorized to make clinical trials regulations and amend or supplement the law relating to human medicines, taking into consideration the safety of human medicines and the availability of human medicines. As indicated in GBR-71 and GBR-90, the Medicines and Healthcare Products Regulatory Agency (MHRA) is an executive agency, sponsored by the DHSC, and is responsible for regulating medicines and medical devices in the United Kingdom (UK) (i.e., it is the licensing authority).

MHRA-More states that the MHRA regulates medicines, including vaccines, supplied in the UK, spanning the whole of a medicine’s lifecycle. The MHRA decides whether medicines should be granted licenses (i.e., marketing authorizations) and whether licenses can be varied. These decisions are based on safety, quality, and effectiveness data submitted. Further, the MHRA conducts several regulatory activities including the following:

• Inspecting facilities that manufacture and carry out safety tests on medicines to ensure they comply with Good Manufacturing Practice and Good Laboratory Practice standards
• Approving UK-based clinical trials and inspecting them to ensure they comply with Good Clinical Practice standards
• Carrying out vital research to support the development of new biological medicines and vaccines
• Developing reference materials for biological medicines to ensure their quality can be assessed in a standard way
• Monitoring the safety of the medicine while on the market, for example by actively assessing post-market safety reports
• Reclassifying existing medicines, if there is evidence to safely support doing so
• Regulating the importation of licensed medicines to the UK from European Union countries
• Carrying out inspections to ensure that medicines are developed, manufactured, distributed, and monitored to internationally recognized standards
• Helping set and enforce the legal advertising regulations for medicines in the UK
• Independent quality testing of batches of biological medicines before they go onto the market to make sure that it is consistent with batches previously shown to be safe and effective
• Regulating the supply of unlicensed medicines into the UK
• Carrying out enforcement activities to prevent the illegal supply of unlicensed medicines, to or within the UK

In addition, according to GBR-57, the MHRA’s responsibilities are to:

• Ensure that medicines, medical devices, and blood components for transfusion meet applicable standards of safety, quality, and efficacy
• Ensure that the supply chain for medicines, medical devices, and blood components is safe and secure
• Promote international standardization and harmonization to assure the effectiveness and safety of biological medicines
• Help to educate the public and healthcare professionals about the risks and benefits of medicines, medical devices, and blood components
• Enable innovation and research and development that is beneficial to public health
• Collaborate with partners in the UK and internationally to enable the earliest access to safe medicines and medical devices and to protect public health

For a listing of MHRA services and information, see GBR-36.

G-ATMP states that the MHRA is also the competent authority for advanced therapy medicinal products (ATMPs) and for UK manufacturers or importers of ATMPs. An ATMP is a medicinal product which is either a gene therapy medicinal product, a somatic cell therapy medicinal product, or a tissue engineered product.

Changes to the UK Clinical Trials Regulations

As summarized in the CT-Hub and the MHCTR-Chgs, the amended MHCTR updates the UK framework for clinical trials involving investigational medicinal products (CTIMPs), including changes relating to definitions and terminology, the approvals process, ethics committee review, simplified consent arrangements, pharmacovigilance, risk proportionality, and transparency requirements. The MHCTR-Chgs also provides an overview of the changes to policies and standards. The amended regulations apply across all four (4) nations of the UK. The CT-Transtn lays out the transitional provisions because some requirements depend on whether the application for trial approval was submitted before or on/after April 28, 2026, and certain amended requirements will also apply to older trials from that date. (Note: Transitional details are described in the relevant sections of this profile.)

International Alignment

Per GBR-44, the MHRA is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the ICH GCP, as amended from time to time. The UK-ICHE6-Comply explains that this legal requirement applies to the ICH E6 GCP conditions and principles rather than the entirety of the guideline. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the MHRA has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—to support compliance with the ICH efficacy guidelines by clarifying how the ICH provisions should be read alongside applicable UK legal requirements and by directing users to relevant UK requirements. (Note: As these applicable requirements are addressed throughout the profile, the annotations are cited only where they provide additional UK-specific clarification, exceptions, or requirements.) See ICH-UKimp for all the current ICH guidelines that have been implemented by the MHRA.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR. The Hlsnki-Align explains that reference to specific versions of GBR-81 have been removed as compliance is expected with the principles of GBR-81 rather than with a specific version.

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.

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

Contact Information

Per GBR-58, the following is the MHRA’s contact information:

Medicines and Healthcare Products Regulatory Agency
10 South Colonnade
Canary Wharf
London E14 4PU
United Kingdom

Main Phone: +44 020 3080 6000
General Email: info@mhra.gov.uk
Clinical Trials of Medicines:
Email: clintrialhelpline@mhra.gov.uk
Telephone: +44 020 3080 6456

Pharmacovigilance: vigilanceservice@mhra.gov.uk and gpvpinspectors@mhra.gov.uk
Data Protection Email: DataProtection@mhra.gov.uk
Importing or Exporting Investigational Medical Products Email: for queries, complete the GMP contact form and email it to gmpinspectorate@mhra.gov.uk
Scotland-related regulatory matters: Scotland-support@mhra.gov.uk
Wales-related regulatory matters: Wales-support@mhra.gov.uk
Northern Ireland-related regulatory matters: NI-support@mhra.gov.uk

See GBR-58 for additional MHRA contact information.

For help with setting up and conducting research in the National Health Service (NHS) across multiple UK nations, the UKwide-Rsrch provides the following emails for queries:

• England: queries@hra.nhs.uk
• Northern Ireland: Research.Approvals@hscni.net
• Wales: healthandcareresearch@wales.nhs.uk
• Scotland: enquiries@nrs.org.uk

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 Trials 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. (See CTCDates). 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 CTCDates for 2026 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.

Overview

In accordance with the MHCTR and as described in GBR-71, the Medicines and Healthcare Products Regulatory Agency (MHRA) is the licensing authority responsible for reviewing, evaluating, and approving applications for clinical trials of investigational medicinal products (CTIMPs). Per the MHCTR and the CTApp-Appvl, a person must not start or conduct a clinical trial without prior MHRA authorization and a favorable ethics committee (EC) opinion. The CTApp-Appvl calls it a joint ‘clinical trial approval’. The MHCTR-Chgs states that a clinical trial application is submitted to the MHRA and the EC using the combined review part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78). As explained in GBR-72, 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 the MHRA and the EC (and study-wide review, which is discussed below) leading to a single United Kingdom (UK) decision for clinical trials. See GBR-72 for additional updates and information on combined review.

Per the G-Biosimilars, the MHRA also regulates the licensing of biosimilars (i.e., similar biological medicinal products).

See Schedule 14 of the MHCTR, and the CT-Transtn for background information on transitional arrangements from the ‘old rules clinical trial’ to the ‘new rules clinical trial’.

Clinical Trial Review Process

Per the MHCTR, the MHRA and the EC — collectively, “the authorities” — must confirm whether a request for approval is valid within seven (7) days beginning with the date of submission and must notify the sponsor. Once the request for approval is deemed valid, the MHRA must assess the request for authorization, and the EC must assess the application for an EC opinion. The MHCTR-Chgs indicates that the authorities will aim to notify sponsors of the outcome of the validation check within one (1) working day. As indicated in the CTApp-Appvl, the outcome of these checks will be communicated by email and through IRAS within seven (7) calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the MHRA may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated, and the applicant will need to resubmit the application with the deficiencies corrected. The MHRA’s CTApp-Appvl and the Health Research Authority (HRA)’s MHCTR-Chgs provide operational guidance on the joint review and approval process laid out in the MHCTR.

The CT-Transtn provide that the “new rules” under MHCTR apply to the whole process of requesting approval for a clinical trial that is submitted on or after April 28, 2026. If an application to approve a clinical trial is submitted before April 28, 2026:

• The “old rules” apply to the whole process of requesting approval (even after April 28, 2026, if the MHRA and the EC have not issued a decision or opinion by then)
• If the MHRA issues a notice of grounds for non-acceptance after April 28, 2026, the old rules still apply following the applicant’s response to the grounds for non-acceptance
• The provision that a clinical trial approval will lapse two (2) years from the date on which the trial was approved if no participants have been recruited to take part does not apply

As part of its assessment, MHCTR states that the MHRA must consider the safety of the clinical trial and the safeguarding of clinical trial participants. The MHRA may consider whether the sponsor has failed to comply with clinical trial transparency requirements in relation to another clinical trial and, if so, whether the failure has been rectified (e.g., registering a previous clinical trial and/or publishing a summary of final results). Where the request for authorization contains a statement that the trial is a notifiable trial (i.e., eligible low-risk trials), the MHRA may, if it considers appropriate and without undertaking further assessment, rely on that statement to provide an automatic authorization of the clinical trial (more details below). The MHRA may consult a relevant committee and/or a specialist group or committee if it considers it appropriate (more details on this below). The authorities must not authorize a clinical trial involving products for gene therapy if the use of those products in that trial would result in modifications to any participant’s germ line genetic identity. Also see the CTApp-Appvl, and the MHCTR-Chgs for additional details.

After completing the initial review, MHCTR stipulates that the MHRA must provide its decision on the request for authorization, and the EC must give its opinion on the clinical trial. The authorities must notify the sponsor in writing of the joint outcome, which is one (1) of the following:

• Approve the request for approval
• Approve the request for approval, subject to conditions specified in the notice
• Not approve the request for approval, setting out the grounds for the decision and requesting the further information (RFI) required for the application to be reconsidered

Per the MHCTR, subject to applicable extensions and special circumstances, the authorities must take all reasonable steps to ensure that the joint notice is given within 30 days beginning with the date on which the authorities notified the sponsor that the request for approval was valid. Where approval is subject to conditions, the notice must specify whether the conditions relate to the MHRA’s decision, the EC opinion, or both. The clinical trial is treated as approved only if the conditions specified in the notice are satisfied. Following an RFI, the amended request for approval must be reviewed by the appropriate authority. The MHRA reviews the amended request where the RFI relates to the MHRA’s authorization decision; the EC reviews it where the RFI relates to the EC opinion; and both authorities review it where the request relates to both.

Next, the MHCTR states that applicants have 60 calendar days from the date on which the decision letter was issued to provide the requested information for the application to be reconsidered. The CTApp-Appvl indicates that the applicant’s submittal can be either a written response or an amended application for approval. The application is treated as rejected if this deadline is not met. However, extensions to this deadline can be requested by contacting the MHRA at clintrialhelpline@mhra.gov.uk (or by contacting the EC directly, if the information requested relates only to its opinion), explaining why the extension is needed and proposing an alternative submission date. The MHCTR-Chgs explains that the applicant must wait for the full RFI (issued in GBR-125) before responding to any points received individually from the MHRA or EC. The full RFI will have the final consolidated feedback, including any queries or issues, from both the MHRA and EC. See G-IRASCombRev and IRAS-User for additional details on using GBR-125 during the review process.

Next, MHCTR provides that after reviewing the amended request, the appropriate authority must notify the sponsor in writing of the outcome, which is one (1) of the following:

• Approve the amended request
• Approve the amended request, subject to conditions specified in the notice
• Not approve the amended request, setting out the grounds for the decision

As per the MHCTR, subject to applicable extensions and special circumstances, the appropriate authority must take all reasonable steps to ensure that notice is given within 10 days beginning with the date of receipt of the amended request. The CTApp-Appvl further provides that for approvals with conditions, it is not necessary to inform the authorities that the conditions have been met before starting the trial, unless otherwise specified in the approval letter. In some cases, the MHRA and/or the EC may allow a condition of approval to be fulfilled at a specific timepoint after the trial begins. In these cases, the trial may begin before meeting the condition, but failure to meet the condition by the specified timepoint will mean that the approval is not valid and the trial must be stopped until the condition is discharged. A substantial modification can then be submitted requesting approval to restart the trial.

For the initial review, the MHCTR provides that the 30-day period is extended by 90 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee. For review of an amended request, the 10-day period is extended by 30 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee, or by 60 days where the investigational medicinal product (IP) is an advanced therapy medicinal product (ATMP) and such consultation occurs. If the clinical trial involves a medicinal product for xenogenic cell therapy, the usual time periods do not apply. See below and the Submission Process section for more details on consultations.

Per the MHCTR, in exceptional circumstances (for example, in an urgent situation where it would be beneficial to progress one (1) request or application while preparing the other), and if agreed in advance by the MHRA or the EC, a request for authorization and an application for an EC opinion may be made separately outside of combined review. Where an agreement has been reached, the MHRA or the EC must confirm which of the particulars and documents specified in Part A1 of Schedule 3 must accompany the request for authorization and the application for an EC opinion; and the arrangements for the payment of the fee.

The MHCTR-Chgs states that the sponsor can appeal an MHRA non-approval or an EC unfavorable opinion by contacting appeals@hra.nhs.uk within 28 calendar days of receiving the outcome. In their appeal, the sponsor must explain why they disagree with the outcome. See the CTApp-Appvl for additional details on the appeals process and requirements.

See GBR-82 for a flowchart summarizing the process of applying for clinical trial approval. In addition, see MHCTR-Chgs for more descriptions of the approval process to the MHCTR.

Per the MHCTR, if a clinical trial is to be conducted in another country as well as the UK, the MHRA may require the sponsor, and/or the owner or occupier of any premises in that country, to permit those premises to be inspected by or on behalf of the MHRA for the purpose of establishing whether the conditions and principles of good clinical practice (GCP) are satisfied or adhered to in relation to that trial.

The MHCTR and the EndingCT state that a clinical trial approval will lapse two (2) years from the date on which the trial was approved if no participants have been recruited. The EndingCT indicates that the MHRA will monitor the status of the trial’s approval. If the approval lapses, the sponsor will be contacted via email to confirm this. The sponsor will then need to submit an end of trial notification. To enable the MHRA to monitor approval status, all sponsors will need to notify the MHRA and the EC of the date on which the first participant was recruited to a clinical trial through the modification of an important detail process. Sponsors can apply to the authorities for an extension of this period by emailing clintrialhelpline@mhra.gov.uk, explaining both why the extension is needed and the length of the proposed extension. The authorities can grant an initial extension of up to 36 months beyond the lapse date and a further extension of up to 24 months, which must be requested (through the same process) before the previous extensions end. The MHRA and the EC will respond to extension requests via email within 30 calendar days or, if the trial is awaiting approval, at the same time as the outcome of the application for clinical trial approval is issued.

Per the MHCTR, the MHRA may, by notice, require that a clinical trial, or the conduct of a trial at a particular trial location, be suspended or terminated where it has objective grounds for considering that an applicable condition, restriction, or limitation is no longer satisfied, has information raising doubts about the safety or scientific validity of the trial, or where the trial has lapsed and the sponsor has not notified the MHRA that the trial has ended. The notice must specify whether it applies generally or to specific trial locations, whether it requires suspension or termination in whole or in part, and when it takes effect; for a suspension, whether it continues until further notice or for a specified period and any conditions for recommencement. The notice must be served to the sponsor or the investigator(s) at the relevant trial location(s). Additionally, the MHRA must inform the relevant EC and the sponsor (if the notice was not served to the sponsor). Unless the MHRA believes there is an imminent risk to the health or safety of any participants, the MHRA must inform the sponsor or investigator in writing of its intent to issue the notice at least one (1) week before issuance, and provide an opportunity for written representations within one (1) week as to whether the trial should be suspended or terminated. A person served with the notice of suspension or termination may, within 28 days or an extended period as allowed, give notice of a wish to make written or oral representations to the appropriate committee, and any referred suspension or termination remains in force unless revoked in accordance with Schedule 5.

To support compliance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3) (GBR-91), the GCP-Inspct states that the MHRA:

• Requires organizations sponsoring clinical trials to notify them of serious breaches
• May conduct triggered inspections of organizations where serious breaches are suspected
• May conduct routine risk-based inspections of organizations that sponsor or conduct clinical trials
• May conduct inspections of clinical trials, and associated activities, submitted in support of a marketing authorization application

The G-GMP-GDP specifies that the MHRA follows a risk-based approach to inspections. Once an inspection has been completed, a formal report outlining the findings will be sent to the inspected organization.

Consultations for Expert Advice

Regarding consultations, the CT-Experts explains that the MHRA or the EC may consult a relevant committee or specialist group before issuing a clinical trial decision, including for certain scientifically complex or higher-risk trials. In deciding whether to seek expert advice, the authorities may consider factors such as the IP’s mode of action, the nature of the target, and the relevance of animal species and models; examples include novel compounds and certain first-in-human trials. See the CT-Experts for additional details and a process flowchart. (See Submission Process section for more details.)

