South African Health Products Regulatory Authority

As stated in the MRSA and ZAF-9, 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, the 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-GCPs, 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 Trial 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-GCPs 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.

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

As provided in the G-CTA-Electronic and ZAF-36, the following are the SAHPRA Clinical Trial 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 ZAF-47 for clinical evaluation and management contacts.

Clinical research in Tanzania is regulated and overseen by the Tanzania Medicines and Medical Devices Authority (TMDA) and the Tanzania Commission for Science and Technology (COSTECH).

Tanzania Medicines and Medical Devices Authority

As per the TMMDAct and TZA-4, the TMDA is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Tanzania. (Note: while the TMMDAct is formatted as a “Revised Draft,” it incorporates the final changes from 2019 that are codified in the FinanceAct.) The TMDA grants permission for clinical trials to be conducted in the country in accordance with the TMMDAct and the CT-Regs.

Per TZA-29, the TMDA is an executive agency under the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC). The TMDA is responsible for regulating the safety, quality, and effectiveness of medicines, medical devices, and diagnostics.

Per the TMMDAct, the agency has a Ministerial Advisory Board (MAB), which consists of:

• The MoHCDGEC Permanent Secretary who serves as Chairman
• Up to 12 Minister-appointed members
• The Director General who serves as Secretary to the board

In accordance with TZA-29, TMDA is responsible for the following regulatory processes:

• Regulating the manufacture, importation, distribution, and sale of medicines, medical devices, and diagnostics
• Prescribing standards of quality, safety, and effectiveness for medicines, medical devices, and diagnostics
• Inspecting manufacturing industries and business premises dealing with regulated products and ensuring the standards required are attained
• Evaluating and registering medicines, medical devices, and diagnostics so as to reach the required standards before marketing authorization
• Issuing business permits for premises dealing with regulated products
• Assessing the quality, safety, and efficacy of controlled drugs
• Conducting laboratory investigations for regulated products to ascertain their quality specifications
• Conducting pharmacovigilance of medical products and vigilance of medical devices and diagnostics circulating on the market
• Promoting rational use of medicines, medical devices, and diagnostics
• Educating and sharing accurate and reliable information to stakeholders and the general public on regulatory matters

As described in TZA-2, TMDA’s Clinical Trials Control and Pharmacovigilance (CTPV) section is under the Directorate of Human and Veterinary Medicines, and is responsible for the regulation of clinical trials, pharmacovigilance, and post-marketing surveillance. The regulation of clinical trials mainly includes authorization of clinical trials and good clinical practice (GCP) inspection of investigator sites. See the Scope of Assessment section for additional details.

The PV-Regs established the Pharmacovigilance Technical Committee, under the National Pharmacovigilance Centre of TMDA, to provide recommendations to the Director General on pharmacovigilance-related safety issues, including causality assessment of adverse drug reactions and adverse events. In addition, as stated in TZA-37, there is a TMDA Clinical Trials Technical Committee (CTTC), pursuant to the TMMDAct, that provides independent technical advice to the Director General. Members of the CTTC provide technical advice to assure that clinical trials are designed, conducted, analyzed, and reported in accordance with TMDA and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) guidelines. Members of the CTTC are required to be prudent, transparent, independent, and committed to their professional ethics while discussing all matters pertaining to clinical trials. The CTTC, which meets at least once quarterly, is composed of experts with knowledge and experience in at least the following fields:

• Clinical Trials
• Medical Research
• Clinical Pharmacology
• Clinical Epidemiology
• Medicine
• Dental Surgery
• Pharmacy
• Medical Statistics
• Public Health
• Toxicology
• Microbiology
• Pathology
• Regulatory Affairs

Other Considerations

Per TZA-9, Tanzania has adopted several clinical trial related guidelines of the International Council for Harmonisation (ICH) of Technical Requirements for Pharmaceuticals for Human Use including the ICH Guideline for Good Clinical Practice E6(R2) (TZA-13). See TZA-9 for a listing of the adopted guidelines.

Tanzania Commission for Science and Technology

According to TZA-45 and TZA-16, COSTECH is under the Ministry of Education, Science and Technology and is responsible for coordinating and promoting research and technology as the chief advisor to the government. Its principal roles and responsibilities include (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Preparing and reviewing national science, technology, and innovation programs, including dissemination and transfer of technology
• Monitoring and coordinating the activities relating to scientific research, technology development, and innovation of all persons or body concerned with such activities
• Acquiring, storing, and disseminating scientific and technical information
• Registering scientific research institutions operating in Tanzania
• Advising the government on matters such as priority areas for scientific research; the allocation and use of research and innovation funds; regional and international cooperation in scientific research, innovation, and technology development and transfer; and matters relating to the training and recruitment of research personnel
• Defining national resource priorities and research guidelines
• Communicating research results
• Providing technical support to institutions related to ethics and monitoring implementation of research and innovative activities

Per the G-ResearchClearance and TZA-47, the COSTECH must review, approve, and issue permits for all research in Tanzania. The G-ResearchClearance specifies that COSTECH, through its National Research Clearance Committee (NRCC), receives and reviews research proposals for their scientific merit, safety, and ethics. Upon approval, NRCC issues research permits. (Note that TZA-47 refers to it as the National Research Registration Committee.)

Contact Information

Tanzania Medicines and Medical Devices Authority

Tanzania Commission for Science and Technology

According to TZA-46 and TZA-47, COSTECH’s contact information is as follows:

Tanzania Commission for Science and Technology
Ali Hassan Mwinyi Road, Kijitonyama (Sayansi) COSTECH Building
Dar es Salaam, Tanzania

Email: info@costech.or.tz
Research Clearance Email: rclearance@costech.or.tz

Overview

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

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

Clinical Trial Review Process

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

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

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

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

Other Considerations

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

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

Overview

As indicated in the TMMDAct and the CT-Regs, the Tanzania Medicines and Medical Devices Authority (TMDA) is responsible for reviewing, evaluating, and approving clinical trial applications in Tanzania. The scope of the TMDA’s assessment includes all clinical trials (Phases I-IV). As delineated in the TMMDAct, the CT-Regs, and the G-AppConductCT, the TMDA’s approval of a clinical trial application is dependent upon obtaining proof of national ethics committee (EC) approval from the National Health Research Ethics Committee (NatHREC). According to the G-AppConductCT and TZA-4, the TMDA and national EC reviews may be conducted in parallel. However, the TMDA application must include a copy of the national EC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once national EC approval is obtained.

As described in TZA-2, TMDA’s Clinical Trials Control and Pharmacovigilance (CTPV) section is responsible for the regulation of clinical trials, pharmacovigilance, and post-marketing surveillance. Its functions include the following:

• Review and assess applications to conduct clinical trials in Tanzania, including evaluating clinical trial protocols, including preclinical studies, clinical data, and quality of investigational products (IPs)
• Approve clinical trial applications with minimum requirements
• Inspect clinical trial sites to ensure compliance with good clinical practices (GCPs), good clinical laboratory practices (GCLPs), clinical trials regulations, guidelines, standard operating procedures (SOPs), and internationally accepted standards
• Update and maintain the Tanzania Clinical Trials Registry, which is accessed via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34)
• Review and evaluate all safety information (adverse events) from clinical trials
• Review and evaluate progress reports of all approved clinical trials
• Serve as Secretariat to Tanzania’s Clinical Trials Technical Committee
• Monitor and respond to all inquiries regarding conduct of clinical trials in Tanzania

Per the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) must review and approve all research in Tanzania to:

• Ensure research conduct complies with national laws and regulations
• Document and register research
• Secure research results and promote its use in policy and practice
• Safeguard the dignity, rights, safety, and well-being of research participants
• Reduce systemic risks imposed through the research
• Provide research permits

Clinical Trial Review Process

Tanzania Medicines and Medical Devices Authority

As set forth in the TMMDAct, the CT-Regs, and G-AppConductCT, the TMDA coordinates the clinical trial application process. Upon receipt of a clinical trial application, the TMDA initially screens the application for completeness. If complete, the TMDA officer acknowledges receipt of the application by returning a signed copy of the cover sheet to the applicant (see Annex 1 of the G-AppConductCT). The TMMDAct states that the TMDA Director General must issue a Clinical Trial Certificate to authorize the trial to be conducted. (See the Submission Content section for submission requirements.) TZA-4 indicates that the TMDA may request a clarification or additional documents through the online submission system (TZA-34). The assessment will resume once the applicant has provided clarification and responded to the queries.

Per the G-AppConductCT, the TMDA reviews clinical trial applications and amendments to assess the quality of the products and determine that the use of the IP for the purposes of the clinical trial does not endanger the health of participants or other persons, the clinical trial is not contrary to the best interests of a participant, and the objectives of the clinical trial may be achieved. Evaluation of applications is conducted on a first-in, first-out basis unless the IP meets the fast-track criteria. The application assessment must involve the TMDA and external evaluators. If the TMDA requests additional information from the applicant, the evaluation process will stop until the TMDA receives a written response to the query. The response should be submitted within six (6) months after being issued with a query letter. All queries issued in the same letter must be submitted together in one (1) transaction. Non-compliance to these requirements in content and format will lead to rejection of the clinical trial. Evaluation of applications will be completed within 60 working days of receiving the application. A new clinical trial application may be fast tracked and assessed within 30 working days of its submission if the applicant has requested this and paid twice the prescribed clinical trials application fees.

Per the G-AppConductCT, the clinical trials certification will be valid up to the proposed duration of the study indicated in the application. However, the validity will not extend beyond five (5) years. If the trial will last more than five (5) years, the applicant must request an extension. Further, the TMDA must approve amendments to a previously authorized protocol for changes that affect participant selection and monitoring; changes that affect clinical efficacy and safety requirements; changes that affect participant discontinuation; addition/deletion of an investigational site(s); changes that result in the extension of trial duration; and/or changes that relate to the chemistry and manufacturing information that may affect drug safety and quality. An application for amendment(s) must be accompanied by clearance or authorization from NatHREC.

The G-AppConductCT indicates that the TMDA must not authorize a clinical trial where it finds that:

• The information and documents as set out in the guidelines have not been provided
• The application contains false or misleading information
• The information provided is insufficient to enable the TMDA to assess the safety and risks of the IP or clinical trial
• Queries raised by the TMDA in relation to the application were not adequately responded to
• The applicant has not submitted an ethical clearance from any approved medical research institute
• The use of the IP for the purposes of the clinical trial endangers the health of a clinical trial participant or any other person
• The objectives of the clinical trial will not be achieved
• It is not in the public interest to authorize the clinical trial
• Any other reasonable grounds as may be determined by the TMDA

Next, the G-AppConductCT states that following the TMDA’s authorization of a new clinical trial or amendment, information regarding refusals by other regulatory authorities or ECs should be submitted as a notification. Further, the TMDA may suspend, terminate, or withdraw authorization of a clinical trial if it finds that the conditions of authorization of a trial have been violated; or there is information raising doubts about the safety or scientific validity of the trial or the conduct of the trial at a particular trial site. For additional information, see TZA-4.

(See the Submission Process section for additional details on the clinical trial application and amendments submissions.)

Tanzania Commission for Science and Technology

As for COSTECH review, the G-ResearchClearance indicates that once COSTECH receives a new application, the Secretariat screens the application for completeness; registers the application; sends an acknowledgement to the applicant; submits the application for the appropriate expert, local, and National Research Clearance Committee (NRCC) review; records NRCC’s final decision; and informs the applicant of the decision. COSTECH’s NRCC must reach a decision through a consensus of members forming a quorum at their meeting. The decision may be approval without amendments, approval subject to minor or major amendments, a denial, or a postponement pending further information. If approved, researchers should collect their permit within 90 days after the decision is communicated, and failure to do so requires a new application.

Per the G-ResearchClearance, permits are valid for one (1) year, and can be renewed, provided that COSTECH receives satisfactory progress reports for the previous periods. COSTECH must review the research to ensure compliance with the approved permit and see if any material changes have occurred in the research or if there are findings that may cause termination. The PI must write to COSTECH two (2) months before the expiration date to request a renewal of the permit. For renewals, COSTECH will submit the registered application to an internal reviewer for evaluation, and otherwise, follow the same review and notification procedures as outlined above for a new permit. Regarding applications for amendments, if there is a change in PI, the affiliate institution must notify COSTECH within one (1) month of the departure of the outgoing PI in writing with an accompanying progress report. If a new researcher joins an ongoing project, the PI must submit a request for a research permit for the new member to COSTECH at least two (2) months prior to joining the team, accompanied with a detailed CV and rationale. Changes to the study site, objectives, and methodologies for an ongoing research project must be submitted in writing to COSTECH at least two (2) months prior to implementing the change.

See TZA-47 for additional information about national research registration.

South African Health Products Regulatory Authority

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

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

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

For amendments to clinical trials:

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

For licenses:

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

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

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

Payment Instructions

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

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

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

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

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

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

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

Tanzania Medicines and Medical Devices Authority

As per the G-AppConductCT and the TMMDAFees, applicants are responsible for paying a processing fee to submit a clinical trial application. The TMMDAFees indicates that the Tanzania Medicines and Medical Devices Authority (TMDA) levies the following processing fees:

• $3,000 USD for submitting a clinical trial application

• Double the cost of registration and analysis fee for fast-track clinical trial applications

• $500 USD for amendments for major changes in clinical trials

• $300 USD for amendments for minor changes in clinical trials

See the TMMDAFees for a complete list of TMDA fees and charges.

Payment Instructions

The G-AppConductCT states that the fee must be paid to the order of the TMDA directly to the bank by draft electronic transfer through the following accounts:

Foreign applicants: Account Numbers 100380013 Citibank (T) and 02J1021399100 CRDB
Local applicants: Account Number 2041100069 NMB

Applicants are responsible for all bank charges when payment is made by bank transfer. In addition, applicants must include a note with payment details, including the applicant’s name, the product(s) paid for, and the amount of fees paid.

TZA-4 indicates that the banks accounts are linked to Government Electronic Payment Gateway (GEPG) payments as follows:

• Name: GEPG TMDA Collection Account (USD), Bank: NMB Revenue Bank, Account No: 20810015291, Branch University
• Name: GEPG TMDA Collection Account (USD), Bank: NBC USD, Account No: 040105002468, Branch: UDSM
• Name: GEPG TMDA Collection Account (USD), Bank: CRDB Bank US, Account No: 0250021399100, Branch: Holland House

Tanzania Commission for Science and Technology

As delineated in the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) charges an application fee of $50 USD to review and register a research proposal. The principal investigator (PI) should pay the nonrefundable research application fee, which is paid per project. Before the permit is issued, COSTECH requires foreign researchers to pay a research permit fee of $300 USD.

Payment Instructions

Per the G-ResearchClearance and TZA-47, foreign researchers can pay the research permit fee via the following bank account:

Account name or beneficiary: Tanzania Commission for Science and Technology

Bank Name: National Bank of Commerce Ltd
Branch: Samora Avenue, P.O. Box 9002, Dar es Salaam, Tanzania
Account Number: 012105018998
Account Currency: US Dollars
Swift Number/Code: NLCBTZTX

According TZA-47, in-country applicants can pay the fee with a control number (payment bill), which will be used for a deposit. A control number for payment can be obtained through an email request to COSTECH at rclearance@costech.or.tz.

Overview

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

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

Ethics Committee Composition

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

Overview

As indicated in the G-AppConductCT, all clinical trials require national ethics committee (EC) approval for each trial site. Per the G-TMRCC and TZA-50, the national EC in Tanzania is the National Health Research Ethics Committee (NatHREC), which focuses on the ethical issues surrounding submitted research proposals. As delineated in the G-TMRCC, NatHREC-Charter, TZA-5, and TZA-18, NatHREC is a subcommittee of the Medical Research Coordination Committee (MRCC), which serves as the national health research coordinating body, and is responsible for supervising, controlling, coordinating, evaluating, and promoting health research in Tanzania or elsewhere on behalf of or for the benefit of Tanzania. The MRCC, which is part of the National Institute for Medical Research (NIMR), delegates the registration, review, approval, and monitoring of clinical research to the NatHREC.

As delineated in NatHREC-Charter, NatHREC provides ethical review and clearance of health research protocols and monitors and evaluates research studies. In addition, NatHREC conducts the following activities:

• Receiving and registering all health research carried out in Tanzania
• Ensuring that all health research protocols are thoroughly reviewed to safeguard the dignity, rights, safety, and well-being of research participants
• Advising researchers on the risks and responsibilities of conducting research
• Recommending to the MRCC for ethics clearance approval, all health research protocols that have complied with the country’s ethics regulations and guidelines
• Monitoring and coordinating all approved health research conducted in Tanzania
• Advocating for and overseeing all issues pertaining to health research data and material sharing and/or transfer
• Supporting health research institutions in Tanzania to establish institutional ECs or Institutional Review Boards (IRBs)
• Accrediting health research institutions’ ECs

Per the G-AppConductCT, G-EthicsHR-TZA, the G-ResearchIntegrity, the G-RevPrtcl, TZA-18, TZA-5, and TZA-1, proposed health research in Tanzania must also get institutional EC approval at the host institution where the research will be based. If there is no institutional EC, approval must still be obtained from the NatHREC. For all health research involving foreign collaborators, the applicant must get both the institutional EC and NatHREC’s ethical approval. TZA-5 states that both institutional ECs and NatHREC review and approval are also required for clinical trials, research dealing with vulnerable, special, or marginalized groups, sensitive topics, or indigenous communities. The NatHREC-Charter indicates that institutional and zonal ECs complement NatHREC’s function of issuing institutional ethics clearance certificates and monitoring the approved research at their institutions. According to TZA-18, not all human participant research requires review and approval at the national level, and consequently, institutional ethics review is complementary to NatHREC’s national-level review.