Modifications to a CTIMP Approval

Per the MHCTR and the CTMod, a clinical trial approval may be modified by the trial’s sponsor, the MHRA, or the EC. Modifications to a clinical trial approval can be categorized into substantial modifications (Route A or Route B), modifications of an important detail, and minor modifications. Approval to make substantial modifications must be received from the MHRA and EC before implementation. The exception to this is for substantial modifications that relate to urgent safety measures. When considering implementing substantial modifications, sponsors should assess whether such modifications alter the original clinical trial approval to the extent that it should be considered a new clinical trial. If this is the case, a new application for clinical trial approval should be submitted. As described in the CTMod, the sponsor is responsible for using a risk-based approach to determine which of the following modification categories applies:

• Minor modifications: A sponsor may make a minor modification to a clinical trial approval at any time and without submitting a modification request or informing the MHRA and the EC at the point of implementation; the sponsor must keep records and provide them if requested.
• Modifications of an important detail: These do not significantly impact the safety or rights of the participants, but the authorities need to be aware of them for administrative or oversight purposes. Instructions for notifying the authorities about a modification of an important detail are provided on completion of the Modification Tool in GBR-125. See the CTMod for examples of modifications of an important detail.
• Route A substantial modification: This modification to a clinical trial approval is likely to have a substantial impact on the safety or rights of the participants or on the reliability or robustness of the data generated in the trial. If the sponsor proposes to make a substantial modification of this kind, the sponsor must submit a modification request to the authorities before implementation.
• Route B substantial modification: This modification poses no new significant safety concerns with any IP and the modification meets Condition A, B, or C. Condition A applies where the trial does not involve an IP used for the first time in humans and the modification has already been reviewed and approved by the clinical trials authority in the European Union (EU), an European Economic Area (EEA) State, or the United States, based on the same particulars and documents submitted in the UK, excluding UK-specific particulars. Condition B applies where the modification is limited to certain protocol changes. Condition C applies where the modification is limited to certain changes to the investigator’s brochure or summary of product characteristics. These modifications are eligible for automatic approval by the MHRA, with EC approval issued within 35 days of validation if needed.

Per GBR-83, the MHRA and the EC will manage submitted modifications in the Modification Tool of GBR-125. See GBR-106 for help using the Tool. For additional resources on clinical trial modifications, see the following:

• GBR-84: A decision tree for determining the correct category for a modification
• GBR-88: A flowchart for applying for approval of Route A substantial modifications
• GBR-85: Table of Route B substantial modifications
• GBR-134: Notification form for a substantial modification when the Modification Tool is not appropriate (for example for bulk modification (See CTMod, for more information on this))
• MHCTR-Chgs: Background on amendment/modification terminology updates, modification process overview, and examples
• GBR-98: Examples of modification types

With regard to transitional arrangements (i.e., old rules clinical trials vs. new rules clinical trials) relating to approval for modifications, CT-Transtn explains that the applicable regulations are determined by the date on which the application to approve the substantial modification was submitted. Therefore, if the sponsor submits an application to approve a substantial modification (or receives notice of a proposed modification by the MHRA or EC) prior to April 28, 2026, the old rules clinical trials apply to the whole process of requesting approval (even after April 28, 2026, if the authorities have not issued a decision by then). If an application to approve a substantial modification is submitted on or after April 28, 2026, the new rules (i.e., the MHCTR) apply to the approval process even if the clinical trial approval to be modified is for an old rules clinical trial.

Per the CTMod, to request approval for a Route A or Route B substantial modification, applicants must submit a single application, including all documentation, through IRAS (GBR-125) for trials approved through the combined review process. Applications undergo validation checks, with the outcome communicated within seven (7) calendar days. Any deficiencies must be resolved within that period or the application will be invalidated and must be resubmitted. A joint decision on a valid Route A application will be issued within 35 calendar days of validation. For an eligible Route B modification, automatic approval from the MHRA will be issued within 14 calendar days; however, the modification cannot be implemented until a combined decision approving it, or approving it with conditions, is received. If the MHRA or EC do not approve the applicant’s proposed substantial modification, the applicant will be given one (1) opportunity to provide further information and have the application reconsidered. The additional information needed will be specified in the notice stating that the application has not been approved, and it will be made clear whether the additional information requested relates to the MHRA’s decision, the EC’s opinion, or both.

Next, the CTMod states that applicants have 60 calendar days from the date on which the decision letter was issued to submit the RFI, either as a written response or an amended application for approval, in order for the application to be reconsidered. The application will be treated as rejected if this deadline is not met. Note that it is not currently possible to submit a response to an RFI about a substantial modification through IRAS (GBR-125). The response must be submitted to the MHRA through MHRA Submissions (GBR-13) and to the relevant EC via email. The MHRA cannot accept responses to RFIs that are submitted via email to an assessor or via the Clinical Trial Helpline unless this has been agreed to in advance. Extensions to the 60-day deadline can be requested by contacting the MHRA at clintrialhelpline@mhra.gov.uk or by contacting the EC directly, and the applicant should explain why the extension is needed and propose an alternative submission date. A decision will be issued by email within 10 calendar days of the response being submitted, stating that the application is either approved, approved with conditions, or not approved. If the application is still not approved, the reasons will be outlined and the application will be treated as rejected.

As per MHCTR and the CTMod, either or both the MHRA or EC may require the sponsor to make modifications to a clinical trial to ensure the trial’s safety or scientific validity or to ensure adherence to the principles of GCP. Sponsors will receive a notification of the proposed modification, and the reasoning behind the proposal via email at least seven (7) calendar days before the modification is set to take effect. The sponsor may accept the proposal, or otherwise has seven (7) calendar days to submit representations against the proposal in writing to the relevant authority. The appropriate authority will issue a final decision on whether the modification must be implemented after considering the sponsor’s representations. The date on which the proposed modification is to take effect may be delayed so that the MHRA and/or the EC has sufficient time to consider these proposals. The CTMod states that where the appropriate authority makes a final decision to modify a clinical trial approval, the sponsor has 28 calendar days from the date on which the decision letter was issued to provide written notice to the authorities of their intention to appeal. This notice should be sent to appeals@hra.nhs.uk, after which the authorities will contact the applicant to discuss the appeals process.

Notifiable Trials

The MHCTR includes a notifiable trial pathway under which certain eligible low-risk trials may receive automatic authorization from the MHRA (but an EC review is still mandatory). A notifiable trial is a trial in which, as far as the sponsor is aware having made reasonable inquiries, there are no significant safety concerns with any IP; the trial meets Condition A, Condition B, or Condition C; and the trial does not involve participants who are under 18 years of age, pregnant, or breastfeeding, or an IP that is an advanced therapy medicinal product or is used for the first time in humans. Following are the requirements for each Condition:

• Condition A: The IP/s is/are authorized for use in the UK and is used either in accordance with that authorization or in a manner supported by established clinical practice
• Condition B: A trial relating to the IP/s has/have been approved in the UK within the preceding two (2) years of the request for approval, and in that approved trial, the IP was investigated at the same or higher dose, same or higher frequency, and same or longer duration; the same manufacturing process was used; and the product was administered by the same route of administration and investigated for the same indication
• Condition C: The trial has undergone assessment and been approved by the authority responsible for licensing clinical trials in the EU, an EEA State, or the United States

Per the MHCTR, where the request for approval contains a statement confirming that the trial is a notifiable trial, the MHRA may, if it considers appropriate and without undertaking further assessment, rely on that statement to provide an authorization of the clinical trial.

The CT-Ntfble states that notifiable trial applications undergo the same validation checks as non-notifiable trial applications. After validation, the MHRA assesses whether the application meets the eligibility criteria for automatic authorization. If the criteria are met, the MHRA will issue confirmation of automatic authorization within 14 calendar days of validation. Next, a combined decision is issued, following EC review, within 30 calendar days of validation. If the MHRA finds that the application does not meet the eligibility criteria, or otherwise decides that a full review is needed, it will notify the applicant, and the application will automatically proceed through the non-notifiable review pathway. The MHRA also reserves the right to undertake a full review before issuing a decision, even where the trial is otherwise eligible for notification. See the CT-Ntfble for more details and a process flowchart.

UK-wide Research

The UKwide-Rsrch indicates that the UK’s four (4) nations—England, Northern Ireland, Scotland, and Wales—work together and with a range of organizations to support and regulate different aspects of health research. Study-wide review is the process by which all research in the UK is reviewed and approved, bringing together the assessment of governance and legal compliance of research in healthcare. The UK nations take a consistent approach to study-wide reviews, so sponsors only need to submit one (1) application in GBR-125 (combined review section of IRAS) or GBR-78 (non-combined section of IRAS). GBR-78 explains that the system 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. If a project is led from Northern Ireland or Scotland and involves NHS sites, then applications should be made through the appropriate permission process for that lead nation. Studies with sites in Northern Ireland or Scotland are supported through existing UK-wide compatibility systems where each country accepts relevant centralized assurances from national coordinating functions to avoid duplication.

The UKwide-Rsrch specifies that 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 (HSC) R&D Approvals Service 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

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 ZAF-37, applicants are responsible for paying several fees to submit a clinical trial application. MRSA-Fees, per Fees-Info, 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)33 700
• Clinical trial application (bioequivalence study): R31 700
• Clinical trial application (postgraduate study) with pharmaceutical company involvement: R11 200
• Phase 4 clinical trial application and any other clinical trial application, including university-involved postgraduate qualification and/or pre-consultation of clinical trials: R5 100

For amendments to clinical trials:

• Technical amendment applications: R7 200
• Administrative amendment applications: R4 200
• Any other application except for the purpose of performing a clinical trial: R400

For licenses:

• New manufacturing license: R26 200
• New import/export license to the holder of certificate of registration: R15 600
• Renewal of manufacturing license: R22 900
• Renewal of import license to the holder of the certificate of registration: R9 600
• Renewal of export license to the holder of the certificate of registration: R9 600
• Annual retention of all licenses: R4 400

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

• Manufacturing sites: R1 660 per hour per inspector, plus reimbursement for travel time
• Desktop inspection, including good practice compliance status after license amendments: R2 200 per day per inspector

Payment Instructions

Per the G-SAHPRAFees, SAHPRA has initiated a process to phase in an electronic application system through various Application Portals that will create unique reference numbers for the application and relevant payment. 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 Annexure 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.

Medicines and Healthcare Products Regulatory Agency

As per MHCTR and CTApp-Appvl, an application for a clinical trial approval must be accompanied by a fee to the Medicines and Healthcare Products Regulatory Agency (MHRA) as specified in the G-MHRAFees. 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 indicated in the CTMod, the applicable fees for submission of an application to modify a clinical trial approval are in G-MHRAFees. If the MHRA determines that a Route B substantial modification does not meet the eligibility criteria, the applicant may withdraw the application before it undergoes Route A review and receive a refund of the application fee. If an applicant withdraws a substantial modification application before a decision or request for further information is issued, part of the application fee may be refunded depending on how much of the review has been completed. There are no fees for a modification of an important detail.

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

• 4,656 British Pounds – Applications with an Investigational Medicinal Product (IMP) dossier (higher fee for phase 1, full and simplified IMP dossier)
• 343 British Pounds – Applications without an IMP dossier (lower fee for phase IV, cross referral, additional protocol)
• 343 British Pounds – Clinical trial variation/amendment
• 343 British Pounds – Assessment of annual safety reports (which are in the form of a development safety update report (DSUR) per the CT-Sfty)

Note per the G-MHRAFees, there is no annual clinical trials fee. 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.

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, 2nd 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. The 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.

Per the CT-Sfty, fees applicable to submission of a DSUR must be paid through the MHRA payment center on the dedicated DSUR payments page (GBR-43). Following payment, a receipt will be sent by email to the payee, which must be included in the submission in its original format as a standalone document that serves as proof of payment. Failure to provide this evidence of payment will result in the submission being invalidated.

Overview

As stipulated in the NHA and ZAF-52, 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, 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-GCP, 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-GCP 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, counseling, 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-GCP 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.

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 final 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-GCP, 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.

Overview

Per MHCTR, research ethics committees (ECs) in the United Kingdom (UK) are established, recognized, and monitored by the UK Ethics Committee Authority (UKECA). As explained in the REC-Policy, UKECA is responsible for recognizing ECs that can review clinical trials of investigational medicinal products (CTIMPs) in the UK and ensuring compliance with MHCTR. Per the REC-Policy and GBR-62, ECs are part of an accountable and independent Research Ethics Service (RES) (GBR-62). The REC-Policy indicates that the Health Research Authority (HRA) and Devolved Administrations (i.e., Governments of Scotland, Wales, and Northern Ireland responsible for health and social care services in their nations) work together to deliver the RES through the UKECA. For ECs that review CTIMPs, Appointing Authorities in each UK nation operate and work on behalf of UKECA to enable the discharge of its functions. Outside of CTIMP reviews, REC-Policy explains that ECs also review a broad range of proposed research in health and care settings in the UK, and certain functions may be carried out under nation-specific arrangements or bilateral agreements.

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 the REC-Policy, the RES encompasses England’s HRA under the Department of Health and Social Care (DHSC), Northern Ireland’s Department of Health, the Scottish Government Health and Social Care Finance Directorate, and the Welsh Government’s Health, Social Care and Early Years Group. In addition to its functions as the Appointing Authority for the RES for England, by agreement and through consultation with the Devolved Administrations (i.e., Scotland, Wales, and Northern Ireland), the HRA performs national coordinating functions for the RES. Per GBR-90, HRA is “an arm’s length body” of England’s DHSC, which means the government has devolved some of its responsibilities to HRA.

GBR-9 establishes an EC allocation framework for CTIMP ethics review, under which CTIMP applications must be reviewed by an EC recognized by UKECA to review the appropriate type of CTIMP as well as flagged ECs (e.g., for gene therapy or research on children). See GBR-9 for more guidance and the EC allocation categories.

See GBR-111 for an overview of ECs and GBR-112 to search listings, contact information, and meeting dates for ECs.

Ethics Committee Composition

As delineated in the MHCTR, an EC must be constituted of five (5) or more members, appointed by the Appointing Authority, who collectively have the qualifications and experience to review and evaluate the science, medical aspects, and ethics of the proposed trial; and include one (1) member appointed to be a chairperson. The REC-Policy additionally provides that each EC should comprise a range of people with individual expertise and experience, including registered health and social care professionals, research professionals, and members of the public who have experience using health and social care services and no professional knowledge. EC members are appointed to provide a broad range of perspectives on the committees, which scrutinize the rationale, aims, and objectives of the proposed research to reconcile this effectively with protecting the dignity, rights, safety, and well-being of potential participants. They are appointed independently of their employing organization and are expected to reflect their own experience and ethical judgement on an individual basis, bringing sound judgement and personal experience, underpinned and supported by relevant training and RES standard operating procedures (SOPs) (GBR-9).

Per the REC-Policy, each EC will be established and membership maintained by the Appointing Authority to ensure that the EC collectively has the qualifications and experience to review the ethics of proposed research. Where an EC member has an interest in a research proposal or affiliation with a research organization where impartiality and independence cannot be maintained, the declaration of interest process is followed. Each EC must have a chair and a vice-chair and the option to appoint an alternate vice-chair, which are appointed by the relevant Appointing Authority. Chairs, vice chairs, and alternate vice chairs are appointed for a specified period not exceeding five (5) years, but can resign anytime. An acting chair’s appointment ceases when the chair, vice chair, and alternate vice chair of that EC becomes available again or when their term as a member expires, whichever is sooner. EC members are appointed for up to five (5) years, but can resign at any time. Members may stay on for another term of five (5) years, subject to agreement with the Appointing Authority. After this time, they will be required to join a different EC if their membership extends for longer than a 10-year period. The Appointing Authority may extend a member’s term while new members are appointed, to ensure continuity of service. Former members may be reappointed to the same EC no sooner than one (1) year after the end of their last term, or to another EC without interval.

See the REC-Policy and GBR-9 for additional details.

Terms of Reference, Review Procedures, and Meeting Schedule

Per the MHCTR, an EC must make standing orders and adopt SOPs for its proceedings and business. The meetings and proceedings of an EC and its sub-committees must be conducted in accordance with the standing orders made, and the SOPs adopted. All applications for an EC opinion must be considered by a full meeting of an EC. REC-Policy states that a volunteer agreement outlining the expectations of appointment for EC members is required and includes: duration of appointment, renewal policy, process for resignation, process to be followed if a member who is a registered professional becomes disqualified, and the policy relating to declaration of interests. Also see REC-Policy for additional guidance.

As delineated the MHCTR and GBR-9, the quorum for EC meetings is five (5) members. However, GBR-9 states that ECs should always aim to have seven (7) members at a meeting where possible. The EC meeting will include at least the following: a chairperson (this can be a chair, vice chair, or alternate vice chair); at least one (1) lay member; and at least one (1) member with a healthcare designation. The EC membership will collectively reflect the qualifications and experience to review the science, medical aspects, and ethics of the research applications. For applications relating to research with funding support from the U.S. Department of Health and Human Services or one of its agencies, the quorum is a majority of the EC membership. Where the EC has an even number of members, a majority means 50% of the members plus one (1). A co-opted member should also be counted for the purpose of the quorum. An EC may co-opt additional members at any EC meeting only if they are a member of another EC within the RES or a member of Ministry of Defense Research Ethics Committee. A CTIMP review meeting may not co-opt more than two (2) members. Where a quorum is not present, the EC may not give an ethics opinion on any new application for ethics review.