The G-EthicsHR-TZA further states that institutional ECs should monitor their hosted research activities to ensure compliance. Institutional ECs may function at the institutional, zonal, or national levels. ECs act as independent reviewers of any proposed study on human research participants, to ensure ethical conduct of research, and that participant’s rights and welfare are not violated. The major responsibility of ECs is to safeguard the rights, safety, and well-being of research participants. See the Oversight of Ethics Committees section for information on the registration and accreditation of ECs by NatHREC.

Ethics Committee Composition

National Health Research Ethics Committee

Per the G-EthicsHR-TZA and TZA-5, the Director General of NIMR is responsible for appointing NatHREC members. Members are selected based on their capacity, interest, ethical and scientific knowledge, and expertise, as well as their commitment and willingness to volunteer the necessary time and effort for the NatHREC’s work. NatHREC must consist of not less than nine (9) and up to 15 members with the relevant qualifications and experience to review and evaluate the science, medical, and ethical aspects of health research protocols. In addition, NatHREC must be composed of members with varying backgrounds to promote a complete and adequate review of health research protocols commonly received by the NatHREC. Per TZA-5, committee members must include medical scientists, biomedical scientists, social scientists, legal representatives, unaffiliated community representatives, representatives of religious or faith-based organizations, a representative from the President’s Office-Regional Administration and Local Government (PO-RALG), and a representative from the Tanzania Ministry of Health. The Director General may appoint additional members depending on the need for expertise and/or representation and not exceeding the maximum number of members. See TZA-5 for additional information on NatHREC’s standard operating procedures (SOPs).

Per the G-TMRCC, the NatHREC is represented by the following organizations:

• NIMR
• Tanzania Commission for Science and Technology (COSTECH)
• Muhimbili University of Health and Allied Sciences (MUHAS)) (formerly known as Muhimbili University College of Health Science (MUCHS))
• Christian Social Services Commission (CSSC)
• The National Muslim Council of Tanzania (BAKWATA)
• Economic and Social Research Foundation (ESRF)
• Tanzania Gender Networking Programme (TGNP)
• Legal and Human Rights Centre (LHRC)
• University of Dar es Salaam (UDSM)
• Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC)
• Ministry of Education (MoE)

Institutional Ethics Committees

As per the G-EthicsHR-TZA, institutional ECs must have members capable of providing a competent and thorough review of research protocols. Membership typically includes physicians, scientists, laboratory experts, nurses, lawyers, ethicists, and other professionals. In addition, the above membership also includes community members or representatives of patients’ groups who can represent the cultural and moral values of study participants. When a proposed study involves vulnerable individuals or groups, as may be the case in research involving prisoners or illiterate persons, representatives of relevant advocacy groups should be invited to meetings where such protocols will be reviewed. Regular rotation of members is desirable for balancing the advantage of experience with that of fresh perspectives. In addition, each institutional EC must include at least one (1) member who is not affiliated with the institution and is not part of the immediate family of a person who is affiliated with the institution. Further, an EC may invite individuals with competence in particular areas to assist in the review of issues, which require expertise beyond, or in addition to that available in the EC; these individuals do not vote with the EC.

Per IERC-Accredit, following are the membership requirements for ECs accredited with NIMR:

• The Chairperson must have adequate experience in health research, leadership, and have basic knowledge of bioethics
• An EC must comprise at least five (5) members or more, and the total must be an odd number
• At least one-third of the members of the EC must be of either gender
• At least one (1) member should come from outside the institution
• At least two (2) members should have research expertise and experience, and one (1) of these should be in the health field
• At least one (1) member should represent a lay group
• For ECs reviewing clinical research, the committee should have representation from medicine, laboratory, pharmacy, and nursing as needed; a clinician who is active in clinical practice (with a valid practicing license) or in clinical research is mandatory
• At least one (1) member of the EC should possess knowledge and understanding of Tanzanian law
• Where an EC has been formed to serve more than one (1) institution, the institution hosting the Secretariat is responsible for the functioning of the EC in all aspects
• Where multiple institutions are involved in one (1) EC, the appointing authority must make appointments in consultation with the relevant heads of the respective institutions

The G-ResearchIntegrity recommends that composition should not only be multi-disciplinary and multi-sector but should also balance scientific expertise, age, and gender distribution, and should have a non-technical member representing community interests. The institution should determine the type of members needed and establish procedures for selecting/appointing members and number of persons. It is recommended that ECs have seven (7) to 15 members. See the G-ResearchIntegrity and TZA-23 for additional recommendations.

Terms of Reference, Review Procedures, and Meeting Schedule

National Health Research Ethics Committee

The G-TMRCC and TZA-5 state that the NatHREC must operate within written standard operating procedures (SOPs), including a process to be followed for conducting reviews. The G-TMRCC states that the SOPs should include information on NatHREC composition, meeting schedules, frequency of reviews, requirements for initial and ongoing evaluation of the research study, and requirements for notifying the investigator and the institution of results related to the study’s initial and ongoing evaluation. Committee members should agree to disclose their names, occupations, and affiliations, and to sign the confidentiality and conflict of interest agreements. Per TZA-5, the SOPs facilitate and support ethical review by improving the standard and uniformity of decision-making and assuring and gaining the confidence of the public in the NatHREC. Membership must be for three (3) years, renewable once, under the discretion of the MRCC Chairperson. A member of the NatHREC may resign by submitting an official letter of resignation to the MRCC Chairperson. A member of the NatHREC may also be disqualified from membership should the appointing authority provide adequate written reasons to the NatHREC and there is unanimous agreement. The NatHREC must request a replacement of any member when there is protracted illness that prevents the member from participating; persistent absenteeism or missing three (3) consecutive committee meetings; voluntary withdrawal or resignation; and/or ethical misconduct.

According to TZA-5, the NatHREC Secretary oversees the daily operations of the Secretariat and arranges training and educational programs to new and continuing committee members and the scientific community on health research ethics. The training must include programs about the basic principles of human participant protection, current literature, and regulations and guidelines affecting the committee and NIMR. Further, the Secretary assists in recruiting new committee members, as well as preparing and submitting an annual committee operational budget and plan to NIMR in consultation with the Chair. See TZA-5 for details on the functions of the NatHREC Secretariat.

Per TZA-5, NatHREC members must fulfill the following responsibilities:

• Review, discuss, and consider health research protocols submitted for ethical clearance evaluation
• Review research study progress reports and monitor on-going studies as appropriate
• Review reports on adverse events, serious adverse events, and/or suspected unexpected serious adverse reactions, as well as any other safety reports and recommend appropriate actions
• Maintain professional confidentiality of documents and deliberations of the committee review proceedings and meetings
• Declare conflicts of interest when they exist
• Participate in continuing education activities in biomedical ethics and research
• Undertake committee duties assigned to them by the NatHREC Chairperson
• Attend NatHREC meetings regularly and participate actively during deliberations
• Participate in the review of NatHREC SOPs
• Conduct research site monitoring visits as deemed necessary

According to TZA-5, the NatHREC must convene at least once a month with a quorum of at least half the number of committee members. The NatHREC Secretary, with support from the Secretariat, must prepare an annual almanac of meetings. The meeting package must include the agenda; all research protocols; and all related materials including, but not limited to, copies of the protocols, informed consent materials, continuing and final reviews, and safety reports. The Secretariat must keep a record of attendance as well as meeting deliberations, indicating which members were present and the discussions of review applications. If members have reviewed a protocol and identified issues that require the principal investigator (PI) to be present during the meeting for further deliberations, then the PI of that research protocol may be invited to answer questions or clarify issues. The meeting members must reach decisions by a consensus; however, if a consensus cannot be achieved, a formal vote must be taken. All members have the right to vote. The committee must provide formal recommendations to the MRCC on the approval of applications, along with minutes that include protocol title and date of review, a checklist of documents reviewed, and a decision reached by the committee, whether approved, approved with stipulation, recommended for resubmission after revision, or not recommended with reasons. For detailed NatHREC procedures and information, see TZA-5.

Institutional Ethics Committees

Per the G-EthicsHR-TZA, the EC members are appointed by institutional appointing authorities. The EC must be constituted according to a document that specifies the manner in which members and the Chair will be appointed, reappointed, and replaced. EC members must regularly update their knowledge about the ethical conduct of health-related research. If committees do not have the relevant expertise to adequately review a specific protocol, they must consult external persons with the required skills or certification. Each EC member must undergo at least one (1) basic training in research ethics within one (1) year of appointment and, thereafter, should undergo continued ethics training at least once every two (2) years. Members of an EC must serve for a term of three (3) years. EC members must guard against any tendencies of unethical conduct on their part. For example, they must protect the confidentiality of research projects, documents, and discussions; an EC member must not appropriate the submitted protocol for their own use; and they must not compel investigators to submit to an unnecessary repetition of review.

In addition, as delineated in the G-EthicsHR-TZA, ECs are responsible for determining whether the research objectives are responsive to the health needs and priorities of the proposed study population, particularly in Tanzania. The ability to judge the ethical acceptability of various aspects of a research protocol requires a thorough understanding of a community’s customs and traditions. For example, the EC should include members that are able to indicate suitable community members to serve as intermediaries between investigators and research participants and to advise on whether material benefits or inducements may be regarded as appropriate considering a community’s gift exchange and other customs and traditions. ECs must have mechanisms to ensure the independence of their operations. They must avoid undue influence and minimize and manage conflicts of interest. ECs must require that their members disclose to the committee any interests that could constitute a conflict of interest or otherwise bias their evaluation of a research protocol. ECs must evaluate each study considering any disclosed interests and ensure appropriate steps are taken to mitigate possible conflicts of interest. ECs may receive a fee for reviewing protocols, and this need not constitute a conflict of interest.

As required in the G-EthicsHR-TZA, ECs should hold meetings as frequently as possible to facilitate timely ethical clearance. ECs must review proposed research at convened meetings where at least 50 percent of the members are present, including at least one (1) member who represents the interests of the community. The Chairperson may be given powers to approve minor matters on behalf of the EC but ensure that the papers are made available to the rest of the EC members at the next meeting. ECs should have the power to co-opt professional or lay members where necessary. For a research protocol to be approved, it must receive the approval of a simple majority of those members present at the meeting; the only exception to the simple majority requirement is in the case of expedited review. 

Regarding documentation, per the G-EthicsHR-TZA, the institution must ensure that the EC prepares and maintains adequate documentation and retain the records for at least five (5) years after the completion of the study. All records must be accessible for inspection and copying by authorized representatives, including the following:

• Detailed written procedures for the EC
• Copies of all research protocols reviewed, scientific evaluations that accompany the protocols, approved sample consent documents, progress reports submitted by the investigator(s), reports of injuries to research participants, etc.
• Minutes of EC Meetings that must be in sufficient detail to show attendance at the meetings; actions taken by the IRB; the vote on these actions, including the number of members voting for, against, and abstaining; the basis for requiring changes in or disapproving research; and a written summary of the discussion of controversial issues and their resolution
• Records of continuing review activities
• Copies of all correspondence between the EC and investigator(s)
• Statements of significant new findings that were provided to research participants

Per the G-ResearchIntegrity, institutions should have clear documentation of candidacy requirements and procedures for identifying or recruiting EC members. The recruitment methods, duration of membership, terms of service, qualifications, disqualifications, resignation procedures, re-appointment/renewal, and other duties and responsibilities should be documented in EC SOPs. Appointment of EC members must be done at the institutional managerial level in consultation with experts, relevant boards, and peer institutions. Institutions should minimize conflicts of interest and establish mechanisms for maximizing transparency and confidentiality of review processes. These qualities may be enhanced by rotation and turnaround of members to allow inflow of new ideas and accountability. The conditions of appointment must clearly indicate the decision on whether to release professional profiles to the public, level of accessibility, members’ cost recovery ceilings for EC-related activities, confidentiality, and any other mechanisms geared to enhancing confidence over the EC’s operations. The pros and cons of each option must be carefully considered and communicated to candidates. Both scientific and support staff must sign a confidentiality agreement and declare any conflicts of interest from the outset.

Overview

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

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

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

Role in Clinical Trial Approval Process

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

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

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

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

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

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

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

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

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

Overview

According to the G-TMRCC and the G-EthicsHR-TZA, the primary scope of information assessed by the National Health Research Ethics Committee (NatHREC) and the institutional ethics committees (ECs) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in health research studies. The NatHREC and the institutional ECs must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations).The NatHREC is responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. TZA-5 states that the NatHREC must function in accordance with national and international standards and guidelines on health research, and guided specifically by the ethical principles expressed in the Declaration of Helsinki (TZA-30), international ethical guidelines such as the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), and the G-EthicsHR-TZA.

As indicated in the G-ResearchIntegrity, institutional ECs review, approve, and recommend for approval, research proposals that have met scientific merit, ethical, and professional standards. The institutional ECs are expected to provide recommendations on proposals that would need approval from a nationally overseeing ethics body where available. Per the G-EthicsHR-TZA, institutional ECs act as independent reviewers of any proposed study on human research participants to ensure ethical conduct of research and that participant’s rights and welfare are not violated. The major responsibility of institutional ECs is to safeguard the rights, safety, and well-being of research participants. In addition, it is essential that they review the scientific soundness of the research protocols, which involves a proper scientific review to verify that a competent expert body has determined the research to be scientifically sound, or consult with qualified experts to ensure that the research design and methods are appropriate. If the EC does not have expertise to judge science or feasibility, they must draw on relevant expertise. See G-EthicsHR-TZA for more information on the scientific review.

Role in Clinical Trial Approval Process

National Health Research Ethics Committee

As per the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) and the NatHREC must approve a clinical trial application prior to the sponsor, the contract research organization (CRO), or the principal investigator (PI) initiating the clinical trial. According to the G-AppConductCT and TZA-4, the TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of the national EC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once national EC approval is obtained.

As described in TZA-31, the NatHREC’s ethics review is managed through its Research Ethics Information Management System (REIMS) (TZA-32), an online web application for the submission of research protocols for NatHREC’s review, validation of protocols per NatHREC checklist (TZA-1), online review of proposals, and application status tracking. The G-RevPrtcl indicates that the NatHREC Secretariat will validate submissions for completeness upon receipt in REIMS. The G-RevPrtcl recommends the following review sequence after the materials are checked for completeness: write comments in an MS Word document; read the PI’s cover letter, the institution’s commitment letter, and other supporting letters; review the abstract/summary; review the application form, protocol, and appendices; and synthesize and submit comments online through REIMS (TZA-32). Per TZA-5, following successful validation of an application to the REIMS, the system generates a unique protocol number/identifier; this unique identifier must be used in reference to all communications to the PI or applicant regarding the application. Depending on the research area of the submitted protocols, at least two (2) primary reviewers must be assigned to review a new protocol by the NatHREC Secretariat. Comments from reviewers will reach the PI within two (2) days, depending on the type of study protocol. If the applicant fails to respond to the comments within 30 days, the NatHREC Secretariat must notify the PI of its intent to remove the protocol from the REIMS. Once the research protocol is removed from the REIMS, the PI must re-apply for ethical clearance and pay the application fee. For clinical trial applications, reviewers’ comments and the outcome of the NatHREC meeting must be forwarded to the PI within 30 days from the date of acceptance by the NatHREC. If the research protocol is cleared and the ethical clearance certificate is issued, the PI must receive it through mail to the institution’s postal address. Additionally, the PI may be able to download the soft copy of the ethical clearance certificate from the REIMS account. A PI may appeal a decision in writing to the Medical Research Coordination Committee (MRCC) Chairperson within 30 days of receipt of the decision, stating the precise issues upon which the appeal is based. The MRCC will respond to PIs in writing within 30 days or upon scrutiny of the appeal. The MRCC Chairperson may invite the PI to appear in person to the MRCC within 30 days of receiving the written appeal.

Expedited Review

TZA-5 delineates the categories of research that qualify for NatHREC expedited review:

• Research activities that present no more than minimal risk to human participants
• Minor changes (modification or amendment) to a previously approved research proposal
• Studies that involve interviews of a non-confidential nature and not likely to harm the status or interest of study participants
• Studies that involve collection of small amounts of biological specimens by non-invasive means (e.g., body fluids, excreta, hair or nail in non-disfiguring or threatening manner) for local analysis and no transfer of specimens outside of Tanzania
• Collection of data for research purposes through non-invasive procedures (not involving general anesthesia or sedation), routinely employed in clinical practices and using medical devices which have been already approved for use
• Research involving data, documents, or specimens that have been already collected or will be collected for on-going medical treatment or diagnosis
• Continuing review of certain research previously approved by the NatHREC
• Research that aligns with disease outbreaks or public health emergencies

TZA-5 states that expedited review must be conducted by two (2) or more experienced reviewers designated by the Secretariat. The expedited review must include a review of the complete study protocol with all required attachments. Results of the review process may be communicated to the PI even before being reported to the NatHREC. Expedited reviewers may exercise all the authorities of the committee except that the NatHREC reviewers may not disapprove of the research. Any research activity may be disapproved only after reviewing the protocol in accordance with the non-expedited procedure. Approval for expedited protocols is given by the MRCC through the Chairperson upon recommendation for approval from the reviewers. Once expedited approval has been granted, the protocol may be implemented as approved. Clinical trials with investigational products (IP) are not eligible for expedited review but may be considered for accelerated review. The final decision for a protocol to undergo an expedited review is determined by the NatHREC Chairperson, the NatHREC Secretariat, and/or the MRCC Chairperson, as needed. The Secretariat must notify the NatHREC of all expedited reviews at the next scheduled meeting through a listing in the meeting agenda.