REC-Policy states that members are expected to attend as many full meetings as possible, as well as participate in proportionate review and sub-committee meetings. Expenses incurred during an EC members’ duties are reimbursed, which may cover travel, subsistence, and care arrangements, but not loss of earnings. EC members are required to complete specific training modules to ensure that the approach to reviewing research is consistent across the RES and that members have the right information to support their reviews. EC members have a duty to maintain confidentiality regarding applications, meeting deliberations and any other information about research applications that they have access to. Each Appointing Authority provides indemnity cover for their EC members.

GBR-9 specifies that ECs should normally hold at least 10 scheduled full meetings each year for ethics review of applications, at 1-month intervals, with schedules staggered to ensure valid applications can be reviewed within the relevant time limit. The annual schedule should be agreed to by December 1 for the financial year beginning April 1 and should include meeting dates, times, and application closing dates. Closing dates for full applications should normally be 14 calendar days before the EC meeting, with later closing dates permitted for Phase 1 healthy volunteer trials in certain circumstances. A standard agenda should be prepared for each EC meeting and should include quoracy, declarations of interest, previous minutes, previous matters to discuss, applications for ethics review, lead reviewers, and the EC Report. Agendas may also include general ethics issues, EC establishment or membership matters, procedures, training issues, quality control (QC)/quality assurance (QA) reports, and workload or decision-making data. ECs should review around 3–4 new applications per meeting on average. The EC Report should notify members in writing of business undertaken outside EC meetings, including delegated decisions or actions, sub-committee decisions, conclusions or early termination of research, minor modifications, and final study reports. ECs are strongly recommended to appoint one (1) or more lead reviewers for each full application, and a lead reviewer must be appointed for each application reviewed by a proportionate review sub-committee. Documents for meetings should be made available as soon as possible after the agenda is finalized and applications are validated, and in any case no later than 10 calendar days before the meeting, except for expedited, proportionate review, and Phase 1 applications where agreed.

In accordance with GBR-9, the chief investigator (CI) or delegated representative should be invited to attend the meeting, and the sponsor’s representative and other research team members may attend alongside the CI. Attendance is intended to allow the EC to request further information, clarification, or reassurance directly, but it is not compulsory and the application should not be prejudiced if the CI is unable or unwilling to attend. The CI should not make a formal presentation at the meeting. EC members who cannot attend may submit written comments which should be recorded in the minutes. An EC may seek referee advice on aspects of an application relevant to forming an ethics opinion where the issue lies beyond members’ expertise or where the EC is unable to agree. Referees may provide written advice before or after the meeting or may attend the meeting to discuss the application, but they are not voting members and should not question the CI or take part in EC business beyond the application for which advice is sought. The application clock does not stop while referee advice is sought, only once a written request for further information is made to the CI. EC meetings should be held in private so members can discuss applications freely, and members are required to keep EC business confidential. EC members should delete any saved electronic copies of documents after a final ethics opinion has been issued. Internal and external observers may attend meetings subject to applicable requirements, including confidentiality arrangements for external observers, but observers should take no part in EC deliberations or ethics decisions. The Chair is responsible for the conduct of business and for ensuring that the EC reaches clearly agreed decisions. The meeting should reach unanimous decisions by consensus wherever possible; where consensus is not achievable, a formal vote should be taken by show of hands, with the decision determined by a simple majority of members present and entitled to vote. Where the vote is tied, the Chair may give a casting vote but should first consider other options to reach a more consensual decision.

Next, GBR-9 provides that EC meeting minutes should be prepared by the relevant staff and should contain an accurate record of what was discussed during the meeting. For each study, the minutes should record:

• The members, co-opted members, referees, and observers present for the review
• Any material interests declared and the EC’s decision on the member’s participation
• Any written comments submitted by members or deputy members
• The substance of any referee advice
• The EC’s decision on the application
• A summary of the main ethics issues considered
• For a favorable opinion, any conditions to be met before the study starts or any additional non-binding advice
• For an unfavorable opinion, the predominant reasons for the decision, clearly distinguished from other comments or advice
• For a provisional opinion, the further information requested and the arrangements for considering the information and issuing the final opinion
• The outcome of any vote taken
• Any formal dissent by a named member, with reasons
• Whether the application was reviewed voluntarily rather than as a requirement of policy or legislation

GBR-9 further indicates that minutes should be presented as the outcome of collective discussion, written in the third person, and should not attribute statements to individual members or include verbatim comments. A draft version should be provided to the Chair, and in England and Wales the Approvals Specialist, within two (2) working days of the meeting, and checked within three (3) working days. Draft minutes should be uploaded to the HRA Assessment and Review Portal (HARP) (GBR-139), with a watermark “management in confidence”; once ratified, the final signed minutes must be uploaded to HARP, and the draft version should be deleted. Signed final copies of the minutes of full EC meetings and sub-committee business, where relevant, should be retained electronically for at least 20 years and then transferred to the place of deposit, as per the records management policy in the relevant UK nation. See GBR-9 for a list of other EC documents that should be retained and their associated retention dates.

Overview

Per the SA-GCP, 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-GCP, 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-GCP, 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-GCP 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-GCP 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 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, the 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
• Extent and communication of researchers’ interpretation of AI models
• Responsibility and accountability of the researchers
• Equity and fairness
• Benefit sharing
• Safety risks and attack vulnerabilities
• Safety prioritization and risk mitigation strategies

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

Overview

The REC-Policy states that the role of the ethics committee (EC) is to help ensure that proposed research conforms to recognized ethical standards, which includes respecting the dignity, rights, safety, and well-being of the people who will take part. In addition, per GBR-46, the ethical review process should evaluate how the study involves the public in research, especially at the design stage (e.g., the participant information sheets).

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; or research involving prisoners or prisons.

Role in Clinical Trial Approval Process

In accordance with the MHCTR, the EC is responsible for giving an opinion on applications for clinical trials using investigational medicinal products (CTIMPs). As explained in the REC-Policy, ECs recognized by the UK Ethics Committee Authority (UKECA) can review CTIMPs. Per the MHCTR and the CTApp-Appvl, a person must not start or conduct a clinical trial without a favorable EC opinion and prior Medicines and Healthcare Products Regulatory Agency (MHRA) authorization. The CTApp-Appvl calls it a joint ‘clinical trial approval’. The MHCTR-Chgs states that a clinical trial application is submitted to and managed by the EC and MHRA using the combined review part (GBR-125) of the Integrated Research Application System (IRAS) (GBR-78). As explained in GBR-72, the combined review process offers a single application route and parallel/coordinated review from the EC and MHRA leading to a single UK decision for clinical trials. See GBR-72 for additional updates and information on combined review.

Per the MHCTR, the EC and the MHRA — collectively, “the authorities” — must confirm whether a request for approval is valid within seven (7) days beginning with the date of submission and must notify the sponsor. Once the request for approval is deemed valid, the EC must assess the application for an EC opinion and the MHRA must assess the request for authorization. The MHCTR-Chgs indicates that the authorities will aim to notify sponsors of the outcome of the validation check within one (1) working day. As indicated in the CTApp-Appvl, the outcome of these checks will be communicated by email and through IRAS (GBR-78) within seven (7) calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the MHRA may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated, and the applicant will need to resubmit the application with the deficiencies corrected. The MHRA’s CTApp-Appvl and the Health Research Authority (HRA)’s MHCTR-Chgs provide operational guidance on the joint review and approval process laid out in the MHCTR.

As part of its review, MHCTR and the REC-Policy require the EC to consider whether the anticipated benefits to participants and other individuals or groups affected by the medical condition under investigation outweigh the anticipated risks and inconveniences. In doing so, the EC must take into account the risks to participants’ health posed by the condition under investigation and the nature of the intervention compared to normal clinical care. The EC must also consider the measures used to seek and obtain informed consent and to protect and promote the interests of participants and the general public, including by promoting transparency in research. The EC may also consider and give an opinion on any other issue relating to the clinical trial if the sponsor has asked the EC to consider the issue and, in the EC’s opinion, the issue is relevant to the other matters the EC must consider. Before giving its opinion, the EC may obtain expert advice on any field relating to the clinical trial. The MHCTR-Chgs, explains that the EC conducts its initial review of the application at a full meeting of the EC.

After completing the initial review, MHCTR stipulates that the EC must give its opinion on the clinical trial, and the MHRA must provide its decision on the request for authorization. The authorities must notify the sponsor in writing of the joint outcome, which is one (1) of the following:

• Approve the request for approval
• Approve the request for approval, subject to conditions specified in the notice
• Not approve the request for approval, setting out the grounds for the decision and requesting the further information (RFI) required for the application to be reconsidered

Per the MHCTR, subject to applicable extensions and special circumstances, the authorities must take all reasonable steps to ensure that the joint notice is given within 30 days beginning with the date on which the authorities notified the sponsor that the request for approval was valid. Where approval is subject to conditions, the notice must specify whether the conditions relate to the EC opinion, the MHRA’s decision, or both. The clinical trial is treated as approved only if the conditions specified in the notice are satisfied. Following an RFI, the amended request for approval must be reviewed by the appropriate authority. The EC reviews the amended request where the RFI relates to the EC opinion, and the MHRA reviews it where the RFI relates to the MHRA’s authorization decision; both authorities review it where the request relates to both.

The MHCTR states that applicants will have 60 calendar days from the date on which the decision letter was issued to provide the requested information for the application to be reconsidered. The CTApp-Appvl indicates that the applicant’s submittal can be either a written response or an amended application for approval. The application will be treated as rejected if this deadline is not met. However, extensions to this deadline can be requested by contacting the MHRA at clintrialhelpline@mhra.gov.uk (or contacting the EC directly, if the information requested relates only to its opinion), explaining why the extension is needed and proposing an alternative submission date. The MHCTR-Chgs explains that the applicant must wait for the full RFI (issued in GBR-125) before responding to any points received individually from the EC or the MHRA. The full RFI will have the final consolidated feedback, including any queries or issues, from both the MHRA and EC. See G-IRASCombRev and IRAS-User for additional details on using GBR-125 during the review process.

The MHCTR specifies that after reviewing the amended request, the appropriate authority must notify the sponsor in writing of the outcome, which is one (1) of the following:

• Approve the amended request
• Approve the amended request, subject to conditions specified in the notice
• Not approve the amended request, setting out the grounds for the decision

As per the MHCTR, subject to applicable extensions and special circumstances, the appropriate authority must take all reasonable steps to ensure that notice is given within 10 days beginning with the date of receipt of the amended request. The CTApp-Appvl further provides that for approvals with conditions, it is not necessary to inform the authorities that the conditions have been met before starting the trial, unless otherwise specified in the approval letter. In some cases, the EC and/or the MHRA may allow a condition of approval to be fulfilled at a specific timepoint after the trial begins. In these cases, the trial may begin before meeting the condition, but failure to meet the condition by the specified timepoint will mean that the approval is not valid and the trial must be stopped until the condition is discharged. A substantial modification can then be submitted requesting approval to restart the trial.

For the initial review, the MHCTR specifies that the 30-day period is extended by 90 days where the EC or the MHRA consults a relevant committee and/or specialist group or committee. For review of an amended request, the 10-day period is extended by 30 days where the EC or the MHRA consults a relevant committee and/or specialist group or committee, or by 60 days where the investigational medicinal product (IP) is an advanced therapy medicinal product (ATMP) and such consultation occurs. If the clinical trial involves a medicinal product for xenogenic cell therapy, the usual time periods do not apply. See the Regulatory Authority and Submission Process sections for more details on consultations.

Per the MHCTR, in exceptional circumstances (for example, in an urgent situation where it would be beneficial to proceed with one (1) request or application while preparing the other), and if agreed in advance by the EC or the MHRA, an application for an EC opinion and a request for authorization may be made separately outside of combined review. Where an agreement has been reached, the MHRA or the EC must confirm which of the particulars and documents specified in Part A1 of Schedule 3 must accompany the request for authorization and the application for an EC opinion; and the arrangements for the payment of the fee.

The MHCTR-Chgs states that the sponsor can appeal an MHRA non-approval or an EC unfavorable opinion by contacting appeals@hra.nhs.uk within 28 calendar days of receiving the outcome. In their appeal, the sponsor must explain why they disagree with the outcome. See the CTApp-Appvl for additional details on the appeals process and requirements. Also see GBR-9 for standard operating procedures for ECs giving an ethics opinion.

Per GBR-9, the EC’s favorable ethics opinion for a specific research study applies for the duration of the study, except where action is taken to suspend or terminate the opinion. Where the duration of the study is to be extended beyond the period specified in the application form, the EC should be notified. For additional information on the duration of the EC opinion, see the CTIMP-Condtns.

Per the UKannot-E6R3, there is no legal requirement in the UK for the EC to undertake periodic reviews of a clinical trial once approved. However, the EC will review documentation relating to an ongoing trial under specific circumstances, such as in the event of an urgent safety measure or serious breach, or as part of its review of an application to make a substantial modification. GBR-9 indicates that the EC should continue to assess whether its favorable ethics opinion remains appropriate if significant developments arise during the research, but it is not responsible for proactive monitoring of the study. Rather the sponsor is responsible for EC notification of urgent safety measures; pharmacovigilance and safety reporting; and EC notification of the conclusion or early termination of the trial. The EC may request that the CI and representatives of the sponsor attend a meeting of the EC or sub-committee at any time to discuss any ethical or safety concerns about the research. For additional information on the EC’s right to review an opinion, see the CTIMP-Condtns. In addition, GBR-9 lays out circumstances when the EC should notify the MHRA of CTIMP compliance issues.

See GBR-68 for an overview of the EC review process.

(Because the MHRA and EC review processes are integrated under the UK’s joint/combined review framework, this section does not repeat the identical process information for modifications, notifiable trials, ending a clinical trial, and lapses where no participants are recruited. Refer to the Scope of Assessment section for those joint EC/MHRA review requirements.)

Fast Track Ethics Review

Per GBR-116, 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 U.S. Department of Health and Human Services, and any other type of clinical trial or research study. Also see GBR-9 for more information on the fast-track ethics review.

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 an 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.

As set forth REC-Policy, ethics committees (ECs) may not charge an application fee or seek any other financial contribution or donation to consider a research proposal for which their review is required. Members receive no payment for contributing to the review of applications at scheduled meetings or for attending such meetings. EC members are volunteers and are not paid for their role as part of the Research Ethics Service.

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 oversees and supports ECs across the country, ensures that health research involving human participants upholds the highest ethical standards, and promotes alignment with international best practices through global collaboration.

As delineated in the NHA, the SA-GCP, 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 including clinical trials
• Adjudicate complaints about the functioning of ECs
• Refer professional misconduct to the relevant statutory councils
• Recommend disciplinary action for violations of ethical research standards
• 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-GCP, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study. As indicated in the ECRegstrn, applications from ECs whose scope does not align with the mandate of the NHREC, as defined by the NHA, will not be accepted. The application form requires a clear description of the types of health or health-related research the EC reviews, or will review and monitor. The submission must demonstrate how these activities fall within the mandate of the NHREC. Only applications that clearly align with the NHA and the NHREC's scope will be considered for registration.

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. ZAF-12 indicates that ECs must comply with the NHA and the G-EthicsHR-ZAF to be eligible for NHREC registration. As required in the G-EthicsHR-ZAF, 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. Per ZAF-12, once approved, the EC is formally recognized as a NHREC-registered research EC. To maintain registration, RECs must submit annual reports (ZAF-54), implement any required improvements, and respond to audit outcomes.

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.

Overview

Per MHCTR, research ethics committees (ECs) in the United Kingdom (UK) are established, recognized, and monitored by the UK Ethics Committee Authority (UKECA). As explained in the REC-Policy, the UKECA is responsible for recognizing ECs that can review clinical trials of investigational medicinal products (CTIMPs) in the UK and ensuring compliance with MHCTR.

As stated in REC-Policy, for ECs that review CTIMPs, Appointing Authorities in each UK nation operate and work on behalf of the UKECA to enable the discharge of its functions. Appointing Authorities are responsible for setting up ECs, appointing members, and overseeing delivery of the Research Ethics Service (RES) (GBR-62) for the ECs within their remit. Their functions include establishing ECs to act for the whole or part of their geographical area, establishing ECs to review particular descriptions or classes of research, appointing EC members and chairs, approving EC standard operating procedures (SOPs), and monitoring the extent to which their ECs adequately perform their functions. Where an EC will review CTIMPs, the Appointing Authority must seek UKECA recognition of the EC. The UKECA may also adjust the extent to which an EC is authorized to act and/or abolish or revoke recognition of an EC.

Per the REC-Policy, in addition to its functions as England’s Appointing Authority for the RES, by agreement and through consultation with the Devolved Administrations (i.e., Scotland, Wales, and Northern Ireland), the Health Research Authority (HRA) performs national coordinating functions for the RES. Following are some of the HRA’s functions relating to management of GBR-62 outside of England in consultation with the UKECA:

• Develops and manages a national training program for EC members and EC operational lead staff and provides resources to support this training
• Develops, implements, and maintains SOPs (see GBR-9) for ECs and provides advice and support to ECs on procedural issues
• Develops a quality assurance program, including accreditation of ECs
• Provides and supports information systems for all nations
• Provides guidance and advice to assist ECs in their work and encourages consistency of approach to common issues in research ethics
• Provides advice on the practical implications of implementing legislation, policy, and guidance across the UK
• Acts for the UKECA to provide a national mechanism for operational advice and assistance to ECs recognized for the purposes of clinical trials regulations and to receive, on the UKECA’s behalf, the EC’s annual report
• Acts for the UKECA to handle appeals against the unfavorable opinions of ECs in respect of clinical trials of investigational products
• Acts for the UKECA to transfer an EC’s functions to a successor EC if the original EC has ceased to operate, has been varied or abolished, or had its recognition revoked

Registration, Auditing, and Accreditation

Per the REC-Policy, the HRA, acting for the 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 the HRA implements a rolling accreditation program to audit UK ECs against standards as detailed in the REC-Policy 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, the 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.

Overview

As delineated in the SA-GCP, 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 (see CTCDates) 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 Trials 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 CTCDates), 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 ZAF-40, during a public health emergency, applicants should use the modified clinical trial application form in ZAF-40. 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 ZAF-40 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.

Overview

In accordance with the MHCTR, the sponsor must request Medicines and Healthcare Products Regulatory Agency (MHRA) authorization and apply for an ethics committee (EC) opinion to conduct a clinical trial by submitting a single application dossier, referred to as “request for approval.” GBR-72 explains that in this combined review framework, the regulatory and ethics reviews are done in parallel and any requests for further information (RFIs) are raised jointly. A single response to these requests leads to a single decision from both reviews. See CTApp-Appvl and the MHCTR-Chgs for operational guidance.

Per the MHCTR, in exceptional circumstances (for example, in an urgent situation where it would be beneficial to progress one (1) request or application while preparing the other), and if agreed in advance by the MHRA or the EC, a request for authorization and an application for an EC opinion may be made separately outside of combined review.

See the Scope of Review section for details on the transitional arrangements for applying for clinical trial approval or modifications.

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

In accordance with the MHCTR, the combined request for approval application (i.e., the request for authorization and the application for EC opinion) must be submitted via the online portal and include any required notifiable trial statement, required documentation, and applicable fee. Per the CTApp-Appvl, the MHCTR-Chgs, and GBR-72, the combined request for approval for clinical trials of investigational medicinal products (CTIMPs) are submitted through the Integrated Research Application System (IRAS) (GBR-125). The G-ATMP states that all advanced therapy medicinal products must submit clinical trial applications using the same processes as all other medicines. As described in GBR-78, IRAS is a single system for applying for the permissions and approvals for health and social care/community care research in the United Kingdom (UK). The system generates the IRAS ID, which has been adopted by stakeholders across the UK as the common study identifier, and enables the applicant to enter required information once. The filters collect and collate the data appropriate to the type of study, and consequently the permissions and approvals required. Further, IRAS helps the applicant submit information needed for other relevant review bodies (e.g., the Administration of Radioactive Substances Advisory Committee, the Confidentiality Advisory Group, or the Gene Therapy Advisory Committee (GTAC)).

The 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
• Submit application

IRAS-User indicates that the sponsor/sponsor delegate and chief investigator (CI) “authorize” an application in the system; the application cannot be submitted until the CI has accepted the project, and the sponsor or sponsor delegate has reviewed the completed dataset and confirmed the submission. Once the sponsor or sponsor delegate has confirmed the submission, the applicant must complete the EC booking. The task 'Complete REC booking' is assigned to the individual who sent the request to the sponsor or sponsor delegate for review. To book using the online booking service (GBR-95), applicants should select 'Create booking' on the EC booking page. The EC booking page also provides instructions on what to do if the booking was made directly with the EC, via telephone (or email). When the EC booking page shows the confirmed booking details, the applicant can select “Submit to the regulators” to submit the application.

Per IRAS-User, fast-track EC review is also available for global clinical trials and Phase 1 trials. The Phs1CTs provides that applicants undertaking Phase 1 clinical trials may reserve an EC meeting slot before submission, and most ECs recognized to review Phase 1 healthy volunteer trials accept applications submitted up to seven (7) days before the meeting date. To make a request for 7-day submission for an application, applicants should contact their preferred EC which is flagged to review Phase 1 clinical trials. Per GBR-116, applicants seeking fast-track ethics review of clinical trial applications must also apply via combined review on GBR-125.

GBR-9 reiterates that an application for ethics review via the combined review service is submitted jointly by the CI and the sponsor. Only one (1) application for ethics review should be submitted for any research protocol to be conducted in the UK; however, for research projects with separate protocols governing one (1) or more sub-studies in addition to the main study, a full application should be submitted for each protocol. The MHCTR delineates that the CTIMP application must be made to one (1) EC only, regardless of the number of trial locations at which the trial is to be conducted. The application must be made to a UKECA-recognized EC for the entire UK and in relation to a description or class of clinical trial into which the proposed trial falls. However, an exception is when an application must be made to an EC constituted by regulations made by the Scottish Ministers under the Adults with Incapacity (Scotland) Act 2000 (AIA2000) when a clinical trial is conducted at one (1) or more trial locations in Scotland; the trial involves adults unable by virtue of physical or mental incapacity to give informed consent; and the CI is professionally based at a hospital, health center, surgery, or other establishment or facility in Scotland.

As detailed in GBR-9, when the application is ready to submit, the applicant should book an agenda slot at the next meeting of an appropriate EC. For full meetings, the applicant may decline the first available slot in the UK if they have a preference for a particular EC (for example, it has reviewed an earlier phase of the trial). Once the booking has been accepted, the application form and supporting documentation must be submitted the same day the booking is made. An email confirmation of the booking will be sent to the applicant and the EC to which the application has been allocated. If the applicant is not ready to submit the application including all required authorizations and supporting documentation on the same day, the booking should not be completed. Applications received up to 16:00 hours are considered to be received that working day. Applications received after 16:00 are considered to have been received the following working day.

In accordance with the MHCTR, the CT-Ntfble explains that applications for approval of a notifiable trial must be submitted through the same combined review process as applications for non-notifiable clinical trials. See Scope of Assessment section for details on criteria, eligibility, and other requirements for notifiable clinical trials; and refer to the CT-Ntfble for additional guidance and a process flowchart.

Regarding the exceptional circumstances in which a CTIMP application may be submitted outside of combined review, the MHCTR requires this approach to be agreed in advance by the MHRA or the EC. Per the CTApp-Appvl, applicants must obtain written approval/agreement in advance by contacting the MHRA at clintrialhelpline@mhra.gov.uk. Once this approach has been agreed to, the process for submitting separate applications to the MHRA and the EC will be communicated to the applicant.

The CTapp-Issues offers guidance on common issues identified during clinical trial applications to help applicants avoid requests for further information or grounds for non-acceptance. See the CTApp-Appvl, the MHCTR-Chgs, the G-IRASCombRev, the IRAS-User, and GBR-72 for additional guidance on submitting via GBR-125.

The UKwide-Rsrch provides guidance and requirements for research in more than one (1) 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 delineated in the MHCTR, the clinical trial application and accompanying material must be provided in English.

See IRAS-User and G-IRASCombRev for detailed help on submitting CTIMP applications.

As indicated in the MHRA-advice, applicants can seek scientific advice from the MHRA at any stage of a product’s development or regulatory lifecycle. The MHRA encourages applicants to seek advice on clinical trial topics, including first-in-human studies and design of pivotal clinical trials. See MHRA-advice for details on how to request advice.

Consultation

Per the CT-Experts, prior to submitting an application for clinical trial approval, the applicant should use the criteria in CT-Experts to assess whether their trial may need to be reviewed by a specialist group or relevant committee. If unsure, applicants should contact the MHRA for advice by emailing clintrialhelpline@mhra.gov.uk with a summary of the nature of the compound, its target and mechanism of action, and the relevance of the animal models. If the applicant believes that expert review is required, they should email the MHRA at clintrialhelpline@mhra.gov.uk at least 28 calendar days before submitting the application, stating their intention to submit an application for clinical trial approval that may require review by the Clinical Trials Biologicals and Vaccines Expert Advisory Group (CTBVEAG) of the Commission on Human Medicines (CHM) and specifying their preferred CTBVEAG meeting date. The MHRA will confirm by email that the review has been scheduled. Note that where expert advice from any specialist group or relevant committee other than CTBVEAG is required, the MHRA will discuss this with the applicant. The application should be submitted to IRAS (GBR-125) (using the same process as for trials not identified as requiring expert advice) at least four (4) weeks in advance of the CTBVEAG meeting at which the trial will be discussed. See the CT-Experts for additional details and a process flowchart.

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 ZAF-40, 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 ZAF-40 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 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-GCP, 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-GCP, 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-GCP.

Combined Submission Requirements

As required by the MHCTR, the request for approval (application) in the single application dossier to the Medicines and Healthcare Products Regulatory Agency (MHRA) and the ethics committee (EC) must include the following material:

• A completed application
• A statement or cover letter drawing attention to any features which are particular to the clinical trial, if required
• The protocol for the proposed trial describing the objective, design, methodology, statistical considerations, purpose, and organization of the clinical trial
• The investigator’s brochure (IB) or equivalent document
• Documentation relating to compliance with the principles and guidelines of good manufacturing practice, where applicable
• A dossier providing information on the quality of any investigational medicinal product (IP), the manufacture and control of the IP, and data from non-clinical studies and from clinical use of the IP
• A copy of the scientific advice of the licensing authority, or of any third country, with regard to the clinical trial
• A description of the content of the labelling
• All information given to the participants, or their legal representatives, before their decision to participate or abstain from participation in the clinical trial
• Proof of insurance, a guarantee, or any other similar arrangement, where applicable
• Responses to areas for discussion raised by the Commission on Human Medicines (CHM), where applicable

See the CTApp-Appvl for additional detailed requirements and guidance for each item listed above. In addition, the DocMgt-Apps lists the document types for combined review applications, identifies which are mandatory, and shows which review body each document is sent to upon submission.

Per the MHCTR, where separate applications are permitted in exceptional circumstances, the MHRA or EC must confirm with the applicant which documents must accompany each submission.

In accordance with the MHCTR, the CT-Ntfble indicates that applications for approval of a notifiable trial must include the same documents as applications for non-notifiable clinical trials. In addition, the applicant must also submit the confirmation of notifiable trial criteria form (GBR-135). The cover letter must include a statement that the application is for approval of a notifiable clinical trial.

Per the MHCTR, a request for modification must include the following material:

• The identifying details of the trial, including the title of the trial and any number allocated to the trial by the authorities
• A description of the proposed modification
• A statement of the reasons for proposing that modification, and if more than one (1) modification, a statement for each modification
• A copy of the proposed changes to the clinical trial protocol or any other particulars or documents accompanying the request for approval
• Summaries of any data submitted in support of the proposed modification or modifications, and any change to the summary assessment of the potential risks and benefits of using the product in the proposed trial

Clinical Protocol

Per the CTApp-Appvl, the clinical trial protocol describes the objectives, design, methodology, statistical considerations, and organization of a clinical trial and should include (where applicable):

• A descriptive title, a sponsor-created identification number, the version number, and the date of the last update
• Discussion of the trial’s relevance, design, anticipated risks and benefits, and participant recruitment and informed consent procedures (setting out any particular considerations with respect to inclusion of participants unable to provide informed consent or belonging to other special populations); for a multi-part trial where the submission does not include full details to enable the conduct of all the trial parts, outline any adaptive elements and plans for future substantial modifications
• Justification for the use of placebos, standard of care arms, or real-world data comparators
• An unambiguous definition of the end of the trial; this should usually be the date of the last visit of the last participant, and a justification should be given for any exceptions (e.g., for trials involving human tissue, analysis of samples should be undertaken as part of the data collection before the end of trial is declared)
• A description of any additional care for trial participants once their participation has ended
• A description of any sub-studies conducted at any trial locations
• A discussion of safety events and recording and reporting procedures
• Procedures for unblinding of the IP in the case of an adverse reaction
• A synopsis of the protocol
• A signature from the sponsor and the chief investigator (for single-location trials) or overall coordinating investigator (for multi-center trials) (electronic signatures are acceptable)

For more detailed guidance on the content and format of the protocol, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3) (GBR-91) which the UK is implementing.

Overview

Based on ZAF-23 and the SA-GCP, 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 Trials 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. CTCDates provides the dates of the 2026 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 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.

Overview

Per the MHCTR, all new applications for clinical trials of investigational medicinal 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 MHCTR, the MHRA and the EC must confirm whether a CTIMP request for approval is valid within seven (7) days beginning with the date of submission and must notify the sponsor. The MHCTR-Chgs indicates that the authorities will aim to notify sponsors of the outcome of the validation check within one (1) working day. As indicated in the CTApp-Appvl, the outcome of these checks will be communicated within seven (7) calendar days of submission. As soon as possible during this 7-day period, and no later than on the fifth calendar day, the MHRA may notify the applicant by email of any deficiencies identified during the validation checks and allow them to be addressed. If these deficiencies remain unresolved by the end of this 7-day period, the application will be invalidated and the applicant will need to resubmit the application with the deficiencies corrected.

Once the request for approval is deemed valid, the MHCTR states that the authorities must take all reasonable steps to issue the joint outcome within 30 days from the date the sponsor is notified that the request is valid. The joint outcome may approve the request, approve it subject to conditions, or not approve it and request further information for reconsideration. If further information is requested, applicants will have 60 calendar days from the date of the decision letter to submit a written response or amended application; otherwise, the application will be treated as rejected. Extensions to this 60-day deadline may be requested.

As per the MHCTR, after the applicant submits the amended request, the appropriate authority — the MHRA, the EC, or both, depending on the nature of the request for information — must take all reasonable steps to notify the sponsor of the outcome within 10 days beginning with the date of receipt of the amended request. The amended request may be approved, approved subject to conditions, or not approved.

For the initial review, MHCTR provides that the 30-day period is extended by 90 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee. For review of an amended request, the 10-day period is extended by 30 days where the MHRA or the EC consults a relevant committee and/or specialist group or committee, or by 60 days where the investigational medicinal product (IP) is an advanced therapy medicinal product (ATMP) and such consultation occurs. If the clinical trial involves a medicinal product for xenogenic cell therapy, the usual time periods do not apply.

The MHCTR-Chgs states that the sponsor can appeal an MHRA non-approval or an EC unfavorable opinion by contacting appeals@hra.nhs.uk within 28 calendar days of receiving the outcome. In their appeal, the sponsor must explain why they disagree with the outcome.

See GBR-82 for a flowchart summarizing the timelines and the process of applying for clinical trial approval.

Governance

Per the UKwide-Rsrch, centralized, study-wide review (for a study involving sites across one (1) or more UK nations) coordinates the assessment of governance and legal compliance for healthcare research. GBR-72 indicates that study-wide review is usually issued at the same time as the MHRA and EC decision but may come later if there are still issues to discuss with the applicant. GBR-18 further explains that, during the trial approvals phase, local research and development site review occurs in parallel with the MHRA and EC submissions so that organizations can assess and confirm their capacity and capability to deliver the study at the sites. See Site/Investigator Selection section, GBR-63, and GBR-106 for more information on the UK Local Information Pack (LIP) to support study setup and delivery.

Overview

In accordance with the GRMRSA, the SA-GCP, 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-GCP, the G-EthicsHR-ZAF, and the GRMRSA. Also, per the SA-GCP, all clinical trials must be conducted in a laboratory complying with Good Laboratory Practice (GLP). See ZAF-2 for the World Health Organization (WHO)’s handbook on GLP.

Per the SA-GPP, 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-GCP, 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-GCP, 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-GCP, 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-GCP, 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-GCP, 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-GCP, 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.

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.

Overview

Per the MHCTR, the REC-Policy, and the CTApp-Appvl, a person must not start or conduct a clinical trial of investigational medicinal products (CTIMPs) without prior Medicines and Healthcare Products Regulatory Agency (MHRA) authorization and a favorable ethics committee (EC) opinion. In addition per GBR-9, some health and social care research projects require regulatory approvals under a range of legislation applicable to the United Kingdom (UK) as a whole or to particular countries. It is the responsibility of the sponsor to ensure where necessary that a research study has appropriate regulatory approval. GBR-18 states that contracts and agreements should be in place before the start of a trial and should be subject to periodic review to ensure they remain up to date and relevant.

The MHCTR and the UKannot-E6R3 state that all CTIMPs must be conducted in accordance with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) Guideline for Good Clinical Practice (GCP) conditions and principles, as amended from time to time. The UK-ICHE6-Comply explains that this legal requirement applies to the ICH GCP conditions and principles rather than the entirety of the guideline. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91). Per the UKannot-E6R3, unlike the stated scope of GBR-91, the UK GCP requirement applies to all UK CTIMPs, whether or not the trial is intended to support a marketing authorization application.