Reviews During Public Health Events

Per TZA-5, rapid review of public health research and clinical trials may be implemented during public health events of national and/or international concern. During public health emergencies, the declaration will come from the public health authority of the country or an internationally recognized organization responsible for international public health. To expedite commencement of the research, many of the preliminary research processes (drafting of documents, translations, approvals) will be allowed to happen in parallel. Protocols should be sent to reviewers within 24 hours of submission by the Secretariat, and reviewers should complete their reviews within three (3) days. The consolidated review and suggested revisions (or approval) should be communicated to the PI(s) within five (5) days. The PI should respond to the review notification within 48 hours. See TZA-5 for additional details on the emergency review requirements.

Approval Duration

Regarding duration of the NatHREC approval, per TZA-5, the NatHREC Secretariat determines how often the committee must re-evaluate the research study, appropriate to the degree of risk, but not less than once per year. Studies whose approval has expired must be suspended until an extension through a renewal process is approved. The PI must submit an electronic continuing review report through REIMS with a frequency as indicated in the terms and conditions of the ethics clearance certificate. The NatHREC Secretary must place the continuing review report on the next meeting’s agenda for review. The NatHREC may provide directives or guidance to the study following review that will be communicated to the PI. In addition, the committee may recommend that the research study is halted.

Protocol Amendments

Per TZA-5, the NatHREC recognizes certain protocol amendments as minor/insubstantial or major/substantial; see TZA-5 for examples of each type. Amendments made to protocols may not be implemented until approved by the NatHREC. Upon receipt of the amendment package, the Secretariat must follow the receiving and validation procedures of submitted protocols. After review of the amendment submission, the Secretariat must determine whether the protocol requires expedited or full review. The amended protocol will be sent to the reviewers of the original submission; in absence of the original reviewers, the Secretariat must appoint and send the amendment application to another reviewer with the same or similar expertise. The number of reviewers will range from one (1) to three (3), depending on the number of the amendments. Minor amendments may be reviewed by members of the Secretariat. If the committee requires modifications to any of the documents, specific changes required must be communicated to the PI with instructions to make the necessary changes and resubmit the documents to the Secretariat. If the committee does not recommend approval of the protocol amendment, this information will be communicated to the MRCC who will review the decision and make the final decision on the approval. If an application is not approved, the PI must be informed of the reasons for not approving the amendment.

Institutional Ethics Committees

Per the G-EthicsHR-TZA, ordinary review is the institution’s normal process for reviewing minimal or more than minimal risk studies. For research that is externally sponsored, the ethical standards should not be less stringent than they would be for research carried out in the country of the sponsoring organization. Local ECs must be fully empowered to disapprove a study they believe is unethical. An EC must require that information given to research participants as part of informed consent complies with the general requirements for informed consent. However, the EC may require that more information be given to the research participants, provided such additional information would meaningfully add to the protection of the rights and the welfare of the research participants. An EC must generally require documentation of the informed consent process. For certain types of research, however, the EC may need the investigator to administer a comprehension test (or test of understanding) to ensure that prospective research participants have acquired adequate knowledge of the relevant facts and consequences of participation in the study. Within 14 days of its review, the EC must notify investigators in writing of the outcome of the research protocol review. If an EC does not approve a research activity, it must include in its written notification a statement of the reasons for its decision.

The G-ResearchIntegrity states that ECs must review protocols in accordance with their standard operating procedures (SOPs) and in a timely and professional manner. Names, titles, and institutional affiliation of reviewers for each proposal will be kept confidential. The decision should be communicated to the investigators in a written letter that is signed or stamped by the EC chair. The letter should include the research/study title as written in the application, the name of the applicant, research site, draft number, date submitted, name and date of EC sitting for that proposal, suggested changes, and a clear statement of final decision by EC. The investigators must notify the EC of protocol amendments, unforeseen circumstances affecting the study, termination of the study, progress reporting, and study termination before or at completion. ECs should also establish monitoring and/or inspection mechanisms for ongoing research projects to ensure compliance with approved criteria.

Expedited Review

As delineated in the G-EthicsHR-TZA, expedited review is a process by which studies that involve no more than minimal risk may be reviewed and approved in a timely manner by an individual EC member or a designated subset of the full EC. Relevant authorities or ECs must establish a list of criteria for protocols that qualify for an expedited review process. Further, relevant authorities or ECs may establish procedures for the expedited review of research protocols, which should specify the following:

• The nature of the applications, amendments, and other considerations that will be eligible for expedited review
• The minimum number of committee members required for expedited review
• The status of decisions (for example, subject to confirmation by a full EC or not)

Accelerated Review

Per the G-EthicsHR-TZA, an accelerated review process may be used for a clinical trial protocol submitted for ethical approval. In reviewing a clinical trial, reviewers may exercise all the authorities of the committee to recommend approval of the submitted protocol. Final approval for protocol is granted in accordance with the standard procedures outlined above. However, applications for accelerated review of clinical trial protocols will be reviewed on a case-by-case basis by the EC, and the applicant may be required to undergo an ordinary review process due to the nature of the trial or else, as determined by the EC.

Continuing Review

As required in the G-EthicsHR-TZA, the EC must conduct additional reviews on approved studies as necessary, particularly if there are significant changes in the protocol that require re-consent by participants or affect the safety of participants, or if other ethical matters emerge during the study. These further reviews include amendments, progress reports submitted by researchers, and possible monitoring of researchers’ compliance with approved protocols. For approved studies, ECs must conduct continuing review of research at intervals appropriate to the degree of risk, but not less than once a year, and must have authority to observe or have a third party observe the informed consent process. The EC must investigate research fraud and take appropriate action where scientific fraud has been suspected or proven.

Suspension or Termination

Per the G-EthicsHR-TZA, the EC has the authority to halt, suspend, or terminate approval of research that is not being conducted in accordance with the EC’s requirements, or research that has been associated with unexpected serious harm to research participants. For example, the EC may suspend research when:

• It finds that the investigator has implemented significant changes in the research protocol without the prior approval of the EC
• The investigator has failed to follow specific procedures or requirements articulated by the EC in its initial review of the research protocol
• When there is severe unexpected harm to the research participants, including, but not limited to, serious physical injury or death

Per the G-EthicsHR-TZA, any suspension or termination of ethics approval must include a written statement of the reasons for the EC’s action. It must be reported promptly to the investigator(s), appropriate institutional officials, and the National Institute for Medical Research (NIMR) Director General.

Multicenter Research

For multicenter research, the G-EthicsHR-TZA states that the study must be conducted in a methodologically identical way at each center, and ECs at individual centers have the authority to adapt the informed consent document provided by the lead institution to make it culturally appropriate. To avoid lengthy procedures, multicenter research within Tanzania should be reviewed by only one (1) EC and other applicable ECs should accept that review. To be informed of the necessary approach, the study team should be consulted. In cases of multicenter research, if a local review committee proposes changes to the original protocol that it believes are necessary to protect the research participants, these changes must be reported to the research institution or sponsor responsible for the whole research program for consideration and possible action. This should ensure that all persons are protected and that the research will be valid across sites. Ideally, review procedures should be harmonized, which may decrease the time needed for review and, accordingly, speed up the research process. Joint reviews may be organized and requested by the study team or sponsor across country borders or institutions in compliance with guidelines. Joint reviews are based on voluntary cooperation between the relevant national regulatory authorities and ECs. In the case of multi-country joint reviews, each country is solely responsible for granting regulatory or ethics approval to the sites within its borders. To harmonize review processes and to maintain sufficient quality of these processes, ECs should develop quality indicators for ethical review.

Exemption

Per the G-EthicsHR-TZA, some studies may be exempt from EC review. If an investigator considers that their research project satisfies the requirements for exemption from ethics review, the EC must ensure that the proposed research satisfies the requirements for exemption from EC review and grant exemption through procedures set by the EC. The following studies may be exempt from EC review:

• Research with negligible risk that involves using existing collections of data or records that contain only non-identifiable data about human beings
• Use of publicly available unlinked data that does not identify individuals or communities
• Use of existing collections of data or records that contain only non-identifiable data about human beings
• Quality assurance/evaluation activities undertaken in the normal course of conducting the business of the institution, i.e., educational assessments, student feedback surveys, audits of organizational activities and systems, and quality assurance reviews
• Emergency use of a test article provided that such emergency use is reported to the EC within five (5) working days; any subsequent use of the test article at the institution is subject to EC approval
• Health systems research if public officials are interviewed in their official capacity on issues that are in the public domain

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

National Health Research Ethics Committee

According to the G-TMRCC, the National Health Research Ethics Committee (NatHREC) requires the sponsor, the contract research organization, or the principal investigator (PI) to pay a nonrefundable fee to submit a clinical trial research protocol for ethical review and approval.

As per TZA-33, the fees are as follows:

• Tanzanian researchers, expedited review – 3,100,000 Tanzanian Shillings
• Tanzanian researchers, ordinary review – 2,100,000 Tanzanian Shillings
• Tanzanian researchers, amendment – 500,000 Tanzanian Shillings
• Tanzanian researchers, extension – 200,000 Tanzanian Shillings
• Tanzanian students, expedited review – Not applicable
• Tanzanian students, ordinary review – 1,100,000 Tanzanian Shillings
• Tanzanian students, amendment – 250,000 Tanzanian Shillings
• Tanzanian students, extension – 200,000 Tanzanian Shillings
• International researchers, expedited review – $4,100 USD
• International researchers, ordinary review – $2,100 USD
• International researchers, amendment – $500 USD
• International researchers, extension – $200 USD
• International students, expedited review – Not applicable
• International students, ordinary review – $750 USD
• International students, amendment – $250 USD
• International students, extension – $200 USD

Payment Instructions

Per TZA-33, to pay for NatHREC ethical clearance, applicants should fill out the payment form (TZA-33) and send it to nimrethics@gmail.com. To inquire about how to make the payment with the form, contact the NatHREC at +255 22 2121400 or +255 758 587885 (mobile), as per at TZA-18.

Institutional Ethics Committees

Institutionally based ethics committees (ECs) may independently decide whether to charge fees for a protocol review. Per the G-ResearchIntegrity, ECs should delineate procedures for the fee structure, mode of payment, and proof of payment in their standard operating procedures (SOPs). Applicants should contact ECs individually for specific fees and payment instructions.

Overview

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

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

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

Registration, Auditing, and Accreditation

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

Overview

As mandated by the MedRsrchAct, the National Institute for Medical Research (NIMR) is the central body responsible for oversight, and for the promotion and coordination of research in Tanzania. The NIMR is a semi-autonomous organization under the Ministry of Health, Community Development, Gender, Elderly and Children (MoHCDGEC). The IERC-Accredit, the G-EthicsHR-TZA, the G-TMRCC, and TZA-5 state that the NIMR’s Medical Research Coordination Committee (MRCC) serves as the national health research coordinating body, and is responsible for supervising health research in Tanzania. The MRCC, as the NIMR’s clearance body, delegates the registration, review, approval, and monitoring of research to the National Health Research Ethics Committee (NatHREC), which is a subcommittee of the MRCC. The NatHREC focuses on the ethical issues surrounding submitted research proposals. All clinical trial protocols to be conducted in Tanzania are also reviewed by a specialized nine (9)-member Clinical Trials Sub-Committee, which meets monthly and reports to the NatHREC. For detailed information on NatHREC responsibilities, see the G-TMRCC, the G-EthicsHR-TZA, and TZA-5.

TZA-5 acknowledges that not all human subjects require review and approval at the national level—i.e., research that does not involve investigational products or collaboration with foreign institutions. For studies that may not need national review, the local ethics committee (EC) must submit quarterly reports listing studies that were approved by the local EC. The NatHREC may request any information related to approved research studies at the institutional level, and ECs are subject to audit.

Registration, Auditing, and Accreditation

Per the G-EthicsHR-TZA, institutions that intend to establish an institutional EC must make a written request to the Director General of NIMR and, upon approval, submit quarterly and annual progress reports to NIMR. In the initial request, the institution must indicate that it will comply with the following minimum requirements:

• A statement of principles governing the institution's discharge of its responsibilities for protecting the rights and welfare of human research participants of research conducted at or sponsored by the institution; this may include an appropriate existing code, declaration, or statement of ethical principles or a statement formulated by the institution itself
• Details on ensuring meeting space availability and sufficient staff and resources to support the EC’s review and record-keeping duties
• A list of members identified by name, qualifications, profession, representative capacity, indicators, or experience such as board certification, and licenses
• Written procedures for monitoring the conduct of studies approved by the EC

As delineated in the IERC-Accredit, institutional ECs may apply for accreditation. Registered and accredited ECs support the NatHREC function of facilitating institutional ethical clearance and monitoring the approved research studies at the level of the institutions to which they belong or are affiliated. ECs are not mandated to approve research protocols for clinical trials and those involving foreign collaborators. These types of research are cleared at the national level only. Following are the EC accreditation assessment criteria:

• Suitability of infrastructure and office space for EC activities
• Adequacy of equipment to support ethics review management
• Adequacy of qualified EC Secretariat staff (technical and support staff) to manage the ethics review procedures
• Appropriateness of the EC governance and structure
• Plan for capacity building/training program for the EC Secretariat, members, and reviewers
• Plan for monitoring of research activities by the EC
• Adequacy of institutional support services
• Appropriateness of EC standard operating procedures (SOPs)

The IERC-Accredit indicates that ECs approved for full accreditation will be published on the NIMR website. The duration of accreditation is three (3) years from the date of notification (certification) by NIMR. Applications for renewal must be made six (6) months before the expiry of the accreditation period. Failure to renew accreditation or failure to maintain the appropriate standards for continuity of accreditation will mean that the accreditation status of the EC will lapse at the end of the current accreditation period and the committee must cease to function. Accreditation must be terminated if NIMR, in consultation with NatHREC, finds that the accredited EC has failed to maintain the required standards. See IERC-Accredit for additional accreditation information, including application procedures and reporting.

See the Tanzania Commission for Science and Technology’s (COSTECH) and the G-ResearchIntegrity for institutional guidance on the introduction and strengthening of research integrity mechanisms. When such mechanisms are well established, institutional ECs can advance to a stage of accreditation.

Overview

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

Regulatory Submission

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

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

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

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

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

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

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

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

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

Ethics Review Submission

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

Overview

According to the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) requires the sponsor, the designated contract research organization (CRO), or the investigator to obtain TMDA approval. Per TZA-5, the principal investigator (PI) is required to submit an application for ethical review of a research study to the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC). According to the G-AppConductCT and TZA-4, TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of the national EC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once national EC approval is obtained. Per the G-AppConductCT, TZA-18, TZA-5, and TZA-1, proposed health research in Tanzania must also get institutional EC approval at the host institution where the research will be based. If there is no institutional EC, the approval must still be obtained from NatHREC. For all health research involving foreign collaborators, the applicant must get both institutional EC and NatHREC ethical approval.

Per the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) must review and approve all research in Tanzania.

Regulatory Submission

Tanzania Medicines and Medical Devices Authority

Per the G-AppConductCT, applicants must submit both paper and electronic copies of the clinical trial application (CTA). Per TZA-4 and TZA-36, electronic CTA(s) must be completed online via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34). Applicants must fill out CTAs as per the Modules and the Common Technical Document (CTD) highlighted in the G-AppConductCT. Applications for amendment(s) to a previously authorized clinical trial must be submitted on the applicable form in RIMS. The clinical trial application form is available at TZA-38, and the application forms for protocol amendments are at TZA-43 and TZA-44. Note that a list of clinical trial forms is posted to TZA-35.

Per the G-AppConductCT, the hard copy of the application may be delivered in person or by courier to the TMDA at the following address:

Mabibo External along Mandela Express way
P.O. Box 77150
Dar es Salaam, Tanzania

In addition, TZA-34 provides applicants with various online regulatory services.

As per the G-AppConductCT and the TZA-36, applicants must submit paper (A4) and electronic copies. The paper documents should be arranged in spring file folders. The G-AppConductCT specifies that the electronic documents should be in MS Word format, Bookman Old Style font size 11 and submitted on CD-ROM. TZA-36 requires electronic format on CDs. The number of copies to be submitted is not specified in the G-AppConductCT. Annex 1 of the G-AppConductCT provides the Clinical Trial Application Form template. Applicants should submit their applications as per the Modules in the G-AppConductCT and the CTD highlighted in the G-AppConductCT. The overall organization of the CTD format should not be modified.

Per the G-AppConductCT and per TZA-4, all applications and supporting documents must be in English. The informed consent documents must be in both Kiswahili and English.

Tanzania Commission for Science and Technology

Per the G-ResearchClearance, the PI should submit an application for a research permit. It must be submitted to the Director General of COSTECH through the online system (TZA-48) at least three (3) months before the intended commencement of research in Tanzania. According to TZA-47, when the online COSTECH system is not working, applicants should email COSTECH at either rclearance@costech.or.tz or dg@costech.or.tz. After a foreign researcher obtains a research permit, the researcher is required to apply for a class C residence permit from the Tanzanian Immigration Services Department. See the G-ResearchClearance and TZA-47 for additional information about applying for a research permit through the National Research Clearance Committee (NRCC).