Per the CTIMP-Condtns, if a CTIMP does not recruit within 24 months of the date of the favorable ethical opinion, the approvals are deemed to have lapsed but can be extended upon request. In addition, the trial should not commence at any location until management permission has been obtained from the organization responsible for the care of the participants at the location. For information related to participant recruitment and communication during clinical trial setup, see DigiTrials (GBR-40).

See GBR-55 for an overview of research transparency requirements.

Clinical Trial Agreement

According to GBR-107 and GBR-18, contracts and agreements should be in place prior to the initiation of a trial. GBR-107 provides model templates that apply UK-wide (unless otherwise indicated) and should be used unmodified to avoid delays, including:

• Model Clinical Trial Agreement (mCTA) and Clinical Research Organization mCTA (CRO-mCTA)
• Commercial mCTA for Investigational Advanced Therapy Medicinal Products (ATMP-mCTA and CRO-ATMP-mCTA)
• Commercial Primary Care mCTA
• Model Clinical Investigation Agreement (mCIA) and CRO-mCIA
• Model Non-Interventional Study Agreement (mNISA) and CRO mNISA (CRO-mNISA)
• Model non-commercial agreement (mNCA)
• UK template Hub and Spoke Agreements
• Model agreements for Participant Identification Centres (mC-PICA and mNC-PICA)
• Model Material Transfer Agreement
• Model Confidentiality Disclosure Agreements (mCDA and mMCDA)
• Model Commercial Chief Investigator Agreement (mCCIA) and clinical research organization mCCIA (CRO-mCCIA)
• Model Non-commercial Research Grant Collaboration Agreement
• Other model agreements

The UKwide-Rsrch states that 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 to. Additional details and templates are available in GBR-107.

Clinical Trial Registration

As delineated in the MHCTR and the CTApp-Appvl, the sponsor must register a clinical trial in a public registry by the earliest of the following: the date the first participant is recruited or 90 days after the clinical trial is approved. MHCTR-Chgs explains that this registration requirement applies to CTIMP applications submitted from April 28, 2026; for trials submitted before that date, the requirement depends on whether the trial ended before April 28, 2026, whether it was already registered, and whether the first participant has already been recruited. (See CT-Transtn for additional details on transitional arrangements.) Per the MHCTR and the MHCTR-Chgs, the sponsor may request a deferral or waiver of the registration requirement, including at the time of the request for approval or before the registration deadline. Where appropriate, the MHRA may defer registration for up to 30 months after the trial concludes, including to protect commercially confidential information, or waive the requirement in exceptional circumstances, such as national defense or security reasons. Phase I clinical trials may be eligible for an automatic deferral of up to 30 months from the conclusion of the trial, provided that the required minimum information is registered in a public registry before the aforementioned clinical trial registration deadline.

Per the MHCTR-Chgs, the public registry must be a primary or partner registry of, or data provider to, the World Health Organization International Clinical Trials Registry Platform (GBR-93), which allows public access to UK trial information. The International Standard Randomised Controlled Trial Number (ISRCTN) Registry (GBR-47) and ClinicalTrials.gov (GBR-49) satisfy the public registry requirement, although sponsors should generally register with ISRCTN unless there is a U.S. Food and Drug Administration requirement to register with GBR-49. Registration with the European Union’s Clinical Trials Information System (CTIS) (GBR-39) or previous registration with EudraCT does not satisfy the MHCTR registration requirement because these systems do not facilitate public access to information about trials taking place in the UK.

Further, per the MHCTR-Chgs, if a clinical trial application is submitted in the Integrated Research Application System (IRAS) (GBR-125), the system will share basic trial information with GBR-47 to support registration, but this does not mean that the trial is registered; GBR-47 will contact the sponsor for additional details to complete registration. If the sponsor intends to register with GBR-49 instead, this may be indicated in the IRAS application. Sponsors must also confirm the date the first UK participant was recruited by using the Modification Tool in IRAS to submit a modification of an important detail confirming that first recruitment has occurred.

As indicated in the Phs1CTs, if a sponsor submits a Phase 1 CTIMP application only involving healthy volunteers, it will automatically be deferred for all transparency requirements until 30 months after the end of the trial. However, the sponsor must still publish a minimal record on a publicly accessible registry, which can be done with ISRCTN.

See GBR-102, GBR-18, and CTIMP-Condtns for additional information on clinical trial registration.

Governance

Study-wide Review

The UKwide-Rsrch indicates that the UK’s four (4) nations—England, Northern Ireland, Scotland, and Wales—work together and with a range of organizations to support and regulate different aspects of health research. Study-wide review is the process by which all research in the UK is reviewed and approved, bringing together the assessment of governance and legal compliance of research in healthcare. The UK nations take a consistent approach to study-wide reviews, so sponsors only need to submit one (1) application in the combined review section of IRAS (GBR-125). As described in GBR-67, Health Research Authority (HRA) and Health and Care Research Wales (HCRW) approval applies to all project-based research taking place in the National Health Service (NHS) in England and Wales and brings together the assessment of governance and legal compliance with the EC opinion. Projects led from Northern Ireland or Scotland that involve NHS research sites should follow the appropriate permission process for that lead nation. Studies with research sites in Northern Ireland or Scotland are supported through existing UK-wide compatibility systems, where each country accepts relevant centralized assurances from national coordinating functions to avoid duplication. Also see the Stdy-wide for information on study-wide governance criteria.

The UKwide-Rsrch specifies that 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 (HSC) R&D Approvals Service 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 and development (R&D) permission (see below) after the relevant study-wide reviews and site assessments and arrangements are complete

Research & Development Review

As explained in GBR-18, CTIMPs within the NHS need permission from the local NHS R&D office. The review process varies across the UK, depending on the lead NHS R&D office, typically where the Chief Investigator is based. In England and Wales, HRA and HCRW provide an integrated governance and legal compliance review through the combined review process, submitted via GBR-125 alongside ethics and MHRA applications. Each NHS organization then assesses their capacity and capability before confirming participation. In Scotland, the NHS Research Scotland Permissions Coordinating Centre has a national system that provides a single point for the governance and legal compliance review. The combined review process covers MHRA and ethics approvals. Each NHS Board completes a local capacity and capability assessment before confirming participation. In Northern Ireland, the HSC R&D Approvals Service coordinates governance reviews in secondary care studies. Each HSC Trust completes a local capacity and capability assessment before confirming participation.

Per GBR-106, the UK Local Information Pack is the UK-wide mechanism for setting up participating NHS/HSC organizations. It is used for all studies with participating NHS/HSC organizations. See Site/Investigator Selection section, GBR-63, and GBR-106 for more information on the UK Local Information Pack to support study setup and delivery.

GBR-18 indicates that researchers without contractual arrangements with NHS organizations, but whose research involves direct patient contact or access to NHS premises, may need an Honorary Research Contract (HRC) or Letter of Access (LoA). HRA will determine if an HRC or LoA is required during the governance review. Where a study does not involve the NHS (i.e., patients, their data, tissues, or NHS resources), NHS permission is not required. Investigators should follow their own organization’s governance processes.

GBR-9 states that ECs do not undertake location-specific assessments. A standard condition of a favorable EC opinion is obtaining applicable organization-level capacity, capability, or management approvals before any research project activity begins at an investigator location within the NHS or Northern Ireland Health and Social Care. For non-NHS locations, it is expected that sponsors have arrangements in place to ensure selection of suitable locations and investigators. For CTIMPs, these arrangements need to be submitted to the EC for review with the initial application, and significant changes to these arrangements treated as a substantial modification.

Safety Reporting Definitions

In accordance with the SA-GCP 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-GCP, 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-GCP, 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-GCP 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 ADRs occurring during post-marketing studies (Phase 4 and observational studies) should be reported to the Vigilance Unit of SAHPRA, and ADRs occurring during the use of concomitant and/or comparator medicine in a clinical trial should be reported to the Clinical Trials 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.

In addition, SAE-E2B states that SAHPRA’s Clinical Trials Unit encourages applicants to use the International Council for Harmonisation (ICH) Guideline E2B on Electronic Transmission of Individual Case Safety Reports (ICSRs) as an additional method for reporting SAEs during clinical trials. SAHPRA accepts both the E2B R2 or E2B R3 formats. See ZAF-31 for the ICH technical specifications for the R2 and R3 formats. For E2B submissions, the preferred encoding is ISO-8859-1 (with UTF-8 also acceptable), and SAHPRA is the organization identifier. In addition, applicants must attach a cover letter to the email that includes the SAHPRA reference number, medicine registration form number (if applicable), participant number, study title, protocol number, site name, investigator/reporter name, suspect study drug, AE, report type (initial or follow-up), and outcome. SAEs should be submitted by email to ctcsaes@sahpra.org.za and the subject line should include E2B, the SAHPRA database tracking number, the protocol number, and SAE (e.g., E2B_20220203_NER000_SAE). SAHPRA notes that the current SAE reporting methods using the ZAF-15 or ZAF-19 are still acceptable.

Safety Reporting Definitions

Per the MHCTR and the CT-Sfty, the following definitions provide a basis for a common understanding of the United Kingdom (UK)’s safety reporting requirements:

• Adverse event (AE) – Any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product
• Adverse reaction – Any untoward and unintended response in a participant to an investigational medicinal product (IP) which is related to any dose administered to that participant
• Serious adverse event (SAE), serious adverse reaction (SAR), or unexpected serious adverse reaction (SUSAR) – Any AE, adverse reaction, or unexpected adverse reaction, respectively, that (a) results in death, (b) is life-threatening, (c) requires hospitalization or prolongation of existing hospitalization, (d) results in persistent or significant disability or incapacity, or (e) consists of a congenital anomaly or birth defect
• Unexpected adverse reaction – An adverse reaction the nature and severity of which is not consistent with the information about the medicinal product in question set out in (a) the case of a product with a marketing authorization, the summary of product characteristics, or equivalent document, for that product, and (b) in the case of any other IP, in the investigator’s brochure (IB) relating to the trial in question

See the CT-Sfty and GBR-30 for guidance on reference safety information, including its role in expectedness assessments for SUSARs and annual safety reporting.

See the CT-Transtn for transitional arrangements for pharmacovigilance. See GBR-18 and GBR-9 for additional summaries of safety reporting.

The MHCTR requires that clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. In addition, see CT-Sfty for additional ICH guidance that are relevant to safety reporting, including the Development Safety Update Report (E2F) (GBR-61).

Safety Reporting Requirements

Urgent Safety Measure

Per the MHCTR and the CT-Sfty, an urgent safety measure (USM) is an action that the sponsor and investigator may take to protect the participants of a trial against any immediate hazard to their health or safety. As stated in the CT-Sfty, once trial participants have been recruited, appropriate USMs may be taken at any time to protect the participants from any immediate hazard to their health or safety. USMs may be implemented without first notifying the Medicines and Healthcare Products Regulatory Agency (MHRA) and ethics committee (EC). No later than three (3) days after the measures are taken (but ideally within 24 hours), the sponsor must contact the MHRA through an initial telephone conversation or email. Failure to notify the MHRA of the implementation of an USM for safety reasons may be considered a serious breach.

Per the MHCTR and the CT-Sfty, following the initial telephone conversation or email with the MHRA, the sponsor must provide a written notice to the MHRA and the relevant EC, describing the events requiring action to be taken, and the measures taken in response to those events, including any additional actions requested by the MHRA. The written notification must be done within seven (7) calendar days from the date the measures are taken, or as soon as possible during any period where a disease is pandemic and is a serious or potentially serious risk to human health. The CT-Sfty states that the MHRA will review the written notification and may request additional information. Once the MHRA has sufficient information, it will decide whether the measure taken is a USM and communicate the outcome to the sponsor by email (and through Integrated Research Application System (IRAS) (GBR-125), if this route of submission was used). If the MHRA agrees that the measure is a USM, the sponsor should submit a substantial modification that covers the USM (with no additional changes) within two (2) weeks of the date on which the MHRA was first informed (via telephone) of the USM. If the MHRA does not agree that the measure is a USM, it will confirm with the sponsor whether any further actions are needed. See the CT-Sfty for process flowcharts and GBR-18 and GBR-9 for an overview of USMs.

Investigator Responsibilities

Per MHCTR, and the CT-Sfty, the investigator’s responsibilities include reporting of SAEs to the sponsor and reporting of certain non-serious AEs and/or laboratory abnormalities to the sponsor. The CT-Sfty indicates that an investigator must report any SAE that occurs to a participant at a trial site immediately to the sponsor, and no later than 24 hours following knowledge of the SAE. The MHCTR clarifies that the immediate report may be made orally or in writing, but the investigator must follow it with a detailed written report. These immediate reporting requirements do not apply to SAEs specified in the protocol or IB as not requiring immediate reporting. AEs other than immediately reportable SAEs that are identified in the protocol as critical to safety evaluations must be reported to the sponsor in accordance with the reporting requirements specified in the protocol. Reports must identify each participant by the number assigned to that participant in accordance with the protocol. Where the reported event consists of, or results in, the death of a participant, the investigator must provide any additional information requested by the sponsor or EC (if the death has been reported to that EC).

After the immediate report, the CT-Sfty states that the investigator must send a detailed, written follow-up report to allow the sponsor to determine whether the SAE requires a reassessment of the benefit-risk balance of the clinical trial, if the relevant information was not already available and provided in the initial report. In cases where an initial/immediate report is not required, the investigator should report within the appropriate timeframe, taking account of the specificities of the trial and of the SAE, as well as possible guidance in the protocol or the IB. The investigator does not need to actively monitor participants for AEs once the trial has ended, unless provided otherwise in the protocol. SAEs considered related to the IP occurring to a participant after the treatment of that participant has ended should be reported to the sponsor if the investigator becomes aware of them. Clinically significant abnormal laboratory findings are considered AEs; however, abnormal laboratory findings may not be considered as AEs if there is no change compared to baseline values. Certain abnormal laboratory parameters should also be specified in the protocol as requiring reporting within the same timeframes as SAEs, depending on the IP safety profile. These must be clearly stated in the protocol and made clear to the concerned laboratory to ensure that these alert values are reported immediately to the investigator for onward reporting to the sponsor.

See GBR-18 for an overview including a safety reporting flowchart.

Sponsor Responsibilities

Per the MHCTR, the sponsor must keep detailed records of all SAEs and SARs, including SUSARs, that occur during a UK clinical trial. The sponsor must evaluate these events and reactions with a view to minimizing and preventing risks presented by use of the IP and must take appropriate measures as soon as reasonably practicable to investigate the risks and implement actions for minimizing and preventing them. In addition, the sponsor must keep detailed records of all AEs relating to a clinical trial that are reported by the investigators. The MHRA may require the sponsor, by written notice, to send those records, or copies of those records. The sponsor must ensure that all relevant information about a SUSAR that occurs during a UK clinical trial and is fatal or life-threatening is reported to the MHRA as soon as possible, and no later than seven (7) days after the sponsor is first aware of the reaction. The sponsor must send any additional relevant information to the MHRA within eight (8) days of that report. SUSARs that are not fatal or life-threatening must be reported as soon as possible, and no later than 15 days after the sponsor is first aware of the reaction. These SUSAR reporting timelines do not apply where the protocol specifies that certain SUSARs do not require immediate reporting; in those cases, the SUSARs must be reported to the MHRA in accordance with the protocol.

As specified in the CT-Sfty, there is no mandatory requirement for the sponsor to inform the EC or investigators of SUSARs. However, to comply with the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91), notification of safety information to investigators (which includes SUSARs) may be appropriate. The sponsor may wish to notify investigators of an occurrence through a letter to the investigator or an updated IB. Where urgent action is required because of a SUSAR, the sponsor should also consider whether a USM is required. See the CT-Sfty for additional guidance on sponsor’s causality, seriousness, and expectedness analyses. The UKannot-E6R3 clarifies, with respect to GBR-91, that individual SUSARs are not required to be reported to investigators or the EC under UK law and must instead be reported to the MHRA.

Under the MHCTR, if a clinical trial is being conducted at a trial site in another country in addition to UK sites, the sponsor must ensure that all SUSARs occurring at the non-UK site are reported to the MHRA as soon as possible. Fatal or life-threatening reactions must be reported within seven (7) days beginning with the day after the sponsor is first aware of the reaction, and all other SUSARs must be reported within 15 days beginning with the day after the sponsor is first aware of the reaction.

Per MHCTR, within 60 days beginning with the day after the reporting year ends, the sponsor must provide the MHRA with a report on the safety of the participants of those trials for each IP tested in a clinical trial. The annual safety report must include records and evaluations of SARs and SAEs that occurred during the reporting year, including SUSARs; the record of measures taken to investigate, minimize, and prevent risks; a description of how safety concerns in the clinical trial have been assessed and managed; and a description of the overall safety profile of each IP, along with a summary description of the sponsor’s processes to monitor the overall safety profile. The MHRA may request that the sponsor provide a list of SARs and SAEs, including SUSARs, that occurred at any time during the reporting year where necessary to investigate specific safety issues. The sponsor must provide the requested list within 30 days of receiving the request, or within any shorter period specified by the MHRA. The CT-Sfty states that the annual safety report should be submitted in the form of a Development Safety Update Report (DSUR). This includes clinical trials approved via automatic authorization under the notifiable trials pathway, as well as DSURs covering a combination of notified and non-notified trials. A single DSUR may cover multiple trials as it relates to a single IP and not a specific trial. See CT-Sfty for details on the required contents of the DSUR.

See the CT-Sfty and GBR-18 for additional guidance on safety reporting.

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 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.

Form Completion & Delivery Requirements

Transitional Arrangements

Per GBR-99, for clinical trials of investigational medicinal products (CTIMPs), the submission of some of the reports may differ depending on whether the study was submitted through combined review or not. From April 28, 2026, the safety reporting requirements for CTIMPs change in line with the amended MHCTR. The new requirements apply to all CTIMPs whether they were submitted before or from this date. For example, SUSARs and annual safety reports for CTIMPs are only to be reported to the MHRA (not the EC). If any ethical issues are identified by the MHRA when they receive these reports, they will liaise with the EC directly. See CT-Transtn for additional details on transitional arrangements.

Urgent Safety Measures

As stated in the CT-Sfty, USMs must be reported to the MHRA through an initial telephone conversation or email no later than three (3) days after the measures are taken (but ideally within 24 hours). The sponsor should contact the MHRA through the Clinical Trial Helpline (020 3080 6456) to discuss the USM. If the sponsor is unable to report the USM by telephone, they should email clintrialhelpline@mhra.gov.uk with contact details, the trial’s ID, a description of the USM, and an explanation as to why it was not reported via phone. The MHRA will then contact the sponsor with further actions. The follow-up written report should be submitted to the MHRA and the EC no later than seven (7) days from the date the measures are taken via IRAS (GBR-125). Guidance on submitting an USM through IRAS can be found in the G-IRASCombRev, GBR-9, and GBR-99. If the clinical trials affected were approved through separate applications to the MHRA and the EC, email the report to clintrialhelpline@mhra.gov.uk.

SUSARs

Per the CT-Sfty, SUSARs should be reported to the MHRA in one (1) of the following ways using the format in the ICH E2B(R3) Individual Case Safety Report (ICSR) Specification and Related Files (GBR-94):

• ICSR Submissions (GBR-126) – The ICSR submissions route is used to submit single reports
• MHRA 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

The CT-Sfty further explains that following submission of a SUSAR, the sponsor should expect to receive acknowledgement of the submission within 48 hours. If an acknowledgement is not received, then the sponsor should contact the E2B support team (E2B.support@mhra.gov.uk) to determine next steps, including whether resubmission is required. See the CT-Sfty for SUSAR submission content.

Annual Safety Report

For the annual safety report, CT-Sfty states that the fee for the MHRA to review a DSUR must be paid online (GBR-43) at the point of submission, not in advance. If at least one (1) of the clinical trials covered by the DSUR was approved through the combined review process, the report should be submitted through the combined review section of the IRAS (GBR-125). If all the clinical trials covered by the DSUR were approved through separate applications to the MHRA and the EC, the report should be submitted through MHRA Submissions (GBR-13). As explained in GBR-96, following payment, the emailed receipt must be included with the DSUR submission in its original format as a standalone document serving as proof of payment; failure to provide this evidence will result in the submission being invalidated. The payment reference number must follow the required format: “DSUR-[5 digit MHRA company number]-[Investigational Medicinal Product name]-[Payment date DD/MM/YYYY]”. The company number should be the first five (5) digits of either the product license number or the clinical trial application number from a trial the organization has previously submitted. The format must be adhered to so the MHRA can match the payment to the DSUR submission and allocate monies correctly. The reference number must not be duplicated for future DSUR submissions. Submissions reflecting a fee waiver will be considered valid. DSUR submissions that do not provide proof of payment indicate a failure to submit annual safety reports. Fee-related inquiries should be sent to DSURfees@mhra.gov.uk.

Per the CT-Sfty, ICH DSUR (E2F) (GBR-61) is relevant to the report format.

The CT-Sfty states that after submission, the DSUR undergoes validation checks. The person that submitted the DSUR will receive acknowledgement of their submission by email. If the submission is invalidated, the person that submitted the DSUR will be informed by email and will need to resubmit the DSUR with the deficiencies corrected. Valid DSURs are reviewed and requests for additional information may be made by email (and through IRAS (GBR-125), if this route of submission was used), with a timeline for response set by the MHRA. Once the MHRA has sufficient information, the person that submitted the DSUR will be informed by email (and through IRAS (GBR-125), if this route of submission was used) that the DSUR has been accepted.

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

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

Interim and Annual Progress Reports

In accordance with GBR-18 and GBR-65, it is not a requirement to submit annual progress reports to the ethics committee (EC) for all studies receiving a final EC opinion in England, Wales, Scotland, and Northern Ireland. However, the MHCTR and CT-Sfty indicate that an annual safety report must be submitted to the Medicines and Healthcare Products Regulatory Agency (MHRA) in the form of a Development Safety Update Report (DSUR). See the Safety Reporting section for more details on this annual report.

As a best practice, GBR-18 points out that sponsors should ensure that arrangements are in place for reporting trial progress to stakeholders throughout the life of the study. These stakeholders commonly include Trial Steering Committees, Data Monitoring Committees, funders, sponsors, and governance bodies at each participating site. For research funded by the National Institute for Health and Care Research (NIHR), regular progress reports are required in line with funding agreements.

Final Report

As per the MHCTR and the EndingCT, within the period of 12 months beginning with the day after the conclusion of the clinical trial, the sponsor must:

• Publish a summary of the results of the clinical trial in the same public registry or registries (if more than one (1)) as the trial was registered in
• Offer to all relevant persons a summary of the results written in a manner that is understandable to laypersons

The MHCTR and the EndingCT state that at any point before the 12-month deadline, sponsors may apply for a deferral or waiver to one (1) or both requirements, explaining why this is needed. Phase I clinical trials may be eligible for an automatic deferral of up to 30 months from the conclusion of the trial, which may be further extended on request.

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 the Integrated Research Application System (IRAS) (GBR-125).

As per GBR-9, for all project-based research that have received a favorable ethics opinion from an EC, a final report on the research should be submitted to the UK Health Departments’ Research Ethics Service (RES) (GBR-62) within one (1) year of the trial’s conclusion. In the case of early termination, the provision of a final report is at the discretion of the sponsor. All final reports will be acknowledged within 30 days. The EC should be notified of receipt of the report, and the EC can ask to see a copy of the final report on request. In addition, 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 RES (GBR-62). The information contained in this final report helps the RES 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.

Other Reporting Requirements

Per the MHCTR-Chgs, the sponsor must publish a summary of the trial results in all registries the trial is registered in. It is not acceptable for a sponsor to publish the summary of results in another location (for example the sponsor's website) and insert a link to that in the registry.

The MHCTR and the EndingCT specify that within 90 days of the conclusion of a clinical trial, the sponsor must notify the MHRA and the relevant EC in writing that the trial has ended. If a trial is terminated prior to the date or event specified in the protocol, the sponsor must notify the MHRA and the relevant EC in writing of the termination of the trial within 15 days of the date of termination. According to the EndingCT, if the clinical trial that has ended was approved through the combined review process, the end of trial declaration form should be submitted through Integrated Research Application System (IRAS) (GBR-125). Guidance on using IRAS to submit an end of trial declaration form can be found in G-IRASCombRev and IRAS-User. If the clinical trial was approved through separate applications to the MHRA and the EC, the end of trial declaration form should be submitted to the MHRA via MHRA Submissions (GBR-13) and to the EC via email. The steps for gaining access to MHRA Submissions are contained within the G-MHRASubmiss and GBR-11. After submission, an acknowledgement will be issued by email (and through IRAS for combined review trials). No acknowledgement will be issued if the submission was related to the local end of trial. Details of where the results have been published should be provided to the MHRA and the EC within 12 months of trial completion (except for some pediatric trials involving the use of authorized medicinal products).

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.

As defined in the SA-GCP, 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-GCP, 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.

As per the MHCTR, a sponsor of a clinical trial is the person who takes responsibility for the initiation, management, and financing (or arranging the financing) of that trial. If two (2) or more persons take responsibility for these matters, they may either take joint responsibility for carrying out the functions of the sponsor or allocate responsibility for carrying out the sponsor’s functions. Where two (2) or more persons take joint responsibility, any reference to the sponsor in the regulations is construed as a reference to those persons. If responsibility is allocated instead, one (1) person must be responsible for carrying out the sponsor’s functions related to the clinical trial approval process and for making the request for authorization to the Medicines and Healthcare Products Regulatory Agency (MHRA) and an ethics committee (EC) opinion. The request for approval must specify who is responsible for carrying out the sponsor’s functions related to the approval process, good clinical practice (GCP) and conduct of the clinical trial, and pharmacovigilance. After the clinical trial has been approved, a different person may be specified as responsible for carrying out the sponsor’s functions by making a modification of an important detail to the terms of the clinical trial approval.

As delineated in the MHCTR, a sponsor must be established in the United Kingdom (UK) or in a country included in a list published by the MHRA, or have a legal representative who is so established. The MHRA’s list is published at G-CTApprovedCountries and initially includes European Union (EU) and European Economic Area (EEA) countries.

Further per the MHCTR, a sponsor may delegate any or all of its functions to any person, but such delegation does not affect the responsibility of the sponsor. The functions of the sponsor include the development and maintenance of trial-specific computerized systems, and the selection and oversight of a laboratory in relation to the analysis or evaluation of human samples collected as part of the clinical trial.

GBR-101 provides that 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. All health and social care research has a sponsor. The sponsor is normally expected to be the employer of the chief investigator in the case of non-commercial research or the funder in the case of commercial research. The sponsor has overall responsibility for the research, including:

• Identifying and addressing poorly designed or planned research and poor-quality research proposals, protocols or applications and ensuring that research proposals and protocols take into account systematic reviews of relevant existing research evidence and other relevant research in progress; make appropriate use of patient, service user, and public involvement; and are scientifically sound, safe, ethical, legal, and feasible and remain so for the duration of the research, taking account of developments while the research is ongoing
• Satisfying itself that the investigators, research team, and research sites are suitable
• Ensuring that roles and responsibilities of the parties involved in the research and any delegation by the sponsor of its tasks are agreed and documented
• Ensuring adequate provision is made for insurance or indemnity to cover liabilities which may arise in relation to the design, management, and conduct of the research project
• Ensuring appropriate arrangements are made for making information about the research publicly available before it starts (unless a waiver or deferral is agreed by or on behalf of the EC); agreeing appropriate arrangements for making data and tissue accessible, with adequate consent and privacy safeguards, in a timely manner after it has finished; and ensuring arrangements for information about the findings of the research to be made available, including, where appropriate, to participants
• Ensuring that, where expected or required, the research has approval from an EC and any other relevant approval bodies before it begins
• Verifying that regulatory and practical arrangements are in place, before permitting the research to begin in a safe and timely manner
• Putting and keeping in place arrangements for adequate finance and management of the research project, including its competent risk management and data management
• Ensuring that effective procedures and arrangements are kept in place and adhered to for reporting (e.g., safety reports) and for monitoring the research, including its conduct and the ongoing suitability of the approved proposal or protocol in light of adverse events or other developments

Per GBR-103, sponsors of clinical trials of investigational medicinal products (CTIMPs) have particular legal duties. The sponsor of a CTIMP is responsible for ensuring that a clinical trial complies with the MHCTR and GCP. Regarding GCP compliance, the MHCTR requires that clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others.

GBR-103 states that where it is necessary to appoint a legal representative based in the UK or a country on the MHRA’s list, the details of the legal representative should be entered into Integrated Research Application System (IRAS) (GBR-125). 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 and contactable 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
• May in some cases enter 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

As explained in GBR-103, in all cases, evidence should be provided with the CTIMP application that the legal representative is willing to take on the role of legal representative and is established at an address in the UK or a country on the approved country list. For example, a copy of correspondence between the sponsor and legal representative on appropriate headed paper could be supplied, or a copy of a contract. Where the legal representative is also a co-sponsor, this should be separately recorded on the application form and details given of the allocation of sponsorship responsibilities.

See GBR-103, GBR-9, GBR-18, and GBR-2 for additional guidance on sponsors.

Overview

As set forth in the SA-GCP, 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-GCP, 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 well-being 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-GCP 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-GCP, 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-GCP, 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-GCP. 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-GCP, 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-GCP, 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.

Overview

Per the MHCTR, the investigator for a clinical trial must be a health care professional who is appropriately trained to undertake that role in a clinical trial. Health care professional means a doctor, dentist, registered nurse, pharmacist, optometrist, relevant Health and Care Professions Council registrant, registered osteopath, registered chiropractor, anaesthesia associate or physician associate, or registered midwife. The investigator is responsible for the conduct of the trial at its trial location(s). The CT-Roles states that the appointment of an investigator is the responsibility of a sponsor, and this person must be qualified by education and experience, having the scientific background and experience in participant care required for the clinical trial. Organizations conducting clinical trials should consider what training and support is required for investigators. Consideration should be given to participation in suitable training and provision of mentoring support, for example. The type and level of training for an investigator should facilitate knowledge and understanding of the relevant regulations and guidance, and expectations associated with the role, while being proportionate to the type of trial being conducted. Sponsors should also note that a qualified doctor (or, where appropriate, a qualified dentist) who is an investigator for the trial should have the overall responsibility for trial-related medical care and decisions on behalf of participants.

GBR-18 lists examples of factors that should influence investigator/site selection:

• Interest in the research question
• Experience and qualifications of the investigator
• Sufficient staff to conduct the study and their experience and qualifications
• Availability of suitable patient population, including anticipated rate of patient recruitment (determined through feasibility assessments) and conflicting studies
• Adequate time to conduct and oversee the trial
• Adequate facilities such as the availability of any specialized diagnostic, therapeutic equipment required by the protocol, adequate space and storage conditions (including archive), and available resources in support departments
• Previous track record with similar trials
• Geographic location
• Contractual and budgetary negotiations and arrangements

Regarding investigator training, CT-Roles explains that both the Health Research Authority (HRA) and the Medicines and Healthcare Products Regulatory Agency (MHRA) advocate a proportionate approach to the application of good clinical practice (GCP) to the conduct of clinical trials and the appropriate training of staff involved. Training needs may range from detailed knowledge to just awareness of GCP principles and the MHCTR, and training can be tailored accordingly. For certain trials it may be necessary for staff involved in trial activities to be aware of other regulatory requirements outside those of GCP. For example, healthcare professionals retaining tissue samples should be aware of relevant human tissue and blood safety legislation and regulations. Per the CT-Roles, It is expected that organizations involved in the conduct of clinical trials have considered staff training needs in regard to the MHCTR and GBR-91 (and GBR-104 where relevant).

Regarding GCP compliance, the MHCTR requires that clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others.

GBR-106 provides a site-selected email template, which should be used as the formal notification from the commercial sponsor (or delegated agent) confirming that the organization has been selected to participate as a site in a commercial-contract clinical trial or clinical investigation. Also see GBR-18 additional resources to support investigator and site selection.

The UKannot-E6R3 states that unlike in the GBR-91, there is no regulatory requirement for an investigator to inform the authorities that they are withdrawing from a trial. However, depending on the circumstances of the investigator’s withdrawal, the sponsor may need to temporarily halt the trial or report a serious breach to the MHRA in accordance with the MHCTR. In addition, if the investigator that has withdrawn from the trial is the chief investigator (CI), then the sponsor will need to submit a substantial modification to the authorities with the details of the new CI.

As described in GBR-18, for clinical trials of investigational medicinal products (CTIMPs), adding a new trial location not listed with the original application is considered a modification of an important detail. In addition, if a trial location is added in a UK nation that was not previously involved in the project, the sponsor should ensure that:

• The change is correctly categorized using the Modification Tool and submitted through the combined review process of Integrated Research Application System (IRAS) (GBR-125)
• The appropriate nation-specific study set-up processes are followed for the new trial location(s)

UK Local Information Pack

Per GBR-63 and GBR-106, the HRA's UK Local Information Pack (LIP) provides a consistent set of documents to support study setup and delivery across National Health Service (NHS) organizations in England, Northern Ireland, Scotland, and Wales. While the core contents are standardized, country-specific processes govern how the LIP is distributed and used:

• England and Wales: the sponsor should send the LIP directly to the site's R&D office, delivery team, and local network (if applicable, the National Institute for Health and Care Research's Research Delivery Network Portfolio)
• Scotland: the NHS Research Scotland Permissions Coordinating Centre distributes the LIP to R&D offices and relevant portfolio managers, while sponsors provide it to research teams using a Scotland-specific email template.
• Northern Ireland: the sponsor may send the LIP to participating sites after receiving instruction from the Northern Ireland Health and Social Care (HSC) R&D Approvals Service.