Ethics Review Submission

National Health Research Ethics Committee

The TZA-5 specifies that the NatHREC requires all applicants to complete the Application Form for Ethics Approval (see Form 03 in TZA-5) with the research protocol to obtain ethics approval. PIs or applicants must submit all required documents at least two (2) months prior to the commencement of the research study, and they must select either an expedited or ordinary review (for the case of clinical trials, an accelerated review) and pay the relevant fee. An application for ethical review of a research study should be made by the PI for that study. Applications may not be submitted by the sponsor(s) on behalf of the PI. Applications must be accompanied by a completed checklist (TZA-1). As described in the G-RevPrtcl, TZA-5, and TZA-31, applicants should submit the form to the online Research Ethics Information Management System (REIMS) (TZA-32).

The G-TMRCC indicates that four (4) copies of the research proposal with a cover letter should be submitted to the NatHREC.

Institutional Ethics Committees

While the submission requirements will vary by institution, the G-ResearchIntegrity indicates that the lead researcher or PI is responsible for submitting a research proposal to the EC. The institutional EC’s procedures for receiving an application should be clearly stated, and could include some of the following submission elements:

• The name and/or title of the EC member who will receive applications
• Application template or standard forms for submitting applications
• Recommended channel for submissions (e.g., email) and format (e.g., MS word)
• Proper submission of supporting documents with the application
• Use of appropriate language (as recommended) and number of copies
• Name and addresses of contact person for follow up with comments
• Fee structure, mode of payment, and process for submitting proof of payment
• Applicable procedures for proposal amendments, submissions, and supporting tools

Regulatory Authority Requirements

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

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

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

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

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

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

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

Ethics Committee Requirements

Each EC has its own application form and clearance requirements which can differ significantly regarding the number of copies to be supplied and application format requirements. However, the requirements list provided below is basically consistent across all South African ECs.

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

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

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

Clinical Protocol

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

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

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

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

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

Regulatory Authority Requirements

Tanzania Medicines and Medical Devices Authority

As per the CT-Regs and the G-AppConductCT, the following documentation must be submitted to the Tanzania Medicines and Medical Devices Authority (TMDA):

• Comprehensive table of contents
• Cover letter
• Application form (See the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34) or Annex 1 of the G-AppConductCT and First Schedule of the CT-Regs)
• General investigational plan
• Capacity building plans (including plans for staff training and updates)
• Overall summary of the protocol (See Annex 2 of the G-AppConductCT)
• Protocol, signed and approved with data compiled as prescribed in Annex 3 of G-AppConductCT and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), including case report form (CRF) copies or descriptions; See TZA-42 for a clinical trial protocol template
• Participant Information Leaflet, informed consent forms (ICFs), and any other information to be given to participants
• Declarations by the principal investigator (PI) (TZA-39), co/sub investigators (TZA-41), and monitors (TZA-40) (Also see Annexes 5-7 of the G-AppConductCT)
• Joint declaration by sponsor and national PI in format prescribed in Annex 8 of the G-AppConductCT
• Investigator’s Brochure (IB), nonclinical overall summary (See Annex 10 of the G-AppConductCT), and prescribing information data sheet, if applicable
• Certified copy of insurance of research participants
• Ethics clearance certificate or a copy of protocol submission acknowledgement from the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC) or any approved medical research institute
• Investigator(s) Curriculum Vitae(s) (CVs) (See Annex 9 of the G-AppConductCT)
• Blank CRFs and serious adverse events reporting form to be used in the study
• Certificate of good manufacturing practice (GMP) for manufacture of the trial medicine or other evidence of manufacturing quality, safety, and consistency
• GMP certificate for manufacture of the placebo, if applicable
• Investigational product (IP) labels and packages insert(s)
• Mock-up labels for IPs
• Evidence of accreditation/certifications of the designated laboratories or other evidence of good laboratory practice
• Letters of access (if applicable) authorizing the TMDA to access related files
• Copies of key, peer-reviewed published articles supporting the application
• Completed, quality overall summary – Chemical Entities Template (See Annex 11 of the G-AppConductCT)
• Investigational medicinal product dossier
• Application fees
• Summaries of nonclinical, clinical, and quality data (See Module 2 of the G-AppConductCT)
• Quality of the IP (See Module 3 of the G-AppConductCT)
• Nonclinical study reports (See Module 4 of the G-AppConductCT)
• Clinical study reports (See Module 5 of the G-AppConductCT)

As delineated in G-AppConductCT, an application must not cross reference the details or documentation between different clinical trials. The applicant must include a statement indicating that all the information in the application is complete and accurate. In the case of multi-center trials, a coordinating investigator must also sign the application form. If the trial is part of an international study, information must be provided regarding the other participating countries and the part of the trial that will be conducted locally.

In addition, per the G-AppConductCT, applicants can submit an application for amendment to a previously authorized clinical trial, using the required forms (Annexes 12 and 13). The sponsor or sponsor’s agent must submit the following to the TMDA:

• Amendment fees
• Description and reasons for the proposed amendment
• Original wording, revised wording, and the rationale for the change, including a complete protocol incorporating all amendments
• Supporting data for the amendment: updated overall risk-benefit assessment, possible consequences for participants already in the trial and for assessment of trial results, and summaries of data

For details on when TMDA approval must be obtained for amendments, see G-AppConductCT.

Tanzania Commission for Science and Technology

According to the G-ResearchClearance and TZA-47, to obtain a research permit for a clinical trial, the following must be submitted to the Tanzania Commission for Science and Technology (COSTECH) (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• A full research proposal, including a summary, abstract, introduction, research objectives, problem statement, hypotheses or questions framework, methodologies, and timeframe
• Literature review
• Beneficiaries of the research
• Bibliography
• Detailed CV(s) of all researchers
• Sponsor’s cover letter
• For foreign applicants, scientific and ethics committee approval from an institution in the PI’s country of residence
• Clearance from the TMDA
• A supporting letter from a Tanzanian affiliate institution
• A Tanzanian applicant should submit either a copy of their national ID, passport details, driving license, or voters ID
• A foreign applicant should submit a copy of their passport details page and a current passport size photo with a blue background
• A scanned copy of a receipt as proof of payment of the non-refundable research application fee to COSTECH (See Regulatory Fees section for details)

The G-ResearchClearance indicates that an application to renew a permit must contain a renewal application form, an annual progress report, a supporting letter of recommendation from the affiliate institution, passport information, updated CVs, and an extension table form.

Ethics Committee Requirements

National Health Research Ethics Committee

As per the G-TMRCC, the G-RevPrtcl, and the NatHREC’s Checklist for Ethical Clearance Application Submission (see TZA-1), the NatHREC requires applicants to submit the following documentation for ethics approval (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Application Form for Ethics Approval (see Form 3 in TZA-5 and the Research Ethics Information Management System (REIMS) (TZA-32))
• Full protocol, including benefits sharing, placebo rationale, information on randomization/blinding, and a commitment to register the trial in a public registry
• Cover letter signed by PI or co-PI
• Summary, introduction, and literature review
• Statement of the problem, the rationale, and study objectives
• Budget and budget justification
• Ethical consideration (e.g., written information to be provided to participants in English and Kiswahili, obtaining verbal/written informed consent, obligations of investigators and sponsors, benefits and risks of study participation, recruitment, cultural values, and confidentiality measures)
• Limitations of the study
• Information on the study site(s)
• Review of the known risks and if they are acceptable for the expected benefit
• Interim analysis and stopping rules
• Dissemination of research results
• Commitment letter from affiliated institution and/or local government officials
• Letter from student supervisors
• ICFs/Assent Forms in English and Kiswahili
• EC approval certificate from affiliating institution(s), where applicable
• Methodology, including data collection tools in English and Kiswahili
• Elaborated recruitment procedure
• Research team CVs
• Evidence of payment of application and registration fees (Bank slip)
• Completed Data Transfer Agreement (see TZA-8) and/or Material Transfer Agreement (see TZA-10), where applicable
• IBs and CRFs
• Proof of insurance coverage
• List of Data and Safety Monitoring Board members (with at least one (1) Tanzanian)

Per TZA-5, a request for amendment of a previously approved protocol must describe the requested amendment, provide the rationale for the amendment, and describe the impact, if any, of the amendment on the protocol’s risk-benefit profile.

Institutional Ethics Committees

While the submission requirements vary by institution, the G-ResearchIntegrity indicates that the following are typically required:

• Completed application, signed by the lead investigator/researcher(s)
• Full proposal completed in all sections with supporting documents
• A lay summary of the application and/or a flow chart representing key milestones
• Description of ethical issues pertaining to the research, and how they will be managed
• Tools for operationalizing the research and how they will be applied
• Safety issues related to the use of instruments, materials, and research data
• Investigators’ CVs, up to date and signed
• Research context, including criteria for identifying research participants, research environment, and relevant protection measures
• Information to be provided to participants, which may include tools and use of local translators, if needed
• Procedures for informed consent by participants
• Compensation plans for research participants, if any
• Description of indemnity and/or insurance coverage for participants, if applicable
• A history of rejection of the same research protocol, reasons for rejection, and measures taken to address the concerns; withholding such information should be regarded as misconduct and managed in accordance with misconduct guidelines

Clinical Protocol

The G-AppConductCT indicates that the protocol should state the background, rationale, and objectives of the trial, and describe its design, methodology and organization, including statistical considerations, and the conditions under which it is to be performed and managed. In addition, Tanzania requires the following protocol contents in the format prescribed in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13):

• General information (protocol title, identifying number, and date; contact information for the sponsor, medical expert, investigator(s), trial site(s), qualified physician(s), and laboratory and/or institutions involved in the study)
• Background information
• Objectives and purpose
• Trial design
• Selection, withdrawal, and treatment of participants
• Assessment of efficacy
• Assessment of safety
• A description of the statistical methods to be used in the trial
• Direct access to source data and documents
• Quality control and quality assurance
• Ethical considerations
• Data handling and recordkeeping
• Publication policy

The G-EthicsHR-TZA states that research protocols submitted for ethics review and approval must, at the least, include the following information:

• A clear statement of the objectives of the research, the present state of knowledge, and a justification for undertaking the research
• A precise description of all proposed procedures and interventions, including the duration of the study
• A statistical analysis plan
• Description of the study population, including the number of study participants to be recruited
• The inclusion and exclusion criteria for study participants and procedures for the withdrawal of individual participants
• Complete details of the informed consent process, including the proposed means of obtaining informed consent (or assent in case of minors)
• Evidence that the investigators are appropriately qualified and experienced, and have adequate facilities for the safe and efficient conduct of the research
• Provisions that will be made to protect the confidentiality of information/data obtained from research participants
• The study tool (s) (e.g., questionnaires, case report forms, videos, flip charts, and other data collection tools)

Also see the G-RevPrtcl for additional guidance on the NatHREC’s review of the protocol.

Overview

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

Regulatory Authority Approval

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

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

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

Ethics Committee Approval

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

Governance

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

Overview

Based on the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA)'s approval of a clinical trial application is dependent upon obtaining proof of ethical approval from the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC). According to the G-AppConductCT, TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of the NatHREC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once NatHREC approval is obtained. As per the G-ResearchClearance, after receiving TMDA and NatHREC approvals, the researcher must submit an application for research clearance to the Tanzania Commission for Science and Technology (COSTECH).

Regulatory Authority Approval

Tanzania Medicines and Medical Devices Authority

According to the G-AppConductCT, the TMDA review process is conducted on a first-in, first out basis. The TMDA will evaluate complete applications within 60 working days of receiving the application. The fast-track evaluation provides that a new clinical trial application may be fast tracked and assessed within 30 working days of its submission if the applicant has requested and paid twice the prescribed clinical trial application fee. The CTC-Time validates the timelines in the G-AppConductCT.

As set forth in the TMMDAct, the CT-Regs, and the G-AppConductCT, the TMDA coordinates the clinical trial application process. Upon receipt of a clinical trial application, the TMDA initially screens the application for completeness. If complete, the TMDA officer acknowledges receipt of the application by returning a signed copy of the cover sheet to the applicant (see Annex 1 of the G-AppConductCT or First Schedule of the CT-Regs). Per the G-AppConductCT, the TMDA may request clarification, certificates, and/or samples through a query letter. Once a query has been raised and sent to the applicant, the evaluation process stops until the TMDA receives a written response to the query. The response should be submitted within six (6) months after the query letter was issued. In addition, TMDA reserves the right to request information or set conditions not specifically described in the G-AppConductCT to allow it to adequately assess the safety, efficacy, or quality of an investigational product (IP).

The TMMDAct states that the TMDA Director General must issue a Clinical Trial Certificate to authorize the trial to be conducted. Per the G-AppConductCT, the TMDA’s clinical trial authorization will be valid up to the proposed duration of the study indicated in the application. However, the validity will not extend beyond five (5) years. If the trial needs more than five (5) years, the applicant must request an extension. If granted, the TMDA will issue an updated certificate.

Tanzania Commission for Science and Technology

The G-ResearchClearance indicates that once COSTECH receives a new application, the Secretariat screens the application for completeness; registers the application; and sends an acknowledgement to the applicant within five (5) business days. If approved after COSTECH’s review, the principal investigator (PI) is then required to collect the research permit certificate from COSTECH. Per TZA-47, COSTECH’s review committee meets every two (2) months, and applicants are advised to apply two (2) months before the research commencement date.

Ethics Committee Approval

National Health Research Ethics Committee

As set forth in the G-TMRCC and TZA-5, the NatHREC meets once a month to evaluate application submissions. TZA-5 indicates an e-mail notification acknowledging receipt and successful validation of the clinical trial application must be sent to the PI or applicant by NatHREC within two (2) working days from the date of receipt. Comments from reviewers will reach the PI within two (2) days through the Research Ethics Information Management System (REIMS) (TZA-32), depending on the type of study protocol. If the PI or applicant fails to respond to the committee’s and reviewers’ comments within 30 days, the NatHREC Secretariat must notify the PI of intent to remove the protocol from the REIMS. For clinical trials applications, reviewers’ comments and the outcome of the NatHREC meeting must be forwarded to the PI within 30 days from the date of acceptance by the NatHREC. A PI may appeal that decision in writing to the Medical Research Coordination Committee (MRCC) Chairperson within 30 days of receipt of the decision. The MRCC will respond to PIs in writing within 30 days or upon scrutiny of the appeal. The MRCC Chairperson may invite the PI to appear in person to the MRCC within 30 days of receiving the written appeal. For protocol reviews during public health events of national and/or international concern, protocols should be sent to reviewers within 24 hours of submission by the Secretariat. Reviewers should complete their reviews within three (3) days. The consolidated review and suggested revisions (or approval) should be communicated to the PI(s) within five (5) days. The PI should respond to the review notification within 48 hours.

Per TZA-18, the whole process of receiving, reviewing, and approving the protocols takes a maximum of six (6) weeks.

Institutional Ethics Committees

According to TZA-5, the institutional EC review may occur prior to the proposal review by the NatHREC as the application to the NatHREC requires an EC approval certificate from an affiliated institution(s), where applicable (i.e., for foreign sponsors and when an institution has an EC). As required in the G-EthicsHR-TZA, the EC must notify investigators in writing of the review decision within 14 days of its review.

Overview

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

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

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

Clinical Trial Agreement

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

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

• Comply with data recording/reporting procedures

• Permit monitoring, auditing, and inspection

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

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

Clinical Trial Registration

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

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

Overview

In accordance with the TMMDAct, the CT-Regs, and the G-AppConductCT, a clinical trial can only commence after an applicant receives permission from the Tanzania Medicines and Medical Devices Authority (TMDA) and approval from the national ethics committee (EC), the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC). Per the G-ResearchClearance, following TMDA and NatHREC approvals, the applicant must also apply to the Tanzania Commission for Science and Technology (COSTECH) for review, registration, and to obtain a research permit prior to initiating a study. No waiting period is required following the applicant’s receipt of these approvals.

In addition, as per the TMMDAct, the CT-Regs, the TFDCA-ImptExpt, and the G-AppConductCT, the sponsor or the principal investigator (PI) is required to obtain an import license for the shipment of an investigational product to be used in the trial. (See the Manufacturing & Import section for additional information).

Clinical Trial Agreement

Prior to the trial’s commencement, the G-AppConductCT specifies that the protocol must be dated and signed by the investigator, the host institution, and the sponsor, and can function as a contract. In addition, as per the G-CTInsurance-TZA, a clinical trial agreement must be signed by the chief executive of the host institution, the sponsor, and the PI. G-EthicsHR-TZA also states that the PI must sign the protocol and holds primary responsibility for managing and ensuring the integrity of the research study from initiation to finalization.

Per the G-AppConductCT, the sponsor and researchers are required to conduct the clinical trial in compliance with applicable Tanzanian laws and regulations and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13). TZA-13 states that the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. Quality control should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator, or any other parties involved with the clinical trial, verifying that both parties agree to the trial protocol, the monitoring and auditing practices, the standard operating procedures (SOPs), and their respective duties. The sponsor must also obtain the investigator(s)’ and the institution(s)’ agreement to:

• Conduct the trial in compliance with TZA-13, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the EC
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

Also, per the CT-Regs, the sponsor must ensure that all agreements made with the PI and any other parties involved in a clinical trial are in writing, as part of the protocol or in a separate agreement.

Clinical Trial Registration

As per the CT-Regs and the G-AppConductCT, all clinical trials taking place in Tanzania must be registered with the Tanzania Clinical Trials Registry (TzCTR) which is accessed via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34). An applicant must submit detailed clinical trial information to the TzCTR not later than 21 days after the first participant is enrolled in the trial. See the CT-Regs for complete registry submission requirements. The G-AppConductCT further stipulates that applicants have the option to register in any other publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization (WHO). The registration number should be made available to the TMDA.

Safety Reporting Definitions

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

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

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

Sponsor Responsibilities

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

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

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

The G-SafetyRpt delineates the following reporting timeframes:

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

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

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

Form Completion & Delivery Requirements

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

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

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

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

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

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

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

Safety Reporting Definitions

In accordance with the CT-Regs, the G-ReptSafetyData, and the G-AppConductCT, the following definitions provide a basis for a common understanding of Tanzania’s safety reporting requirements:

• Adverse Event (AE) – Any adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
• Adverse Drug Reaction (ADR) – All noxious and unintended responses to a medicinal product related to any dose
• 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 hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, or is a congenital anomaly/birth defect
• Suspected Unexpected Serious Adverse Reaction (SUSAR) (also referred to as Unexpected ADR) – A serious adverse reaction where the nature and severity of the event is not consistent with the medicinal product

The PV-Regs reaffirms that the reporting of SAEs and SUSARs occurring during clinical trials should comply with the requirements in the CT-Regs.

Per the G-EthicsHR-TZA, the severity of an AE must be graded as follows:

• Mild: Includes events that do not interfere with activities of daily living and do not require treatment
• Moderate: Includes events that have minimal effect on activities of daily living and usually require out-patient treatment
• Severe: Includes activities that significantly affect activities of daily living and may require inpatient hospitalization
• Life-threatening: Includes all events that are life threatening and usually require emergency procedures
• Death

The G-EthicsHR-TZA states that an AE must be deemed unexpected if:

• It is previously unobserved or undocumented in humans under the health research intervention (or one substantially similar)
• The nature or severity is not consistent with information in the investigator’s brochure or other safety information known at the time
• The event is observed with higher frequency or severity than previously documented

See the G-EthicsHR-TZA for additional details on grading AEs.

Safety Reporting Requirements

Investigator Responsibilities

As stated in the G-ReptSafetyData and the G-AppConductCT, the investigator is responsible for documenting and reporting all AEs/ADRs, SAEs/SADRs, and SUSARs to the sponsor using the case report form (CRF)/reporting form and the SAE/SADR Reporting Form approved in the protocol, or the CIOMS Form I (TZA-7). See section 3.0 of the G-ReptSafetyData for key data elements to include on the form. TZA-5 requires the principal investigator (PI) to ensure that the protocol includes all required elements for safety monitoring, including assessment and reporting of any anticipated or unanticipated AEs and SAEs. Ethics committees (ECs) (both the National Health Research Ethics Committee (NatHREC) and institutional ECs) must review and address AEs, SAEs, and/or SUSARs. Investigators must be familiar with the regulations, policies, and procedures concerning reporting and continuing review requirements, as well as timelines for submission of notifications and reports.

The CT-Regs states that the PI must immediately report to the Tanzania Medicines and Medical Devices Authority (TMDA) any SAE/SADR that occurs to a participant at a trial site where the PI is responsible for the conduct of the trial. The report may be made orally or in writing and must be followed up with a written report in 14 days. Also, the PI must report AEs that the protocol identifies as critical to safety evaluations. The reports must identify each participant by a number assigned to that participant in accordance with the protocol.

The CT-Regs further states the PI or sponsor must record and report SUSARs that are fatal or life-threatening to the TMDA within seven (7) days and other SUSARs within 15 days.

The G-EthicsHR-TZA requires the investigator to promptly investigate all SAEs, take appropriate measures to ensure the safety of all research participants, and report these and any other information that is likely to affect the safety of the research participants or the conduct of the research events, to the regulatory authority, institutions, and sponsor within timelines as stated in standard operating procedures. Specifically, the investigator must report the following to the EC and TMDA:

• All SAEs irrespective of relationship to the health-related intervention
• All unexpected events of greater than moderate severity irrespective of relationship to health-related intervention
• All events associated with protocol violations irrespective of severity and relationship to health-related intervention
• When criteria for stopping or pausing a study as stipulated in the protocol are met
• Any event mandated by regulatory authorities
• Any event stipulated in the protocol as reportable to the regulatory bodies

Per the G-EthicsHR-TZA, all SAEs must be reported to the local EC as soon as possible and in any case no later than seven (7) days of becoming aware of the event. Thereafter, a detailed report of the SAE should be submitted within eight (8) days. All other reportable AEs should be reported to the EC as soon as possible and in any case not later than 15 days. TZA-5 requires the investigator to submit an initial report on SAE to NatHREC within 24 hours of its occurrence and a final or follow up report on the SAE within 14 days of its occurrence.

Further the G-EthicsHR-TZA requires the investigator to clearly outline in the protocol how management of both foreseeable and unforeseeable AEs will be done. Certain categories of interventions whose long-term effects are not known or cannot be extrapolated will require extended monitoring for AEs, such as genetically modified substances, gene therapy, and DNA-based therapies.

Sponsor Responsibilities

The G-ReptSafetyData states that the sponsor is responsible for the assessment and timely reporting of SAEs/SADRs and SUSARs to the TMDA. The sponsor must retain detailed records of safety information reported by the investigator(s) and ensure that all reports required by the TMDA are submitted on time. In addition, the sponsor must report all SAEs and SUSARs occurring from trial sites outside the country to the TMDA.

The G-ReptSafetyData requires that fatal or life-threatening SAEs/SADRs or SUSARs must be immediately reported to the TMDA by telephone, fax, or email followed by a complete report within seven (7) additional calendar days. The G-AppConductCT specifies that the immediate reporting period is within 24 hours. Further, the report should include an assessment of the importance and implication of the findings, including relevant previous experience with the same or similar products. All deaths during the study, including the post treatment follow-up period, and deaths that resulted from a process that began during the study, should be reported.

Per the G-ReptSafetyData and the G-AppConductCT, all other SAEs and SUSARs that are not fatal or life-threatening must be filed as soon as possible but no later than 14 calendar days after first knowledge by the sponsor. Please note that the CT-Regs states that non-life-threatening SUSARs should be reported in 15 days.

See the CT-Regs and the G-ReptSafetyData for detailed reporting requirements.

Form Completion & Delivery Requirements

As per the G-ReptSafetyData and the G-AppConductCT, all SAEs/SADRs and SUSARs must be reported on the protocol approved CRF/reporting form, or the CIOMS Form I (TZA-7), and should include trial specific details such as participants’ ID numbers and/or protocol number. The form must be submitted to the TMDA office by courier, mail, email (as an attachment), or by fax.

According to TZA-26, the TMDA address and contact information is as follows:

See Annex 15 of the G-AppConductCT and Appendix 1 of the G-ReptSafetyData for the reporting forms.

Interim and Annual Progress Reports

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

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

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

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

Final Report

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

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

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

Interim and Annual Progress Reports

As delineated in the G-AppConductCT, the sponsor or the principal investigator (PI) must submit progress reports to the Tanzania Medicines and Medical Devices Authority (TMDA) on a six (6)-month basis from the date of the clinical trial’s commencement. The content should be as prescribed in TZA-11. In addition, TMDA provides a six (6)-month progress report form for clinical trials of investigational products (TZA-3). The CT-Regs states that progress reports should be submitted annually, or more frequently, as required by the TMDA.

Per the G-EthicsHR-TZA, researchers must submit progress reports to the ethics committee (EC). The investigator must ensure appropriate and timely feedback on the research process including progress reports at regular intervals as stipulated by the EC. Periodic progress reports enable the EC to determine whether the research study is progressing according to the approved protocol.

According to TZA-5, the investigator must submit written progress reports every six (6) months to the National Health Research Ethics Committee (NatHREC) for all ongoing approved health research activities in Tanzania.

In addition, per the G-ResearchClearance, the PI is required to submit annual progress reports (as part of the annual permit-renewal process) to the Tanzania Commission for Science and Technology (COSTECH) that include the title of the study, COSTECH registration reference number, study site, brief background and objective of the study, progress in the reporting period, any problems encountered, and implementation plan for the next period.

Final Report

The G-AppConductCT requires the sponsor or the PI to submit a closing report to the TMDA within 60 days of the trial’s completion. This report should be followed by a final study report within six (6) months after trial closure unless otherwise justified. The structure and content of the final report should comply with TZA-11.

In addition, per TZA-5, the PI is required to submit a final report to the NatHREC once the last participant has completed all visits and all adverse experiences have been brought to appropriate resolution. Final reports must be submitted to the NatHREC on a Close-out Form (Form 08 in TZA-5) and processed as an expedited review. The Secretariat will review the Close-out Form. The expedited reviewer will request additional information from the researcher, as needed. Written documentation acknowledging the closeout will be provided to the investigator and a copy retained in the proposal file. Further, the G-EthicsHR-TZA requires researchers to submit a final report to the institutional EC containing a summary of the study's key findings, recommendations, and conclusions.

The G-ResearchClearance requires the researcher to submit a soft and hardcopy of the final report to COSTECH. The report should be accompanied with any relevant publications, electronic raw data, and proof of dissemination if applicable. The final report should include:

• COSTECH registration reference number
• Title of study
• Summary of report in English and Swahili
• Brief background and objective of the study
• Methodology, including study sites
• Key findings
• Constraints or problems encountered
• Conclusions and recommendations

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

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

Per the CT-Regs and the G-AppConductCT, a sponsor is defined as an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. The Tanzanian government also permits a sponsor to authorize a contract research organization (CRO) to perform one (1) or more of a sponsor’s trial-related duties and functions.

As required in the G-EthicsHR-TZA, the sponsor is responsible for providing all the necessary financial support for the initiation and completion of the research study. Additional sponsor responsibilities include developing the final study report; providing forms for safety monitoring and reporting; securing compensation or indemnity in the event of research-related injuries, disability, or death; and managing matters related to the investigational new drug.

The G-EthicsHR-TZA states that research may be externally sponsored, meaning that it is sponsored, financed, and sometimes wholly or partly carried out by an external organization with the collaboration or agreement of the appropriate authorities of the host community.

Overview

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

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

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

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

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

Foreign Sponsor Responsibilities

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

Data and Safety Monitoring Board

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

Multicenter Studies

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

Overview

The Tanzanian government complies with the requirements delineated in the G-AppConductCT and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) for conducting clinical trials. As set forth in TZA-13, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, and for ensuring that the investigator(s) are qualified by training and experience. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. As delineated in TZA-13 and the G-AppConductCT, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s).

The G-AppConductCT delineates that the principal investigator (PI) must have the following minimum qualifications and experience:

• University degree in medicine, pharmacy, pharmacology, toxicology, or biochemistry and related fields
• Practical experience within the relevant professional area
• Previous experience as a co-investigator in at least two (2) trials in the relevant professional area
• Must be responsible for the conduct of the clinical trial at a clinical trial site
• Tanzanian resident
• In good standing with a professional organization
• For multicenter studies where the PI is not a resident of Tanzania, the appointed national PI must be a resident and should assume full responsibilities for all local clinical trial sites
• Ensure that sufficient time is available to conduct and complete the trial, and that other commitments or trials do not divert essential subjects, resources, or facilities away from the trial in hand
• The maximum number of clinical trials that a PI is allowed to supervise at the same time is five (5)

All investigators in a clinical trial, as well as the trial monitor, must have had formal training in Good Clinical Practices (GCPs) within the last three (3) years. Evidence of attending the GCP course should be submitted.

Per the G-AppConductCT, clinical trials must be carried out under conditions that ensure adequate safety for the participants. The site selected should be appropriate to the stage of development of the product and the potential risks involved. The trial site must have adequate facilities, including laboratories, equipment, and sufficient medical, paramedical, and clerical staff to support the trial and to deal with all reasonably foreseeable emergencies. All laboratory assays must be validated, and principles of Good Laboratory Practice (GLP) should be observed.

Per G-EthicsHR-TZA, institutions hosting research are overall accountable for research projects within their institutions. The institution must work closely with the investigators and monitor implementation of the research activities. Specifically, the host institution must ensure that they have qualified and competent investigators to carry out the research studies at the institution; facilitate the smooth implementation of research studies conducted at the institution; and take appropriate disciplinary action against investigators for non-compliance.

Foreign Sponsor Responsibilities

The G-EthicsHR-TZA states that research may be externally sponsored. The ethical standards should not be less stringent than they would be for research carried out in the country of the sponsoring organization. Local ethics committees (ECs) are fully empowered to disapprove a study they believe is unethical.

The G-ResearchClearance requires all foreign researchers to identify and affiliate to a local institution that has the appropriate capacity in the relevant type of research and obtain a local collaborator. Minimum qualifications of the local collaborator should be a person with a master’s degree and an expert in the relevant field of study. There should be a memorandum of agreement between the local institution/collaborator and the foreign researcher that includes methods for sharing data, material transfer agreements, access benefit sharing agreements, managing intellectual property, and dissemination of research results.

Data and Safety Monitoring Board

Per the G-EthicsHR-TZA, all Phase I, II, and III clinical trials, including drug efficacy trials, conducted in Tanzania must have a safety monitoring plan and Data and Safety Monitoring Board (DSMB) or a Data Monitoring Committee (DMC). Other interventional studies, such as community trials, may be required to set up DSMBs on a case-by-case basis. The National Health Research Ethics Committee (NatHREC) must ensure the establishment of a DSMB in all clinical trials to periodically assess the progress of implementation of safety data and the efficacy endpoints and to recommend to the sponsor whether to continue, modify, or terminate a trial. See the G-EthicsHR-TZA for details on the DSMB composition, qualifications, affiliation, terms of reference, and reporting.

As delineated in TZA-5, NatHREC considers DSMBs to be relevant in the following kind of studies:

• Controlled studies with mortality and/or severe morbidity as a primary or secondary endpoint
• Randomized controlled studies focused on evaluating the clinical efficacy and safety of a new intervention
• Early studies of a high-risk intervention
• Studies in the early phases of a novel intervention with very limited information on clinical safety
• Studies where the design or expected data accrual is complex, particularly studies with a long duration
• Studies carried out in emergency situations

The CT-Regs states that the DSMB requirement may depend on trial design and scientific background, risk and benefit assessment, or any other reasons determined by the NatHREC.

TZA-5 states that for clinical trials conducted only in Tanzania, the DSMB must include representation from Tanzania. For multi-country clinical trials, the DSMB must include regional representation, and a Tanzanian must be among the members. Where necessary, NatHREC may request that the sponsor submit the most recent report from the DSMB. In contrast, per TZA-1, for clinical trials that require a DSMB, the PI must submit a list of DSMB members, including at least one (1) Tanzanian, to the National Institute for Medical Research (NIMR). Additionally, the CT-Regs requires the following information:

• Trial objectives and terms of reference
• Member composition, qualifications, specific roles, and relationship to the investigators and study
• How meetings will be organized

The G-AppConductCT also specifies that a DSMB/DMC is required in situations where safety concerns may be unusually high. A DMC is recommended for any controlled trial of any size that will compare rates of mortality or major morbidity. It also indicates that a DSMB or DMC must be considered in the following situations:

• The study endpoint is such that a highly favorable or unfavorable result, or even a finding of futility, at an interim analysis might ethically require termination of the study before its planned completion
• There are a priori reasons for a particular safety concern (e.g., if the procedure for administering the treatment is particularly invasive)
• There is prior information suggesting the possibility of serious toxicity with the study treatment
• The study is being performed in a potentially fragile population such as children, pregnant women, the very elderly, other vulnerable populations, or those who are terminally ill or of diminished mental capacity
• The study is being performed in a population at elevated risk of death or other serious outcomes, even when the study objective addresses a lesser endpoint
• The study is large, of long duration, and multi-center

Additional details on the procedures and composition of the DSMB or DMC are provided in the G-AppConductCT and Part VIII of the CT-Regs. In addition, per the G-ReptSafetyData, the sponsor must also ensure that the DSMB’s interim safety data analyses are submitted to the Tanzania Medicines and Medical Devices Authority (TMDA).

Multicenter Studies

Per the G-EthicsHR-TZA, for multicenter studies, the study must be conducted in a methodologically identical way at each center. See the Scope of Review section for more details on multicenter studies.

As delineated in TZA-13, in the event of a multicenter clinical trial, the sponsor must ensure that:

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

The CT-Regs and the G-AppConductCT also state that in the case of multicenter studies where the PI is foreign, the appointed national PI must be a resident and assume full responsibilities for all local clinical trial sites.

Insurance

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

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

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

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

Compensation

Injury or Death

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

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

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

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

• The seriousness of the disease being treated

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

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

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

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

Trial Participation

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

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

Post-Trial Access

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

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

Insurance

As set forth in the CT-Regs, the G-AppConductCT, the G-CTInsurance-TZA, and TZA-5, the sponsor or the designated contract research organization (CRO) is responsible for providing insurance coverage for any unforeseen injury to research participants. Before a clinical trial begins, the sponsor should also provide insurance and indemnify the investigator and the institution against claims arising from malpractice or negligence, and provide a copy of a valid insurance certificate from a recognized insurer in the clinical trial application submission. Additionally, per the CT-Regs, the insurance policy should be obtained from an insurance company registered in Tanzania. The G-CTInsurance-TZA and the G-AppConductCT state that details and proof of insurance must be provided in the ethics review submission. Furthermore, per the CT-Regs, for investigator-initiated trials, proof of current malpractice insurance that covers clinical trials must be provided to the Tanzania Medicines and Medical Devices Authority (TMDA). (See the Submission Content section for additional submission requirements.) The G-EthicsHR-TZA requires that insurance issues are clearly described in all clinical trial protocols, and that sponsors and investigators comply with the G-CTInsurance-TZA.