For templates, detailed instructions, and contact information by country, refer to UKwide-Rsrch, GBR-106, and GBR-63.

Foreign Sponsor Responsibilities

GBR-103 provides that if a sponsor(s) is not established in the UK or on an approved country list, 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. See the G-CTApprovedCountries for 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 European Union (EU)/European Economic Area (EEA).

Data Safety and Monitoring Board

Per GBR-18, the CI should plan oversight structures as appropriate including a data safety and monitoring board (known as a data monitoring committee (DMC) in the UK).

Multicenter Studies

Per the G-Ovrsight, for multi-country trials, global documentation for the trial is acceptable, but it may be necessary to include specific procedures to mitigate any country-specific risks that were identified from the risk assessment – for example, differences in clinical practice or local regulations. It may be necessary to include some site-specific actions such as additional monitoring checks at the CI’s site (for example, if the sponsor has delegated numerous functions) or the site may be responsible for undertaking a specific trial activity or where a site-specific risk may have been identified.

As described in GBR-18, for CTIMPs, change of a principal investigator (PI) (other than a CI) in a multicenter trial is considered a modification of an important detail.

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.

Insurance

As set forth in the G-Insurance and the SA-GCP, 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-GCP. As delineated in the SA-GCP 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-GCP, 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-GCP. 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-GCP 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

CTInsurance indicates that when applying to SAHPRA for approval of a new clinical trial, proof of active participant insurance cover for the trial must be included in the submission. The insurance quotation letters, letters of intent, or pro forma certificates are not acceptable. As indicated in the clinical trial application form (ZAF-23), applications submitted without an insurance certificate will be rejected at the screening phase and will not be accepted for review.

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-GCP. As delineated in the SA-GCP 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-GCP, 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-GCP 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 agrees 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-GCP, the sponsor or the designated representative is responsible for providing compensation to research participants. The SA-GCP states 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-GCP, and the G-TIECompensation, compensation should be based on time, inconvenience, and expenses (TIE). In addition, the G-EthicsHR-ZAF and the SA-GCP 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.

Insurance

As set forth in the MHCTR, all clinical trials must make provisions for insurance or indemnity to cover all liabilities of the investigator and sponsor. Proof of insurance, a guarantee, or any other similar arrangement, must accompany a request for approval, a modification request, and a notification of the conclusion of a trial; or an explanation of why the proof is not being provided. Per GBR-103, if a sponsor of a clinical trial of an investigative medicinal product (CTIMP) is a commercial body, a copy of an insurance or indemnity certificate should normally be included with the ethics committee (EC) application as evidence of the cover in place for the potential liability of the sponsor. This may be a certificate for a trial-specific policy or a block policy covering a number of trials conducted by the sponsor. If the certificate is not yet available, the EC will require as a condition of its favorable opinion that a copy of the certificate is provided prior to the start of the trial. See UKannot-E6R3, GBR-2, GBR-9, GBR-103, GBR-101, and GBR-18 for additional guidance.

The MHCTR requires that clinical trials are conducted in accordance with the principles of good clinical practice (GCP) set out in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the United Kingdom (UK) is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others.

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.

Compensation

Injury or Death

According to GBR-33, before the start of a Phase I study, 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.

Trial Participation

Per Compstn, where payment is proposed for trial participation, the payment should be proportionate to the burden imposed by the research. Such burdens may often be significant without involving excessive risk (e.g., number of hospital visits, tissue samples taken, lifestyle restrictions, diaries, questionnaires, use of technology such as electronic patient reported outcomes, interaction with apps, etc.). Where the risk and burdens of the research are considered by an EC to be justified by the potential benefits, then it will normally be acceptable for competent adults to participate in the research study without being paid (including reimbursement of expenses). Where it is considered ethically acceptable for individuals to take part in a study for no payment, it would also be acceptable to pay individuals for participation in that study proportionate to the level of burdens and/or risk. Financial or other incentives, of themselves, are not considered coercive nor do they present an undue inducement to a potential participant where the risks and burdens involved are those that a competent, adult participant might reasonably accept for no payment. Regarding payment to participants who use drugs to take part in research, where payment is deemed to be acceptable for taking part in research, it is acceptable for that payment to be made in cash or vouchers.

As delineated in the MHCTR, incentives and financial inducements must not be given to a minor or a legal representative/guardian, except provision for compensation in the event of injury or loss. Similarly, incentives and financial inducements must not be given to a participant who is an incapacitated adult or their legal representative, except provision for compensation in the event of injury or loss.

Post-Trial Access

As explained in the Hlsnki-Align, the Declaration of Helsinki (GBR-81) requires arrangements for post-trial access to beneficial interventions, whereas the MHCTR does not impose this as a statutory obligation. In practice, GBR-81 and the MHCTR are aligned regarding expectations. Sponsors should aim to comply with both, but where strict adherence to GBR-81 would undermine UK statutory safeguards or operational feasibility, the Medicines and Healthcare Products Regulatory Agency (MHRA) expects sponsors to prioritize compliance with UK law while documenting the rationale for deviations.

The UKannot-E6R3 clarifies, with respect to GBR-91, that there is no specific regulatory requirement for the sponsor to provide the investigator with information about the treatment taken by participants for blinded trials. However, clinical trials should be designed and conducted in ways that ensure the rights, safety, and well-being of participants, which includes the post-trial transition back to standard of care, and to support this, it may be necessary to know which treatment the participant received. The sponsor should act in accordance with the approved clinical trial protocol.

Quality Assurance/Quality Control

Per the SA-GCP, 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-GCP, 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-GCP, 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-GCP and an international guideline, the SA-GCP take precedence.

Monitoring Requirements

In accordance with the SA-GCP, 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-GCP, 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.

Quality Assurance/Quality Control

As stated in the MHCTR, a person must not conduct a clinical trial or perform the functions of the sponsor of a clinical trial unless it is in accordance with the conditions and principles of good clinical practice (GCP). The GCP conditions and principles include those in the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the United Kingdom (UK) is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—to support compliance with the ICH efficacy guidelines by clarifying how the ICH provisions should be read alongside applicable UK legal requirements and by directing users to relevant UK requirements. Regarding GCP, the CT-Transtn states that from April 28, 2026, the new GCP rules under MHCTR apply to all clinical trials, whether the application was submitted before or after April 28, 2026. The only exception relates to retention of the trial master file for trials where the application was submitted before April 28, 2026.

Per the MHCTR, the sponsor of a clinical trial must put and keep in place arrangements for the purpose of ensuring that the conditions and principles of GCP are satisfied or adhered to. This includes developing and maintaining trial-specific computerized systems, selecting and overseeing a laboratory for human samples, and analyzing and evaluating human samples collected as part of the clinical trial. Further, the sponsor must ensure that the investigational medicinal products (IPs) used in the trial are made available to the participants free of charge.

The Qlty-Risk provides an explanation of the interconnected quality concepts embedded within GBR-91, such as quality by design, risk-based quality management, and risk proportionality, and outlines the practical implications for trial conduct, oversight, and compliance. In addition, the Qlty-Risk should be read in conjunction with GBR-104, which establishes the overarching scientific and quality principles for clinical study design and conduct, including the application of quality by design approaches. See the Qlty-Risk and GBR-18 for additional details on implementing proportionate, risk-based systems for clinical trials.

The MHCTR and the SrsBreachNotif state that the sponsor of a clinical trial must notify the MHRA in writing of any serious breach of the conditions and principles of GCP in connection with that trial or the protocol within seven (7) days of becoming aware of that breach. A serious breach is a breach which 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.

To make the MHRA notification, the SrsBreachNotif emphasizes that the serious breach notification should be carried out by the sponsor or a person legally authorized by the sponsor to perform this function (for example, a legal representative or service provider), if delegated by the sponsor. The sponsor retains legal responsibility even if the function is delegated. To ensure participant safety, reporting should not be delayed by debates about reporting responsibility. If the sponsor does not report a breach to the MHRA but the investigator or institution believes a serious breach has occurred, due diligence is necessary. Investigators or institutions should consider whether to continue with the trial and/or report the breach directly to the MHRA. If the sponsor obtains clear and unequivocal evidence that a serious breach has occurred, the default position should be for the sponsor to notify the MHRA first, within seven (7) days, and investigate and take action simultaneously or after notification. In this case, the sponsor should not wait to obtain all the details of the breach prior to notification. In other cases, some degree of investigation and assessment may be required by the sponsor prior to notification, to confirm that a serious breach has occurred. It is expected that this investigation is expedited to meet the timeline as closely as possible. If in doubt about whether and when to notify, contact the MHRA GCP Team via GCP.SeriousBreaches@mhra.gov.uk. Organizations should also consider if there are any other relevant MHRA units that should be notified.

Per the SrsBreachNotif, GBR-9, and CTIMP-Condtns, the EC must also be notified of a serious breach within seven (7) days. The SrsBreachNotif instructs that organizations should use the MHRA form (GBR-108) to ensure all required information is submitted, and the form should be sent as an MS Word document. Wherever possible, the MHRA will provide an acknowledgement of receipt for notifications. It is recommended that the organization also informs the relevant chief investigator and/or principal investigators (as applicable) of the breach to facilitate the implementation of corrective and preventative actions.

Per the G-RiskAssmt, the 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. 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 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. In addition, see GBR-34 for resources and training on developing and implementing people-centered research.

Monitoring Requirements

Per GBR-18, sponsors should define a monitoring strategy that focuses on critical data and processes, ensuring timely identification of issues that may affect participant safety or data integrity. Proportionate approaches are supported through resources listed at GBR-18. Sponsors should ensure there are clear processes for the identification and escalation of issues, identified through monitoring, as well as implementing and documenting corrective and preventive actions. Further, the sponsor of a clinical trial is responsible for establishing and maintaining robust quality systems, including designing and implementing a formal audit plan. 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 standard operating procedures (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
• System audits, which look at the performance of specific functions, such as the systems and processes used for data management

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 GCP as described in GCP-Inspct and GBR-91. 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 GCP-Inspct for pre-inspection documentation and other resources. Also see Inspct-Resp for information on formulating responses to GCP inspection findings. Per G-RiskAssmt, GCP inspectors will also review risk assessments. The G-Ovrsight provides additional guidance to assist sponsors and those conducting trials on implementing adequate oversight and monitoring processes for clinical trials of investigational medicinal products (CTIMPs).

Premature Study Termination/Suspension

Per the MHCTR and the EndingCT, the sponsor must provide written notice to the MHRA that a clinical trial has ended (and this notice should also be provided to the EC). Where a clinical trial is terminated early, this notice must be provided within 15 days.

MHCTR states that the MHRA may require a trial, or the conduct of the trial at a particular trial location, be suspended or terminated if it has objective grounds for considering that any condition, restriction, or limitation which applies to the conduct of the trial is no longer satisfied; has information raising doubts about the safety or scientific validity of the trial; or the trial has lapsed and the sponsor has not notified the MHRA that the trial has ended. The notice will specify whether it applies to the trial generally or to one (1) or more trial locations; whether it requires suspension or termination of the trial in whole or in part; any period of suspension and any conditions to be satisfied before the trial, or the conduct of the trial at a particular location, may be recommenced; and whether suspension or termination takes effect immediately on receipt of the notice or on a specified date. Except where it appears to the MHRA that there is an imminent risk to the health or safety of any of the participants of the clinical trial, the MHRA must give the sponsor or investigator at least one (1) week’s written notice that it is minded to issue a notice suspending or terminating the trial, in whole or in part, or the conduct of the trial at a particular location, and the reasons why. The sponsor or investigator may, within one (1) week of the date of the notice, furnish the MHRA with written representations as to whether the trial, or the conduct of the trial at a particular location, should be so suspended or terminated. A person on whom a suspension or termination notice has been served may, within 28 days, or such extended period as the MHRA may allow, give notice of their wish to make written or oral representations to the appropriate committee.

Per the EndingCT, if the clinical trial that has ended was approved through the combined review process, the end-of-trial declaration form (GBR-133) should be submitted through the combined review part of IRAS (GBR-125). If approved through separate applications to the MHRA and the EC, it should be submitted to the MHRA via MHRA Submissions (GBR-13) and to the EC via email. For trials terminated prior to the date or event specified in the protocol:

• The end of trial declaration will be reviewed by the MHRA and requests for additional information may be raised
• Once MHRA has sufficient information, the sponsor will be informed that the end of trial declaration has been accepted
• Details of where the results have been published should be provided to MHRA and the EC within 12 months of trial completion (except for some pediatric trials involving the use of authorized medicinal products)

Also see GBR-91, which the MHRA has implemented in ICH-UKimp, for additional guidance on sponsor responsibilities involving premature termination or suspension of a trial. In addition, the MHCTR advises that the investigator and sponsor must have regard to all relevant guidance with respect to conducting a clinical trial.

Also see GBR-18 and GBR-128 for more information and resources.

Electronic Data Processing System

Per the SA-GCP, 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 data ownership 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-GCP, 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).

Electronic Data Processing System

The MHCTR states that the sponsor’s functions include the development and maintenance of trial-specific computerized systems, which supports compliance with good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), as amended from time to time. ICH-UKimp indicates that the United Kingdom (UK) is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. Per GBR-18, the trial-specific computerized system must be fit for its intended use and appropriately validated, ensuring that electronic data meets GCP and regulatory requirements. See GBR-18 for additional resources.

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.

Records Management

Per MHCTR and the CTRecords, the sponsor must keep a trial master file (TMF) for a clinical trial and ensure that the TMF is readily available at all reasonable times for inspection by the Medicines and Healthcare Products Regulatory Agency (MHRA) or any person appointed by the sponsor to audit the arrangements for the trial. The TMF must always contain the essential documents relating to that clinical trial. The sponsor must ensure that any alteration to a document contained in the TMF is traceable. The sponsor and the chief investigator (CI) must ensure that the documents contained, or which have been contained, in the TMF (including documents contained in electronic form) are retained for at least the period of 25 years beginning with the day after the conclusion of the trial and that during that period are readily available to the MHRA upon request and complete and legible. If, at the date of the expiration of the 25 years, the data generated by the trial is being used to support an application for a UK marketing authorization, the sponsor must ensure the documents are retained for a period of at least two (2) years beginning with the day after the UK marketing authorization is granted. Further, the sponsor and CI must ensure that the medical files of trial participants are retained for a period of at least 25 years beginning with the day after conclusion of the trial, or such period as is required by any other enactment, if longer. The sponsor must appoint individuals to be responsible for archiving the documents in the TMF and restrict access to those appointed individuals. See CTRecords and GBR-91 for guidance on what is an essential document.

Per the UKannot-E6R3, in relation to GBR-91, transfer of ownership of essential records must be documented by the sponsor but does not have to be reported to the UK authorities. If the transfer of ownership is related to a change in sponsor, this must be reported to the authorities as a modification of an important detail.

Regarding transitional arrangements, CTRecords specifies that for trials submitted before April 28, 2026, the old rules (pre-2025-amendments) continue to apply for TMF documents. This means the sponsor and CI must keep the TMF documents for at least five (5) years after the trial ends and ensure they remain complete, legible, and readily available to the MHRA upon request. If the trial data is being used to support a UK marketing authorization application when the 5-year period ends, the sponsor must keep the essential records for at least two (2) years after the UK marketing authorization is granted. The sponsor and CI must keep trial participants’ medical files for at least 25 years after the trial ends, or longer if another law requires it. For all trials involving an authorized product, other trial documentation must be kept for as long as the product remains authorized. The final clinical study report must be kept for five (5) years after the product is no longer authorized.

CTRecords states that documents must not be destroyed before the end of the retention period. If documents have been damaged or destroyed accidentally then an assessment should be conducted to determine the extent and impact of the lost or damaged documents. If the assessment is found to impact the ability to present the documents for inspection, then a serious breach notification should be considered.

Per GBR-18, the sponsor should maintain documented procedures for computerized trial-specific systems, including system validation, user training, access and permissions management, security and integrity controls, change control and system updates, back up, disaster recovery and incident management, and ongoing technical support and maintenance. See GBR-18 for additional resources.

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. In addition, an "information officer" is the designated head or deputy of a public or private body responsible for fulfilling the duties and functions related to 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) on the eServices platform (ZAF-14). 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, maintain, and continually improve a compliance framework
• Conduct a personal information impact assessment to ensure compliance with the conditions for the lawful processing of personal information
• Develop internal measures and systems to process requests for information or access
• Conduct internal awareness sessions on protection of personal information requirements

As indicated in the POPIA-Regs, a data subject may object to the processing of personal information at any time during office hours and free of charge. The objection must be made on a form substantially similar to Form 1 (in the POPIA-Regs), and the responsible party must make the form reasonably accessible by hand, fax, post, email, SMS, WhatsApp, or any other expedient means. The responsible party must notify the data subject of the right to object when collecting personal information. If an objection is made telephonically, it must be electronically recorded and made available to the data subject upon request. In addition, a data subject may request the correction, destruction, or deletion of personal information at any time and free of charge, where the information is inaccurate, irrelevant, excessive, out of date, incomplete, misleading, obtained unlawfully, or no longer authorized to be retained. Requests must be made on a form substantially similar to Form 2 (in the POPIA-Regs), which must be reasonably accessible through various means, including hand delivery, fax, post, email, SMS, WhatsApp, or any expedient manner. If a request is made telephonically, the responsible party must record it and make it available on request. The responsible party must also notify the data subject in writing within 30 days of the action taken in response to the request. Also see ZAF-4 for voluntary guidance on complying with the POPIA and 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.