As per the CT-Regs and the G-CTInsurance-TZA, the sponsor or the designated CRO must sign an indemnity agreement with the host institution and the investigator(s) to cover any risks related to a research participant being injured by an investigational product, or from any procedure deemed necessary by the protocol. The sponsor and the institution’s chief executive officer must sign the indemnity. See Appendix 1 of the G-CTInsurance-TZA for a sample agreement. Per the CT-Regs, the sponsor must also indemnify the investigator against claims arising from the trial, except for claims that arise from malpractice or negligence.

The G-CTInsurance-TZA states that the insurance policy must meet the following requirements:

• Cover the conduct of the relevant clinical trial in Tanzania

• Provide a policy registered by the Tanzania Insurance Regulatory Authority (TIRA)

• Contain insurance coverage for an amount sufficient to meet the indemnification requirements applicable to the ethics committee (EC)-specified level of risk

• Cover claims made by research participants during the trial as well as those made after the trial is completed

Compensation

Injury or Death

As specified in the G-CTInsurance-TZA and the G-EthicsHR-TZA, the sponsor or the designated CRO is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries or death. The sponsor must also ensure that participants who suffer any trial-related injuries are provided with free medical treatment for such injuries. The G-EthicsHR-TZA states that research study participants must not be asked to waive the right to compensation and must retain the legal rights to seek monetary compensation for research-related injuries including settlements out of court, in accordance with applicable laws in Tanzania.

Per TZA-5, investigator(s) must ensure participants (or their dependents in case of participant death) are equitably compensated should they sustain unexpected serious injuries (physical, psychological, or social harm) that are judged to be related to the investigational product (IP) or study procedure. Participants must not be compensated if they sustain expected adverse events or those related to other licensed medicines appropriately prescribed during the trial.

As per the G-CTInsurance-TZA, the amount of compensation paid should be appropriate to the nature, severity, and persistence of the injury. 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

Trial Participation

As per the CT-Regs and the G-AppConductCT, participants may also be compensated for travel and incidental expenses incurred while participating in the trial. Per the G-AppConductCT, the clinical trial application must indicate the compensation to be received by participants, including a breakdown of costs.

The G-EthicsHR-TZA indicates that research study participants may be reimbursed for lost earnings, travel costs, lunch, and other expenses incurred in taking part in a study; they may also receive free medical services. Research participants, particularly those who receive no direct benefit from the research, will be compensated for inconvenience and time spent. Compensation must not be so large as to induce potential participants to consent to participate in the research study against their better judgement (undue inducement). A local EC must approve reimbursement and compensation for research study participants. Incentives to research study participants for their participation in research studies must not be considered a research benefit, but a recruitment incentive, and should not present undue influence on potential research participants.

Post-Trial Access

Per the study protocol template in the G-AppConductCT and TZA-42, details on post-trial access to products must be provided in the study protocol.

Per the G-EthicsHR-TZA, where appropriate, the clinical trial protocol should include a provision for the involvement of the community in the research process including the post-research period. The community in this context may be geographical or study population. Further, there should be optimization of collateral benefits to the research communities including access to the products of the research. If the investigational product is found to be beneficial, the investigator should assist to secure its provision, without charge, to participants in the research study following the conclusion of the study.

Quality Assurance/Quality Control

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

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

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

Monitoring Requirements

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

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

Premature Study Termination/Suspension

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

Quality Assurance/Quality Control

As stated in the CT-Regs and the G-AppConductCT, the Tanzanian government complies with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13) requirement that the sponsor implement and maintain quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol.

Per G-EthicsHR-TZA, during the conduct of clinical trials, deviations from the original study might occur, such as changes in the sample size or analysis of the data as described in the protocol. Deviations must be reported to ethics committees (EC). In the case of permanent deviations, researchers may write an amendment. The EC must decide whether a deviation is accidental or purposeful. Protocol violations are deviations from the original protocol that significantly affect the rights or interests of research participants and the scientific validity of the data. In the case of protocol violations, study participants must be informed and provisions made to protect their safety and welfare. ECs may halt the continuation of a previously approved protocol if they find protocol violations or other misconduct. Any serious or continuing non-compliance with ethical standards in the conduct of previously approved research projects must be reported to the sponsor and institutional or governmental authorities by the study’s principal investigator (PI) and the Data and Safety Monitoring Board (DSMB).

Per TZA-13, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

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

Further, TZA-13 indicates that the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

As described in the G-AppConductCT, study design, statistical considerations, choice of control groups, reporting of data, and conduct of the trial should also comply with the International Council for Harmonisation’s Efficacy Guidelines (E3-E16), provided in TZA-24.

Monitoring Requirements

As part of its QA system, the G-AppConductCT and TZA-13 note that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, TZA-13, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial, ensure that the auditors are qualified by training and experience, and document their qualifications. The sponsor must also ensure that the audit is conducted in accordance with any custom SOPs, the auditor observations are documented, and data are available as needed for the Tanzania Medicines and Medical Devices Authority (TMDA). No specific timeframe is provided for the audit process. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

The G-GCPInspections provides guidance on clinical trial inspections to ensure the trial is conducted in accordance with the study protocol, procedures, TZA-13, and regulatory requirements, and that the data are accurate and valid. Inspectees (i.e., sponsor, investigator site, and contract research organization) should follow the G-GCPInspections requirements to ensure consistent conduct of trial inspections, including uniform reporting.

Per Pub-Rpts, to promote transparency of clinical trial oversight in the country, TMDA will publish to its website clinical trial public assessment reports (CTPAR) and clinical trial public inspection reports (CTPIR) of all approved and ongoing clinical trials on an annual basis. The publication will only be undertaken after obtaining the consent of the respective PIs and sponsors. The PIs and sponsors are required to provide their consent within 14 days from TMDA’s notification letter. Failure to respond is assumed to mean that the PIs and sponsors have consented to the publication of the CTPAR and CTPIR. For further clarification on this notice, contact TMDA at clinicaltrials@tmda.go.tz or info@tmda.go.tz.

Premature Study Termination/Suspension

The CT-Regs and the G-AppConductCT state that if a trial is prematurely terminated or suspended, the PI or the sponsor must inform the TMDA no later than 15 days after the date of the termination, and explain the reason(s) for the termination and its impact on the proposed or ongoing clinical trials. The sponsor or PI must also inform all co-investigators of the termination, the reasons for the termination, and advise them in writing of potential health risks to research participants. For each discontinued clinical trial site, the sponsor must stop the use or importation of the investigational product (IP) from the date of the trial’s discontinuation and take all reasonable measures to ensure the recovery of all unused quantities of the IP.

The G-EthicsHR-TZA also indicates that in the event of early termination of the research study, the investigator must inform, in writing, the appropriate EC, the National Institute for Medical Research (NIMR), the TMDA, and the research sponsor of the early termination and the underlying reason for such termination. Per TZA-5, NatHREC should be notified if the investigator chooses to suspend the study. To resume a suspended study regardless of who initiated the suspension, the PI must submit a request to the Medical Research Coordination Committee (MRCC) with a report on the progress of addressing corrective actions. Research studies may be terminated based on the recommendation of the NatHREC, zonal or institutional ECs, DSMB, study sponsor, PI, or regulatory authority. In addition, a research study can be terminated due to an arising conflict of interest among investigators or financial misuse, which negatively affects implementation of the research project.

According to TZA-13, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

Electronic Data Processing System

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

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

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

Records Management

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

Electronic Data Processing System

As stated in the CT-Regs and the G-AppConductCT, the Tanzanian government complies with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13). As per TZA-13, when using electronic trial data processing systems, the sponsor must ensure that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. Per TZA-13, the sponsor should base their approach to validate such systems on a risk assessment that takes into consideration the intended use and the potential of the system to affect participant protection and reliability of trial results. In addition, the sponsor should maintain standard operating procedures (SOPs) for the systems that cover system setup, installation, and use. The responsibilities of the sponsor, investigator, and other parties should be clear, and the system users should be provided with training. Refer to TZA-13 for additional information.

Records Management

The CT-Regs states that the investigator and the sponsor must retain all trial-related records, documents, and information at the trial site for a period not less than 20 years following the trial’s completion. Further, documentation should be retained for at least two (2) years after the last approval of a marketing application. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed. See the CT-Regs for detailed record retention requirements. As set forth in TZA-13, all sponsor-specific essential documents used in the trial should be retained for at least two (2) years after formal discontinuation of the trial.

In addition, TZA-13 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

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

Data Protection

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

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

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

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

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

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

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

Consent for Processing Personal Data

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

Responsible Parties

For the purposes of data protection requirements, PDP-Act delineates that the “data controller” (i.e., the natural/legal person or public body designated by law) is responsible for determining the purpose and means of processing personal data. The "data processor" processes personal data on behalf of the data controller. The “data protection officer” is an individual appointed by the data controller or data processor to ensure compliance with the PDP-Act and its regulations. Data controllers and processors must be registered with the Personal Data Protection Commission (PDPC). See the PDP-Reg-TZA for detailed procedures on registering with PDPC.

Data Protection

Per the PDP-Act, the data controller or data processor must protect personal data by ensuring that it is:

• Processed lawfully, fairly, and transparently
• Collected for explicit, specified, and legitimate purposes and not further processed in a manner incompatible with those purposes
• Adequate, relevant, and limited to what is necessary in relation to the purposes for which it is processed
• Accurate and where necessary, kept up to date, with every reasonable step taken to ensure that any inaccurate personal data is erased or rectified without delay
• Stored in a form which permits identification of data subjects for no longer than is necessary for the purposes for which the personal data is processed
• Processed in accordance with the rights of a data subject
• Processed in a manner that ensures appropriate security of the personal data, including protection against unauthorized or unlawful processing and against any loss, destruction or damage
• Not transferred abroad contrary to the provisions of the PDP-Act

Regarding transborder data flow, the PDP-Act prohibits the transfer of personal data outside of Tanzania except under the following circumstances:

• If the data is transferred to a country that also has a data protection law enacted
• If the country does not have a data protection law, data may only be transferred outside of Tanzania based on several factors, including the recipient state's federal legal frameworks, security and privacy principles, the type of information being shared, the data transfer mechanisms in place, the specific reason for the transfer, and the proposed length of data processing (See the PDP-Act for more details)

See the PDP-Reg-TZA for detailed implementation requirements.

Consent for Processing Personal Data

Per the PDP-Act, before collecting data, a data controller must ensure that the data subject is aware of the purposes for which the personal data is collected; the fact that collection of the personal data is for authorized purposes; and any intended recipients of the personal data. However, the data controller is not required to inform the data subject if the personal data is publicly available, the data subject concerned authorizes the collection of the personal data from a third party, compliance is not reasonably practicable in the circumstances of the particular case, non-compliance is necessary per other written laws, or compliance would prejudice the lawful purpose of the collection.

As required in the PDP-Act, sensitive personal data must not be processed without obtaining prior written consent of the data subject, which may be withdrawn by the data subject at any time and without any explanation or charges. If the data subject is a minor, a person of unsound mind, or any other person unable to consent, such person’s consent must be obtained or sought from the legal representative(s)/guardian(s). Exceptions to this rule apply where the processing is necessary in these circumstances:

• Compliance with other written laws
• To protect the vital interests of the data subject or of another person, where the data subject is incapable of giving consent or is not represented by a legal representative
• Necessary for the institution, trial, or defense of legal claims
• Relates to personal data that has been made public by the data subject
• The purposes of scientific research and the PDPC has, by special guidelines, specified the circumstances under which such processing may be carried out
• For the purposes of medical reasons in the interest of the data subject and the sensitive personal data concerned is processed under the supervision of a health professional in accordance with the law

Further, the PDP-Act delineates that data collected may only be disclosed if the data subject has consented to such disclosure and if the disclosure is authorized or required by law, directly related to the purpose for which such data was collected, and/or would preserve health or reduce harm to another person or the society. Disclosure of information may also be permitted where the data subject is not identified for statistical or research purposes and where it is guaranteed that such data will not be published in a manner that will identify the data subject. Additionally, data collectors must establish a code of ethics for personal data protection during collection or processing of personal data, and they must maintain a proper security system.

Per the PDP-Reg-TZA, the rights of participants regarding their personal data are the autonomous right to control their personal data, the right to communicate and exercise their data rights, and the right to human intervention to minimize biases that automated processes may create. In addition, per the G-EthicsHR-TZA, researchers using online and digital tools must protect the individual’s right to privacy and confidentiality including whether they knew or were expected to know that records and data were being kept. If individuals have reasonable expectations of privacy and impermanence of their online activities, then researchers may need to take specific measures to inform the respondents and obtain their consent to use their data for research. Further, if studies use artificial intelligence, the participant’s “right to be forgotten” must be protected by enabling their ability to request that a search engine remove information about them.

Obtaining Consent

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

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

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

Re-Consent

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

Language Requirements

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

Documenting Consent

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

Waiver of Consent

No information is currently available regarding conditions for waiving consent.

Obtaining Consent

In all Tanzanian clinical trials, a freely given informed consent must be obtained from each participant in accordance with the requirements set forth in the CT-Regs, the G-AppConductCT, and the G-EthicsHR-TZA. As per the G-AppConductCT and the G-EthicsHR-TZA, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC), and provided to the Tanzania Medicines and Medical Devices Authority (TMDA) for approval with the clinical trial application. (See the Required Elements section for details on what should be included in the form.)

The G-AppConductCT and the G-EthicsHR-TZA state that the investigator, or the designated representative, must provide detailed research study information to the participant and/or the legal representative/guardian. The G-AppConductCT, the G-EthicsHR-TZA, and TZA-5 also specify that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and the legal representative/guardian, should also be given adequate time to consider whether to participate. The G-EthicsHR-TZA indicates that informed consent protects the individual’s freedom of choice and respects the individual’s autonomy. The consent process should be a flow of information exchange between the researcher and research participants during the whole research process. The information provided should be adequate, and clearly understood by the research participants. Seeking consent must be carried out under circumstances that provide the prospective research participant or the representative sufficient opportunity to consider whether to participate and minimize the possibility of coercion or undue influence. The information given to the research participant or the representative, whether it is conveyed orally, in writing, or another delivery mechanism, must be in a language and form understandable to the participant or the legal representative/guardian.

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

Per the G-EthicsHR-TZA, for verbal consent, the procedures used to obtain consent must be described within the ethics application, and the verbal consent must still contain all of the elements required for informed consent.

Re-Consent

According to G-AppConductCT, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by the NatHREC and the TMDA prior to implementing any changes. The participant and/or the legal representative/guardian should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented.

Per the G-EthicsHR-TZA, the investigator must ensure that there is continued adequacy of the informed consent process and renewal of informed consent if there are significant changes in the conditions or procedures of the research project or if new information becomes available that could affect the research participant’s willingness to continue in the research project.

Language Requirements

As stated in the G-AppConductCT, the ICF content should be presented in both English and Kiswahili, and all information given to participants, both oral and written, must be in both English Kiswahili.

Documenting Consent

The G-AppConductCT and the G-EthicsHR-TZA state that the participant and/or the legal representative/guardian, and the person who conducted the informed consent discussion must sign and date the ICF. 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 an impartial witness. Before participating in the study, the participant should receive a copy of the signed and dated ICF, and any other written information provided during the informed consent process. The G-AppConductCT states that the participant and/or the legal representative/guardian should also receive a copy of any updates to the signed and dated ICF, and copies of any amendments to the written information originally provided.

Per the G-EthicsHR-TZA, the study participant may imply consent by voluntary actions (e.g., express consent verbally or sign (written consent form)). A verbal or oral consent process is where the researcher and participant have a conversation to give information and obtain consent. Usually, oral consent is used when it is not possible to get written consent. The verbal consent may be deemed appropriate and applied under the following situations where:

• The study is deemed to be of minimal risk
• There are cultural or political concerns with signing contract-like documents
• The researcher and or participants could be put at risk by the existence of a paper record
• The study is conducted remotely via video conferencing software, telephone, etc.
• It may not be feasible in large information-taking settings (e.g., some focus group discussions (FGDs)); however, documentation of verbal consent for participants in FGDs must be written down to include the names of participants who consented verbally and those that did not

Waiver of Consent

Per the G-EthicsHR-TZA, for research that is no more than minimal risk, the EC may approve a request to waive some or all of the required elements of informed consent under specific circumstances. Waivers of informed consent are primarily requested for projects involving the secondary analysis of existing data. To waive or alter informed consent elements, the following conditions must be met:

• The study could not practicably be carried out without the waiver or alteration (whenever appropriate the study participants will be provided with additional pertinent information after participation)
• In situations where deception needs to be applied to achieve the objectives of the study
• The only record linking the study participant and the study would be the consent document and the principal risk to the research participant would be potential harm resulting from a breach of confidentiality
• The study participant presents in an emergency situation and informed consent cannot be reasonably obtained (See the Emergencies section for more information)

The G-EthicsHR-TZA states that if a waiver of written informed consent is granted by the EC, then each study participant should be asked whether they wish to have documentation that links them with the study; and the participant’s wishes must govern.

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

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

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

Based on the G-AppConductCT and the G-EthicsHR-TZA, 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 both sources, which provide overlapping and unique elements):

• The study purpose, procedures, and duration
• Approximate number of participants involved in the trial
• Experimental aspects of the study
• The participant’s responsibilities in participating in the trial
• Expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Disclosure of alternate procedures or treatments available to participants
• Clinical trial treatment schedule(s) and the probability for random assignment to each treatment
• Benefits or prorated payment to the participant or others reasonably expected from the research; if no benefit is expected, the participant should be made aware of this
• Compensation and/or treatment available for the participant in the case of trial-related injury, with a description of such compensation/treatment and where further information may be obtained
• Participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
• A statement of the extent of the investigator’s responsibility, where applicable, to provide medical services to the study participant
• A statement of the nature, form, and extent of compensation for study participation (e.g., reimbursement for transport, time, and meals)
• A brief description of the research project sponsors and the investigators’ institutional affiliation
• Extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the Tanzania Medicines and Medical Devices Authority (TMDA)
• The participant and/or the legal representative/guardian will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant’s willingness to continue
• Individuals to contact for further information regarding the trial, the rights of trial participants, and whom to contact in the event of trial-related injury; these contacts must speak the participant’s language
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• Consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
• The participant and/or the legal representative/guardian will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant’s willingness to continue
• A statement that study participants will get feedback on findings and the progress of the study and that any new information that affects the study or data that has clinical relevance to the participants will be made available to the participants or their health care providers
• Where necessary (e.g., illiterate, mentally incapacitated, or physically disabled study participants), the provision for a witness at appropriate stages of the informed consent process should be ensured
• A statement that the study has been approved by a recognized Tanzanian-based ethics committee (EC)
• Whether, when, and how any of the products or interventions proven by the study to be safe and effective will be made available to the study participants at the end of the study and whether they will be expected to pay for them
• With regard to research involving the collection of biological/genetic materials, an explanation should be provided on how specimens will be managed at the end of the study; if the samples are stored for future use, separate consent should be obtained
• Additional costs to the participant that may result from participation in the research

Per the G-EthicsHR-TZA, for protocols involving verbal consent, the following minimum information must be communicated to the participant:

• Introduction - who is the caller/interviewer, affiliation, organization
• A statement that the study involves research
• Study purpose
• What the participant will be asked to do and the time commitment
• Any compensation and any information to be collected to make that payment (mailing address, email address, etc.)
• The voluntary nature of participation in the study
• Any risks or benefits associated with participating (leave this out if there are none)
• That notes are being taken or data is being recorded, if applicable
• Whether the information collected will remain confidential or if it is planned to keep identifiers with the research data
• Contact information for the researcher and/or the EC
• Ask if the participant has any questions
• Ask explicitly, “Do you agree to participate in this study?”
• Depending on the nature of the study and the participant pool, the researcher may offer other pertinent information to ensure that participants are fully informed about the study and any risks or benefits from participating in it

Compensation Disclosure

Regarding compensation, TZA-5 states that investigator(s) must ensure participants are aware of the compensation guidelines and that their rights regarding compensation are protected. Participants must not be asked to waive their rights to free treatment or compensation for research-related harms, nor must they be required to show negligence or lack of a reasonable degree of skill on the part of the researcher to claim free treatment or compensation. The informed consent process or form must not contain statements that would absolve a researcher from responsibility in the case of harm, or that would imply that participants waive their right to seek compensation.

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

Overview

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

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

The Right to Privacy and Confidentiality

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

Overview

As stated in the G-AppConductCT, the Tanzanian government complies with the ethical principles set forth in the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (TZA-13) and the Declaration of Helsinki (TZA-30), which promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.)

The Right to Participate, Abstain, or Withdraw

As set forth in the G-AppConductCT and the G-EthicsHR-TZA, the participant or the 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

As delineated in the G-AppConductCT and the G-EthicsHR-TZA, a potential research participant and/or the legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. (See the Required Elements section for more detailed information regarding participant rights.) The G-EthicsHR-TZA states that information about the research study must be communicated in understandable and legally accepted language and format, and in a conducive environment, at all stages of the research.

The Right to Privacy and Confidentiality

As per the G-AppConductCT and the G-EthicsHR-TZA, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

The Right of Inquiry/Appeal

The G-AppConductCT and the G-EthicsHR-TZA state that the research participant and/or the legal representative/guardian should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries. (See the Required Elements section for more detailed information regarding participant rights.)

The Right to Safety and Welfare

As specified in the CT-Regs, the G-EthicsHR-TZA, and the G-AppConductCT, the Tanzanian government complies with the principles in TZA-13 that state a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

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

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

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

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

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

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

As per the G-AppConductCT, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If prior consent from the participant or the legal representative/guardian cannot be obtained, participant enrollment should require measures described in the protocol and/or elsewhere. Tanzania Medicines and Medical Devices Authority (TMDA) approval should also be obtained in order to protect the participant’s rights, safety, and well-being and to ensure compliance with National Health Research Ethics Committee (NatHREC) and TMDA requirements. The participant or the legal representative/guardian should provide consent as soon as possible.

In addition, per the G-EthicsHR-TZA, an EC may approve a waiver of consent if the study participant presents in an emergency situation and informed consent cannot be reasonably obtained from the participant or the legal representative/guardian. During a public health emergency of national and international concern, some of the activities focusing on diseases or events threatening national and international health security are considered non-research and need immediate attention. Informed consent may not be required in non-research activities.

Overview

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

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

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

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

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

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

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

Persons in Dependent Relationships or Hierarchical Situations

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

Persons Highly Dependent on Medical Care

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

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

Persons with Physical Disabilities

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

Elderly Persons

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

Research Involving Collectivities

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

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

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

Overview

As per the G-AppConductCT and the G-EthicsHR-TZA, in all Tanzanian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Vulnerable populations include those who are incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes, and have an increased likelihood of being wronged or of incurring additional harm during clinical trials. For example, the G-AppConductCT includes persons who are illiterate, marginalized by their social status or behavior, or living in an authoritarian environment. Vulnerable groups include individuals in hierarchical relationships, institutionalized persons, nomads, refugees or displaced persons, people living with disabilities, people with incurable or stigmatized conditions or diseases, and people faced with physical frailty. The G-EthicsHR-TZA additionally identifies children, mature and emancipated minors, street children, prisoners, the homeless, substance abusers, handicapped (mentally and physically), armed forces, and pregnant women. In some cases, willingness to volunteer to participate in research is unduly influenced by the expectation of benefits associated with their participation, or fear of retaliation from interested senior members of the hierarchy in case of refusal to participate. Characteristics that constitute vulnerability with reference to communities include one (1) or more of the following:

• Limited economic empowerment
• Inadequate protection of human rights
• Discrimination on the basis of health status
• Inadequate understanding of scientific research
• Limited availability of health care and treatment options
• Limited ability in the community to provide informed consent

As per the G-EthicsHR-TZA, clinical trials involving vulnerable persons require additional attention to ensure their protection. Where factors relating to vulnerability are an aspect of the research study, ethics committees (ECs) must ensure that researchers specify how that vulnerability would be addressed, particularly:

• Selection of the particular communities is justified by the research goals
• Research study is relevant to the needs and priorities of the community in which it is to be conducted
• Research study is beneficial to that community
• The community can access products of the research
• Where appropriate, feedback of results should be provided to the community
• Study participants must be fully aware that they are participating in the research and should provide informed consent
• Special attention should be paid to the content, language of the consent document, procedures for obtaining informed consent, monitoring of the process, and testing comprehension

TZA-5 requires the investigator to specify in the clinical trial application if a research protocol involves a vulnerable population or special group, provide adequate justification for their involvement, and provide information on how the participants’ rights and welfare will be safeguarded. Further, the investigator should include information about how they will assess the participants’ capacity to consent for themselves. If the participant is not able to consent, the researcher should include information about how consent will be obtained from the participant’s legal representative/guardian and how assent will be obtained from the participant (where appropriate).

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

Information on the specific vulnerable populations specified in the G-EthicsHR-TZA is provided below.

Persons Highly Dependent on Medical Care

Per the G-EthicsHR-TZA, persons highly dependent on medical care, such as those living with disabilities (physical or mental) or terminally ill patients, require special attention because they are prone to being socially marginalized. Therefore, their dignity, rights, and well-being in research must be respected. For persons living with disabilities, careful consideration should be made where proxy consent is used, and where the use of signed consent forms is not feasible, alternative viable methods should be employed. Persons living with disabilities should not be unfairly excluded from participating in research. Researchers should make efforts to address communication, disability, and comprehension constraints. (See Mentally Impaired section for requirements on persons with mental disabilities). For terminally ill patients, their dire state may affect their ability to make voluntary decisions regarding participation in research studies. A research protocol involving terminally ill patients as study participants must meet the following additional requirements: the research can only be conducted with terminally ill patients; if the research objectives of the study cannot be addressed using another non-vulnerable group; and the risk-benefit ratio should be favorable to the patients.

Elderly Persons

As per the G-EthicsHR-TZA, it is important to exercise special care when involving the elderly who have been in the hospital or in a residential home for a long time because they may be more dependent on others for their care. Independent but caring observer(s) for the elderly must be fully informed about the study and be satisfied that the elderly participant understands the intended research activities prior to consent.

As per the G-AppConductCT, TZA-14 should be followed for clinical trials that involve:

• New investigational products that are likely to have significant use in the elderly
• New formulations and new combinations of established medicinal products when there is specific reason to expect that conditions common in the elderly are likely to be encountered and are not already dealt with in current labeling
• New formulation or new combination is likely to alter the geriatric patient’s response in a way different from previous formulations
• New uses that have significant potential applicability to the elderly

Students

The G-EthicsHR-TZA states that research studies involving students can be conducted as long as the following conditions are met:

• The tutor involved in the tuition of the student should not be involved in the recruitment and other negotiations on the terms and research conditions
• The informed consent should clearly state that the student may wish at any stage of the research study to withdraw without any undue consequences
• An impression should not be created that acceptance to participate in the study will benefit the student in the passing of their examinations
• An impression should not be created that non-acceptance will result in discrimination and consequences on the student’s studies
• There should not be any form of coercion, pressure, or financial inducement other than that proposed as reimbursements for participants

Homeless Persons

Per the G-EthicsHR-TZA, the category of homeless persons includes street children, adults staying on the street, refugees, and internally displaced persons. In conducting research with people who are homeless, researchers should be guided by the following principles:

• Research must be conducted with respect to the human rights, welfare, and dignity of study participants
• The research study must be conducted in a non-judgmental way regarding the person’s appearance, strategies for making money, or personal habits
• The right to privacy and security must be respected at all times for people who are homeless

Armed Forces

For research involving participants in the armed forces, the G-EthicsHR-TZA requires the following consent conditions:

• Any possible advantages accruing to participants through their participation in the research study (when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings) are not of such magnitude so that it might impair participants’ ability to weigh the risks of the study against the value of these advantages in the military environment
• The risks involved in the research study are commensurate with the risks that would be accepted by non-armed force volunteer participants
• Procedures for the selection of study participants from within the military are fair to all military personnel and insulated from arbitrary intervention by military authorities or by other members of the armed forces
• The information conveyed to the participants is presented in language that is understandable to them
• There is adequate assurance that a participant’s participation or refusal to participate in the study will not be considered in decisions regarding their promotion, pay, or any other career opportunities

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

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

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

• The minor/child who is competent to make the decision

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

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

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

• It is in the best interests of the minor/child

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

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

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

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

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

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

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

See the NHAParticipants for detailed application requirements.

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

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

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

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

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

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

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

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

• The research study presents minimal risk

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

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

• Adults are not appropriate participants for the research

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

Assent Requirements

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

Consent for Processing Personal Data

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

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

The ChildAct states that a person less than 18 years of age should be known as a child. As per the G-AppConductCT and the G-EthicsHR-TZA, when the research participant is a child, the informed consent form (ICF) must be signed by the child’s parent/legal guardian.

According to the G-EthicsHR-TZA, research involving greater than minimal risk, but presenting the prospect of direct benefit to a child, may be conducted only if:

• The risk is justified by the anticipated benefit to the child
• The relation of the anticipated benefit to the risk is at least as favorable to the research study participants (children) as that presented by available alternative approaches
• Adequate provisions have been made for the solicitation of the child’s assent and the informed consent of the child’s parent/legal guardian

Further, per the G-EthicsHR-TZA, research that involves greater than minimal risk and entails no prospect of direct benefit to the individual child participant, but is likely to yield generalizable knowledge about the child’s disorder or condition may not be conducted unless:

• The risk represents a minor increase over minimal risk
• The intervention or procedure presents experiences that are commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations
• The intervention or procedure is likely to yield generalizable knowledge about the child’s disorder or condition that is of vital importance for the understanding or amelioration of that disorder or condition
• Adequate provisions have been made for the solicitation of the child’s assent and their parents’/legal guardians’ informed consent
• When the child’s participation is indispensable and participation is not contrary to the child’s best interest

As delineated in the G-EthicsHR-TZA, mature minors are individuals 14 to 17 years of age who are able to demonstrate the ability and capacity to manage their own affairs and to live wholly or partially independent of their parent/legal guardian. This is someone who has not reached adulthood (as defined by country law) but who may be treated as an adult for certain purposes (e.g., consenting to medical care). Emancipated minors refer to persons who have not reached the age of majority (18 years) and are empowered by law to make autonomous decisions. They are free from control by their parent/legal guardian, and the parent/legal guardian is free from the responsibility for the child. Mature and emancipated minors may independently provide informed consent to participate in research if:

• In the ethics committee’s (EC’s) view, the research is not objectionable to parents/legal guardians in the community (established with evidence from the community)
• The research protocol includes clear justification for targeting mature and emancipated minors as participants, and a clear justification for not involving parents/legal guardians in the consent process

The G-AppConductCT delineates that data on the appropriate use of investigational products (IPs) in the pediatric population should be generated unless its use in pediatric patients is clearly inappropriate. The pediatric development program should not delay completion of adult studies and availability of IPs for adults. The decision to proceed with a pediatric development program for an IP and the nature of that program should follow the requirements in TZA-12.

Assent Requirements

The G-EthicsHR-TZA, states that the child’s assent takes precedence over the parent’s/legal guardian’s consent. For all research involving children, there must be no financial or other inducements to participate for the parent, guardian, or child, although reimbursements and a token for the child after completion of the study may be acceptable.

Per the G-EthicsHR-TZA, children and adolescents who are minors cannot give legally-valid informed consent, but they may be able to give assent. To give assent means that the child or adolescent is meaningfully engaged in the research study discussion in accordance with their capacities. Assent must be considered as a process and is not merely the absence of dissent. Furthermore, the researcher must involve the child or adolescent in the actual decision-making process and use age-appropriate information. It is particularly important to inform the child or adolescent and obtain assent as described above, preferably in writing for children who are literate. Specific protections to safeguard children and adolescents’ rights and welfare in the study are necessary. Before undertaking research studies involving children and adolescents, the researcher and the ECs must ensure that:

• A parent/legal guardian of the child or adolescent has given permission
• Assent of the child or adolescent has been obtained, after having been provided with adequate information about the study tailored to the child’s or adolescent’s level of maturity
• If children reach the legal age of maturity during the study period, their consent to continued participation should be obtained

Per the G-EthicsHR-TZA, children or adolescents are required to assent if they are between 10 and 17 years old and can read and write, as well as understand the description of the study. In general, the refusal of a child or adolescent to participate or continue in the study must be respected unless, in exceptional circumstances, where participation is considered the best medical option. For research interventions or procedures that have the potential to benefit children or adolescents, the risks must be minimized and outweighed by the prospect of potential individual benefit. For research interventions or procedures that have no potential individual benefits for children/adolescents, the interventions should be studied in adults first, unless the necessary data cannot be obtained without participation of children/adolescents and the risks are minimized.

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

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

The G-AppConductCT recommends that women of child-bearing potential be included at the earliest possible stages of clinical trial research so that potential sex-related differences are identified and taken into consideration when planning Phase III trials. The timing of including women of childbearing potential or pregnant women in clinical trials should comply with guidance in the International Council for Harmonisation's Guidance on Nonclinical Safety Studies for the Conduct of Human Clinical Trials and Marketing Authorization for Pharmaceuticals (TZA-15). Any research involving pregnant women should be individualized and based on a careful risk/benefit assessment, considering:

• The nature and severity of the disease
• The availability and results of previous nonclinical and clinical data
• The availability of alternative therapy and knowledge about their risks
• The stage of pregnancy in relation to the overall development of the fetus, especially regarding fetal brain development
• The potential for harm to the woman, the fetus, or child
• The long-term follow up of the pregnancy, fetus, and child, when possible

Additional considerations for including pregnant women in clinical trials are provided in the G-AppConductCT.