See ZAF-4 for voluntary guidance on complying with the POPIA, and ZAF-28 for more background on information officers. 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 also be established 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.

Responsible Parties

For purposes of data protection requirements, the UK-GDPR the UK-DPAct, and the G-GDPR delineate the following responsible parties (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Controller – the natural or legal person, public authority, agency or other body which, alone or jointly with others, determines the purposes and means of the processing of personal data
• Processor – a natural or legal person, public authority, agency or other body which processes personal data on behalf of the controller
• Recipient – a natural or legal person, public authority, agency or another body, to which the personal data are disclosed, whether a third party or not; however, public authorities which may receive personal data in the framework of a particular inquiry in accordance with domestic law must not be regarded as recipients
• Third party – a natural or legal person, public authority, agency, or body other than the data subject, controller, processor and persons who, under the direct authority of the controller or processor, are authorized to process personal data

Per the UK-GDPR and the UK-DPAct, the data protection legislation requires 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.

Data Protection

Per the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, the controller must comply with the following principles of the data protection legislation:

• Lawfulness, fairness, and transparency
• Purpose limitation (See the DUAA for clarifications on purpose limitation and further processing)
• Data minimization
• Accuracy
• Storage limitation
• Integrity and confidentiality (security)
• Accountability

As stated in the UK-GDPR, the UK-DPAct, the G-GDPR, and GBR-89, it must be shown that each data processing activity has a lawful basis under United Kingdom (UK) 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 required 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. Per GDPR-Trspcy, to help ensure research participants have all the information they need to make an informed decision about the use of their data, sponsors are expected to use the Medicines and Healthcare Products Regulatory Agency (MHRA) template at GDPR-Trspcy, which includes information on:

• When the GDPR wording should be used
• If individual bespoke GDPR wording is used
• If the GDPR wording in open studies is updated
• Instructions for use
• The GDPR transparency wording for all sponsors
• Definitions
• Communicating GDPR information to children and young people

For international transfers of personal information, per the UK-GDPR, a controller or processor may transfer personal data to a third country or international organization only where the transfer is covered by adequacy regulations, is subject to appropriate safeguards, or relies on a derogation for a specific situation, and otherwise complies with the UK-GDPR and any applicable transfer restrictions. The GBR-138 contains guidance, templates, and other resources that are suitable for all types of organizations, and covers areas such as adequacy regulations, appropriate safeguards, completing a transfer risk assessment, using an exception, and receiving personal information from the European Economic Area.

As explained in the DUAA-Org, the DUAA amends, but does not replace, the UK-GDPR and the UK-DPAct. The DUAA-Sum contains a summary of clarifications on changes to data protection law from the DUAA amendments. DUAA-Cmmct brings many of the provisions of the DUAA into force, including those related to the definition of research, consent to processing for purposes of scientific research, and transfers of personal data to third countries. See GBR-136 and DUAA-Org for more details on the DUAA and what it means for organizations and research. See DUAA-Sum for additional clarifications on data protection, including safeguards and restrictions when using automated decision-making. In addition, GBR-100 contains additional templates to help sponsors comply with the UK-GDPR.

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 Health Research Authority (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.

Per GBR-100, children must be provided with the same information as adults regarding what will be done with their personal data, even if consent is sought from the parent/legal guardian. The UK-GDPR states that information provided to individuals should be in a concise, transparent, intelligible, and easily accessible form, using clear and plain language.

For variations among the UK countries regarding accessing identifiable data without consent, see information on the Confidentiality Advisory Group at the UKwide-Rsrch, CAG-Applcts, and GBR-38.

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 United States (US) 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 Data-US-UK, 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 Data-US-UK, GBR-22, and GBR-23 for additional information about the UK Extension to the Data Privacy Framework.

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-GCP, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27).

As per the SA-GCP 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-GCP 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 for 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-GCP, 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, 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-GCP, 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-GCP 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-GCP 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-GCP, the G-EthicsHR-ZAF, the G-GPHlthCare, and the G-GPHlthCare-IC, written informed consent must be obtained in all cases. 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-GCP 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 with regard 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.

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, which states that a person gives informed consent to take part in a clinical trial only if the decision is given freely after that person is informed of the nature, significance, implications, and risks of the trial.

Further, the MHCTR requires the following conditions to obtain consent from an adult able to consent or who has given consent prior to the onset of incapacity:

• The participant has had an interview with the investigator, or another member of the investigating team, in which there was an opportunity to understand the objectives, risks, and inconveniences of the trial and the conditions under which it is to be conducted
• The participant has been informed of the right to withdraw from the trial at any time
• The participant has given informed consent to take part in the trial
• The participant may, without being subject to any resulting detriment, withdraw from the clinical trial at any time by revoking informed consent
• The participant has been provided with a contact point where more information about the trial may be obtained

Regarding ethics committee (EC) review, the MHCTR stipulates that where the EC receives a valid request for approval, it must consider the measures used to seek and obtain informed consent for participation in the trial.

G-ConsentPIS states that the investigator(s) must provide detailed research study information to the participant or legal representative/guardian. The oral and written information concerning the trial 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. A signature on a consent form does not in itself make consent valid. A person’s agreement with each statement contained in the consent form can be indicated by initialing or ticking boxes, or by providing the answers ‘yes’ or ‘no’ after each statement. The form itself is then signed by the parties involved in the consent conversation. 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.) Testing the PIS with an appropriate group of people (patient groups or other members of the public) is strongly encouraged to ensure the language used is appropriate, the PIS format aids understanding, and the PIS covers risks and benefits that are relevant to potential participants. EC approval is not needed to test the PIS in this manner. For more guidance on the PIS, see the PrtInfoQty-Stds, the PrtInfo-DesignPrin, and GBR-14, which include frequently asked questions (FAQs), information principles, and standards. G-ConsentPIS provides PIS and consent form templates suitable for different types of research.

The MHCTR and MHCTR-Chgs further provide that the protocol may make provisions for simplified arrangements for obtaining and evidencing consent if the following conditions are met:

• The investigational medicinal product (IP) is authorized for use in the UK and is used in accordance with that authorization
• The IP is given to the participant during that participant’s routine health care
• The participant receives no additional medication and undergoes no additional intervention or diagnostic procedure, solely for the purposes of the clinical trial

As explained in the MHCTR-Chgs, if a sponsor is planning to use simplified arrangements, these will need to be detailed in the protocol including the reason for obtaining consent using simplified arrangements, the information to be provided to the participant, the means of providing that information, and the means by which consent shall be evidenced. These arrangements may include proportionate approaches to the information provided, the way consent discussions are undertaken, and how consent is evidenced, provided that consent remains informed, freely given, explicit, and prospectively obtained. Any such arrangements must be clearly described in the protocol and approved by an EC. See the MHCTR-Chgs for additional information.

Per the Cnst-Proprt, the Health Research Authority (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

For more guidance on obtaining consent, see GBR-69, GBR-18, and GBR-9.

Regarding consent in good clinical practice (GCP), the MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR.

Re-Consent

Per GBR-18, during a clinical trial if new information arises during a study that may affect participants' willingness to continue, they should be re-consented using updated, EC-approved documents.

Language Requirements

As stated in the MHCTR, applications to the EC and the MHRA and any accompanying material, such as the informed consent material, should be presented in English.

Documenting Consent

The MHCTR states that consent must be evidenced in writing, dated, and signed, or otherwise marked, by that person so as to indicate consent, or if the person is unable to sign or to mark a document, is communicated (whether by talking, using sign language or any other means) in the presence of at least one (1) witness and recorded in writing. As provided in the G-ConsentPIS, consent for clinical trials of investigational medicinal products (CTIMPs) must be in writing. Electronic methods for documenting consent, including the use of electronic signatures, are also considered to be 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

The MHCTR-Chgs states that consent must not be waived or presumed.

Based on the informed consent essential elements in the SA-GCP, 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.

As required in the MHCTR, informed consent is only valid if the person’s decision is given freely after being informed of the nature, significance, implications, and risks of the trial. The G-ConsentPIS specifies that the participant information sheet (PIS) should include the following:

• Title – Head the document “Patient information sheet,” “Participant information sheet,” or “Information about the research;” use a consistent study title across documents, understandable to the intended audience, and explaining the study in simple English
• Invitation – Make clear that potential participants are being invited to consider taking part and that participation is entirely voluntary; briefly explain how they were identified and why they were selected
• Summary of the research – Provide a short, clear summary explaining why the research is being done, what research question is being addressed, why it is relevant/important, what is being studied or tested, what participants will have to do, who is eligible, where the study will take place, and how long it will last
• Purpose and background – Explain the purpose of and background to the research, giving enough context for participants to understand why the study is being conducted
• What taking part involves – Describe what will happen to participants during and after the research study, including what they will have to do and what taking part will mean for them
• Research vs standard care – For studies involving therapeutic interventions, clearly explain which elements are research and which constitute standard care
• Alternatives to participation – Explain alternatives to taking part, especially in therapeutic trials involving patients
• Possible benefits – Describe the potential benefits participants might expect from taking part, where applicable
• Possible disadvantages, risks, inconveniences, or restrictions – Explain the potential risks, disadvantages, inconveniences, or restrictions participants might expect
• Treatment that may be withheld
• Participant responsibilities
• Results and study arm information – Explain when and how participants will find out the results of the study, and when/how it is planned to reveal which arm of the study they have been on, where applicable
• What if something goes wrong? – Explain what will happen if something goes wrong during the study
• Withdrawal from the study – Explain what will happen if the participant does not want to carry on with the study
• Confidentiality – Explain whether and how the participant’s information will be kept confidential
• Use and publication of results – Explain what will happen to the results of the study
• Organization and funding – State who is organizing and funding the study
• Patient and public involvement – Explain how patients and the public have been involved in the study
• Review/approval – State who has reviewed and approved the study
• Further information and contact details
• Version control of the information sheet
• Consent process – Explain the consent process, including how consent will be sought and documented

Next, G-ConsentPIS indicates that a consent form should be used to record the consent process and the participant’s agreement to take part in the study. The form should be on headed paper or equivalent, including where consent is recorded electronically, and include the following information:

• Study identifiers – Study title and IRAS ID; a study identification number may also be included
• Site/participant identifiers
• Multiple consent forms – Clear labels if using more than one (1) consent form, for example for different types of participants or different UK nations
• Content of form – Information should be appropriate for the type of study and the participants involved
• PIS acknowledgement – A statement confirming that the participant has read the PIS, including its date and version number, and has had the opportunity to consider the information, ask questions, and receive satisfactory answers
• Voluntary participation and withdrawal – A statement that participation is voluntary and that the participant is free to withdraw at any time without giving a reason, and without medical care or legal rights being affected
• Access to medical notes/data – A statement that relevant sections of medical notes and study data may be looked at by individuals from the company or regulatory authorities, and that the participant gives permission for access to those records
• Future research/data sharing – Where appropriate, a statement that information collected about the participant will be used to support other research in the future and may be shared anonymously with other researchers
• General practitioner notification – Where appropriate, include a statement that the participant agrees to their General Practitioner being informed of their participation
• Agreement to participate – Include a clear statement that the participant agrees to take part in the study
• Specific agreement for each item – Provide a box after each item for participants to initial, tick, or answer “yes” or “no” to indicate specific agreement with each statement
• Legal representatives – If consent forms are used by legal representatives, ensure the language addresses them appropriately and makes clear that they are being asked to give consent on behalf of, or advice with respect to, a child/young person or adult lacking capacity
• Itemizing specific elements – For some studies, consider itemizing specific elements of consent so participants can clearly indicate agreement to particular parts of the study

See the G-ConsentPIS for examples and templates on various scenarios. For more information about informed consent required elements, see Cnst-Proprt, GBR-18, GBR-100, and GBR-69.

Regarding consent in good clinical practice (GCP), the MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of GCP, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), among others. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR.

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 SA-GCP, the G-EthicsHR-ZAF, the G-GPHlthCare, the G-GPHlthCare-IC, the NHAParticipants, the Declaration of Helsinki (ZAF-44), 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 a right to information about any condition or disease from which they are suffering, and investigators must inform users of their health status (except where there is substantial evidence that disclosure would be contrary to the user’s best interests), the range of diagnostic procedures and treatment options generally available, the benefits, risks, costs and consequences generally associated with each option, and the user’s right to refuse health services and the implications, risks, and obligations of such refusal. (See the Required Elements section for a more detailed list of the ICF’s contents.

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-EthicsHR-ZAF and the G-GPHlthCare, participants have the right to privacy and confidentiality. The G-GPHlthCare states that the researcher must ensure that where personal information about research participants or a community is collected, stored, used, or destroyed, it is done in ways that respect the privacy or confidentiality of participants or the community and complies with any agreements made with the participants or the community.

The Right of Inquiry/Appeal

The SA-GCP indicates that potential participants must have the identity of the person(s) to contact for trial-related queries and injuries, the ethics committee’s contact details for information and concerns on the rights of trial participants, and the identity of the sponsor. The G-EthicsHR-ZAF also indicates that all research study-related information and consent documentation must include contact details for a participant to make a complaint about being a research participant.

The Right to Safety and Welfare

The SA-GCP 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.

Overview

Per the REC-Policy, the ethics committee (EC) helps to ensure that proposed research conforms to recognized ethical standards, which includes respecting the dignity, rights, safety, and well-being of the people who will take part. The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), which address the rights laid out in this section. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

In addition, the MHCTR requires that clinical trials must be conducted in accordance with the principles of the Declaration of Helsinki (GBR-81) except where it would be a contravention of the MHCTR.

The Right to Participate, Abstain, or Withdraw

As set forth in the MHCTR and the G-ConsentPIS, the participant 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 and the G-ConsentPIS, a potential research participant 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 UKannot-E6R3 and the UKannot-E8, confidentiality of information that could identify participants should be protected in accordance with the UK-GDPR, the UK-DPAct, and the G-GDPR.

The Right of Inquiry/Appeal

The MHCTR states that the research participant should be provided with contact information to obtain further information about the trial.

The Right to Safety and Welfare

The MHCTR requires the EC to ensure there are measures to protect and promote the interests of participants and the general public.

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 ZAF-40, 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 SAHPRA with the clinical trial application.

The MHCTR states that for minors or incapacitated adults who need urgent treatment, the usual informed consent requirements may not apply if urgent trial-related action is needed and it is not reasonably practicable to obtain consent first. Any such action must follow a procedure approved by the ethics committee (EC) when it gave its favorable opinion. As stated in the G-ConsentPIS and the Rsrch-Emrgcy, emergency research is when treatment needs to be given urgently, and it is necessary to take urgent action for the purposes of the study. In some emergency situations, potential participants may lack capacity to give consent themselves, and obtaining consent from a legal representative is not reasonably practicable. The United Kingdom (UK) allows adults and children not able to consent for themselves to be recruited into clinical trials of investigational medicinal products (CTIMPs) 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 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/guardian as soon as possible

The Rsrch-Emrgcy provides that adults may regain their capacity to give consent and should then be involved in the ongoing consent process. In most cases, it is appropriate to ask them to give their own consent when and if they are able. If investigators intend to ask participants who regain capacity for their ongoing consent, they should inform the legal representative/guardian of this at the outset of asking. In addition, an appropriate Participant Information Sheet and consent form should be prepared for the participants themselves.

Per the PubHlth-Emrgcy, in a public health emergency, fast-track approval is an option during exceptional circumstances (e.g., bird flu and Ebola). Fast-track ethics review is subject to the same scrutiny as other studies. Before an application can be made, the first step is to request fast-track approval by emailing Hra.approval@hra.nhs.uk with a summary of the study. See the Scope of Review section for more details.

The MHCTR requires that all clinical trials must be conducted in accordance with the conditions and principles of good clinical practice (GCP), including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) GCP, as amended from time to time. ICH-UKimp indicates that the UK is implementing the ICH’s Guideline for Good Clinical Practice E6(R3) (GBR-91) and the ICH’s General Considerations for Clinical Studies E8(R1) (GBR-104), which address the rights laid out in this section. As explained in the UKannot-ICH, the Medicines and Healthcare Products Regulatory Agency (MHRA) has issued UK-specific annotations—UKannot-E6R3 and UKannot-E8—which discuss consent requirements.

See the G-ConsentPIS for additional UK-nation specific guidance and GBR-18 for additional resources.

Overview

The NHA, the SA-GCP, 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-GCP state that ethics committees (ECs) must pay special attention to protecting participants from vulnerable populations. The ECs may impose additional measures such as requiring 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-GCP 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.

Overview

As per the MHCTR, 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 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 should 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