The G-AppConductCT identifies the following considerations for deciding whether to include breastfeeding women in clinical trials:

• A new indication is being sought for an approved therapeutic product and there is evidence of use or anticipated use by breastfeeding women
• After market authorization, use of a therapeutic product in breastfeeding women becomes evident
• There is concern that the consequences of uninformed dosages for use while breastfeeding are potentially serious and/or severe
• A therapeutic product is under review for market authorization and is expected to be used by women of reproductive age
• The trial involves marketed medications that are commonly used by women of reproductive age
• The risk to the infant or mother is not greater than that from established procedures routinely used during breastfeeding, is comparable to those being studied, and the purpose of the research is the development of biomedical knowledge which cannot be obtained by any other means

As per the G-EthicsHR-TZA, research studies relating to pregnant women or fetuses may be undertaken under the following conditions:

• The risk to the fetus is minimal and is the least possible risk for achieving the objectives of the research study, except where the purpose of the research study is to meet the health needs of the mother and the fetus, and the foreseeable benefits outweigh the potential risks
• No procedural changes that could cause greater than minimal risk to the fetus or to the pregnant woman may be introduced into the procedure for termination of the pregnancy
• No inducements, whether financial or any other form, may be offered to terminate the pregnancy for the purposes of the research study
• Appropriate studies on animals and non-pregnant individuals have been completed
• The purpose of the proposed research is to meet the health needs of the mother and the fetus will be placed at risk to the minimum extent necessary to meet these needs or the risk to the fetus is minimal
• The mother and the father are both legally competent and have been fully informed of the possible impact on the fetus and have given their informed consent to proceed; however, the father’s consent is not required if the purpose of the research is primarily to meet the health needs of the mother, the father’s identity and/or whereabouts are unknown, the father is not available, or the pregnancy resulted from rape or incest

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

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

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

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

According to the G-EthicsHR-TZA, prisoners are vulnerable to abuse by research because their freedom for consent can easily be undermined, which could affect their ability to make a voluntary decision regarding their participation in research. Research involving prisoners may not be approved unless the proposed research has the intent and a reasonable probability of improving the health and well-being of the study participants, and appropriate knowledgeable persons in penology, medicine, and ethics have been consulted in the course of reviewing the research protocol. Further, research with prisoners can be conducted only if:

• The research offers a distinctly favorable benefit to risk ratio, not because the prisoners are a convenient source of participants
• The research improves the well-being of prisoners while taking great care to protect their health, well-being, and human rights
• The ethics committee (EC) reviews and verifies that the criteria for permissible research are satisfied
• EC members have no association with the prison(s) involved other than their status as members of the EC reviewing the proposed research study
• Where possible, a prisoner or an ex-prisoner should be co-opted to the EC in reviewing the proposed research study
• The risks involved in the research study are commensurate with risks that will be accepted by non-prisoner volunteers
• The procedure for selecting participants in the prison are fair to all prisoners
• There is adequate assurance that a prisoner’s participation or refusal to participate will not be considered in decisions regarding their release or further detention and each prisoner is clearly informed in advance that participation in the research study will have no effect on their release
• Any possible advantages accruing to the prisoner through participation in the research study, when compared to the general living conditions, medical care, quality of food, amenities and opportunity for earnings in the prison, are not of such magnitude that the prisoner’s ability to weigh the risks of the research against the value of these advantages in the prison environment is impaired

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

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

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

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

As indicated in the G-EthicsHR-TZA, persons living with mental disabilities require special attention because they are prone to being socially marginalized, and therefore, their dignity, rights, and well-being in research must be respected. Careful consideration should be made where proxy consent is used. Where the use of signed consent forms is not feasible, alternative viable methods should be employed. Persons living with disabilities should not be unfairly excluded from participating in research. Researchers should make efforts to address communication, disability, and comprehension constraints. Persons with mental health conditions including psychiatric, cognitive, or developmental conditions, and substance abuse related disorders at times may be hospitalized or institutionalized, which may further compromise their ability to make voluntary decisions to participate in a research project. Research must not be conducted if the purpose of the research is not relevant to the particular health needs of persons living with disabilities, or alternative interventions exist that are at least as advantageous to the individual participant as that under the proposed study. Further, the following should be scrutinized:

• There is sufficient justification for inclusion
• There are appropriate evaluation procedures for ascertaining study participants’ ability to give informed consent; if such study participants are deemed unable to understand and to make an informed decision, then an appropriate proxy should be identified
• An informed consent process that is free from coercion
• Be of no more than minimal risk; if minimal risk is involved, the risk is outweighed by the anticipated benefits of the research study to the participants

The G-EthicsHR-TZA outlines the requirements to safeguard the rights and welfare of adults who are incapable of giving informed consent in research studies. Before undertaking research with adults who are not capable of giving informed consent, the researcher and the EC must ensure that:

• A legal representative of the person who is incapable of giving informed consent has given permission and this permission takes account of the participant’s previously formed preferences and values (if any)
• The assent of the participant has been obtained to the extent of that person’s capacity, after having been provided with adequate information about the study at the level of the participant’s capacity for understanding this information
• If participants become capable of giving informed consent during the study, their consent to continued participation must be obtained; in general, a potential participant’s refusal to enroll in the study must be respected, unless in exceptional circumstances where study participation is considered the best available medical option for an individual who is incapable of giving informed consent

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

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

• When used for an unapproved indication

• When used to gain further information about an approved use

As delineated in the G-AppConductCT, an investigational medicinal product (IP) is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. Further per the G-EthicsHR-TZA, an IP refers to a preventative (vaccine), therapeutic (drug or biologic), device, diagnostic, or palliative used in a clinical trial. The G-AppConductCT and the G-EthicsHR-TZA state that an IP includes:

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

Manufacturing

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

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

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

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

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

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

Import

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

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

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

Manufacturing

According to the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) is responsible for authorizing the manufacture of investigational products (IPs) in Tanzania. The TMDA will approve the manufacture of an IP after the clinical trial application has been approved. Also see the GMP-Insp for information on the inspection of manufacturing facilities of human medicinal products.

Import

Per the TMMDAct, the CT-Regs, the TFDCA-ImptExpt, the G-AppConductCT, and the G-ImpExp, the TMDA is also responsible for authorizing the import of IPs. As per the TMMDAct, the TFDCA-ImptExpt, and the G-ImpExp, the sponsor or the principal investigator (PI) may apply for an import license once the clinical trial application has been approved by the TMDA. The TFDCA-ImptExpt specifies that in order to be granted an import license, the applicant must:

• Have a pharmacist registered by the Pharmacy Council who must be a Superintendent of the business
• Have premises registered by the TMDA
• Hold a valid business permit

The G-ImpExp states that importation of pharmaceutical products and raw materials must be done by importers whose premises are registered by the TMDA or the relevant government institutions. All importers should import pharmaceutical products and raw materials through authorized ports of entry. A person must not import any pharmaceutical product with a shelf life of more than 24 months whose remaining shelf life is less than 60%, or a pharmaceutical product with a shelf life of less than or equal to 24 months whose remaining shelf life is less than 80%.

The TFDCA-ImptExpt specifies that the import license application should be accompanied by the clinical trial approval letter issued by the TMDA. The applicant must fill out the Application for Importation of Pharmaceutical Products provided in the First Schedule of the TFDCA-ImptExpt and pay the fee pursuant to the TMMDAFees. In addition, the application should be accompanied by three (3) copies of the proforma invoice numbered, dated, and signed by the superintendent of the business. (A proforma invoice is an abridged or estimated invoice sent in advance of a shipment or delivery of goods.) The proforma invoice should include the following:

• Name and address of the supplier
• Name and address of the manufacturer of each product
• Trade or proprietary name of each product
• The international nonproprietary name (generic name) of the drug and its strength
• In the case of the product containing more than one (1) active ingredient, the name and strength of each product
• The pharmacopoeia specification of the ingredient of each product
• Product registration number issued by the authority for each product
• The quantity, pack size, unit value, and total value in convertible currency
• Batch or lot number where applicable for each product
• Manufacturing and expiration date, where applicable, for each product
• Mode of shipment (sea, air, or road)
• Authorized port of entry
• Signature and stamp of the supplier

Per TZA-34, the import license application can be submitted to the TMDA via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34), which can be accessed by first creating a trader account. An online access registration form is available in Annex I of the G-ImpExp.

As delineated in the TFDCA-ImptExpt and the G-ImpExp, the import permit is valid for six (6) months, not transferable, and issued to cover only one (1) shipment. Per the G-ImpExp, in the case of partial shipments, two (2) shipments may be allowed based on the initial import permit. See the TFDCA-ImptExpt and the G-ImpExp for detailed import application requirements.

The TFDCA-ImptExpt and the G-ImpExp identify the authorized ports of entry for pharmaceutical products imported into Tanzania. The TFDCA-ImptExpt states that an importer must provide all necessary documents as may, from time to time, be requested by the inspector. When it is deemed necessary to collect samples or where the inspector suspects that any product may contravene any regulation or law, the inspector may take samples for further investigation.

Investigator’s Brochure

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

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

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

Quality Management

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

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

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

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

Investigator’s Brochure

In accordance with the CT-Regs and the G-AppConductCT, the Tanzanian government follows the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13), and requires the sponsor or the designated contract research organization (CRO) to provide investigators with an Investigator’s Brochure (IB). The G-AppConductCT states that the IB should be presented in a concise, simple, objective, balanced, and non-promotional form that enables a clinician, or potential investigator, to understand it and make an unbiased risk-benefit assessment of the appropriateness of the proposed trial. The contents of the IB should be approved by the disciplines that generated the described data and a medically qualified person should generally participate in the editing of an IB. If the investigational product (IP) is locally marketed and its pharmacology is well established and widely understood by medical practitioners, an extensive IB may not be necessary, and a current summary of product characteristics may be submitted as an alternative. If a marketed product is being studied for a new use (i.e., a new indication), an IB specific to that new use should be prepared. The IB should be reviewed at least annually and revised as necessary in compliance with a sponsor’s written procedures. More frequent revision may be appropriate depending on the stage of development and the generation of relevant new information.

TZA-13 specifies that the IB must contain all of the relevant information on the IP(s) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse event data. Per the CT-Regs, the sponsor should also update the IB as significant new information becomes available and maintain records of each change.

TZA-13 requires the IB to provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; regulatory and post-marketing experiences)
• Summary of data and guidance for the investigator(s)
• Bibliography

See Section 7.3 of TZA-13 for detailed content guidelines.

Quality Management

Per the G-AppConductCT, the sponsor must document details regarding the chemistry, manufacturing, and control of the IP as prescribed in Module 3. This should include data to demonstrate the quality of the IP, including relevant batch analyses results. If a comparator medicinal product is used, the proprietary name of the medicinal product, non-proprietary or common name of the active pharmaceutical ingredient, company name, country from which the clinical supplies were obtained (as well as the market status in that country), dosage form(s), and strength(s) should be listed. Batch analysis results for the active pharmaceutical ingredient may be provided in either the quality summary or by providing a copy of the certificate of analysis. The certificate of good manufacturing practice should also be included in the clinical trial application.

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

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

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

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

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

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

• The investigator name (if not already included above)

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

• “For clinical trial use only” or similar wording

• The storage conditions

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

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

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

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

Investigational product (IP) labeling in Tanzania must comply with the requirements set forth in the CT-Regs, the TFDCA-ImptExpt, and the G-ImpExp. The TFDCA-ImptExpt and the CT-Regs state that for an IP to be used in a clinical trial, it must be properly labeled in English or Kiswahili (also known as Swahili) language or both, and the information printed on the labels must be indelible, engraved, or embossed on a primary and secondary container.

As set forth in the CT-Regs, the TFDCA-ImptExpt, and the G-ImpExp, the following information must be included on the label (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Statement indicating that the product is for “clinical trial purpose only”

• Name, number, or identifying mark

• Recommended storage conditions

• Sponsor name and address

• Protocol code or identification

• Trade or brand name where appropriate

• International Non-Proprietary Name (INN, Generic name)

• Active ingredient quantities listed in the formulation

• Manufacture and expiration dates

• Batch or lot number

• Storage conditions

• Manufacturer name and address

• Product registration number issued by the Tanzania Medicines and Medical Devices Authority (TMDA) included in the outer and inner packaging, where applicable

• Immediate outer packaging and the enclosed and accompanying literature must be in English or Kiswahili

• Active pharmaceutical ingredient specification (BP, USP, etc.)

According to the CT-Regs, where applicable, investigational medicinal products must be labeled in a manner that protects the blinding. Also, re-labelling of any remaining investigational medicinal product from previously manufactured batches must be performed in accordance with established written procedures and good manufacturing practice principles.

Per the G-EthicsHR-TZA, the sponsor is responsible for proper labelling of the IP(s). The investigational and comparator products must be labelled in conformity with the research protocol and the labelling must state that the product is for investigational purposes only.

Supply, Storage, and Handling Requirements

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

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

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

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

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

Record Requirements

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

Supply, Storage, and Handling Requirements

Per the G-AppConductCT, the sponsor must obtain approval from the Tanzania Medicines and Medical Devices Authority (TMDA) for the investigational product (IP) dossier in the clinical trial application and any changes to the IP that relate to the chemistry and manufacturing information that may affect drug safety and quality. For example, specifications for the IP where limits of the test are relaxed or deleted; where a new impurity or degradation product has been identified; and addition of new raw materials, solvents, reagents, catalysts, or any other materials used in the manufacture of the active pharmaceutical ingredient.

The G-AppConductCT requires researchers to comply with the CT-Regs and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (TZA-13). Per TZA-13, the sponsor must supply the investigator(s)/institution(s) with the IP(s), but not until the sponsor obtains approvals from the TMDA and an ethics committee. The sponsor must ensure the following:

• IP product quality and stability over the period of use
• IP manufactured according to any applicable Good Manufacturing Practices (GMPs)
• Proper coding, packaging, and labeling of the IP(s)
• Records maintained for document shipment, receipt, disposition, return, and destruction of the IP(s)
• Acceptable storage temperatures, conditions, and times for the IP
• Timely delivery of the IP(s)
• Written procedures including instructions for handling and storage of the IP(s), adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
• Maintain sufficient quantities of the IP(s) to reconfirm specifications, should this become necessary

The G-AppConductCT further requires the sponsor to be responsible for the destruction of unused and/or returned IPs. IPs should not be destroyed without prior written authorization by the sponsor. The delivered, used, and recovered quantities of product should be recorded, reconciled, and verified by or on behalf of the sponsor for each trial site and each trial period. Destruction of unused IPs should be carried out for a given trial site or a given trial period only after any discrepancies have been investigated and satisfactorily explained and the reconciliation has been accepted. Requests to dispose IPs must be made to and authenticated by the TMDA. The destruction must be done in accordance with applicable environmental regulations.

The TFDCA-ImptExpt requires that every importer or exporter of a pharmaceutical product must, in respect to the premises, make available the following information to the TMDA: an appropriate inventory control system; an inspection reports file; procedures for handling complaints; and registers for unfit medicines, controlled drugs, recalls, and customers. Further, an importer should maintain the following documents on the premises for a period of not less than one (1) year after the expiration date of the pharmaceutical product: final invoices with corresponding import permits; copies of delivery notes; and sales invoices.

Per the G-EthicsHR-TZA, the sponsor must:

• Provide to the ethics committee (EC) and all other regulatory authorities, a description of the investigational and comparator drugs and a dossier
• Ensure that the IP and any comparator products are of appropriate quality and are subject to quality assurance procedures
• Promptly provide the investigator with any relevant new information that arises during the course of the trial, including information relating to IP safety
• Be responsible for proper packaging and labelling of the IP
• Retain sufficient samples of each batch of the IP and a record of analyses and characteristics so that, if necessary, an independent laboratory may check the product for quality control or bioequivalence

Record Requirements

As set forth in the G-AppConductCT, which complies with TZA-13, the sponsor must ensure maintenance of the following:

• Records documenting IP(s) handling, storage, shipment, receipt, disposition, return, and destruction
• A system for retrieving IPs and documenting this retrieval
• A system to dispose of unused IP(s) and corresponding documentation
• Sufficient quantities of the IP(s) used in the trial to reconfirm specifications, should this become necessary, and maintenance of records of batch samples analyses and characteristics

The G-AppConductCT further requires the sponsor to record and retain destruction operations of IPs. These documents should clearly identify, or allow traceability to, the batches and/or patient numbers involved and the actual quantities destroyed.

See the Data & Records Management section for information about clinical trial-related records retention requirements.

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

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

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

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

Import/Export

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

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

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

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

General Import/Export Requirements for Biological Substances

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

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

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

Import/Export Requirements for Specific Biological Substance Categories

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

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

Material Transfer Agreement

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

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

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

In accordance with the NHA, the NHASpecAmend, the NHABiol, and the MTA-Human, prior to removing or withdrawing any biological material from the body of a living person for research purposes, consent must be obtained from that person in writing, before a competent witness. In the event that the person is a minor, the parents or guardians of that person must provide consent. Furthermore, when withdrawing blood, the NHASpecAmend requires written consent from persons older than 16 years. Per the MTA-Human, the sponsor must obtain the completed informed consent form (ICF) from the donors of human biological materials and data, and submit it with the project protocol to the ethics committee (EC) for approval. Further, the sponsor must submit the ICF for secondary uses of the material to the EC should the need arise. Secondary use is defined as the use of the materials for health research purposes other than the uses determined in the approved protocol.

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

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

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

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

The SA-GCPs observe that many biological samples are collected during clinical interventions for diagnostic purposes, which means the potential for future use of these samples may be presented. Use of human biological materials and their associated data facilitates research in new technologies, which include genetic and genomic research, and cell and gene therapy (CGT). Sponsors and researchers should, therefore, follow the fundamental ethical principles that underpin all research involving human biological materials and their associated data. Research proposals must address specifically the social value of the research especially in the local context; how consent, privacy, confidentiality will be managed; and the potential effect on families, communities, and other groups. Specific concerns include protection of privacy and whether and how incidental findings are to be communicated to the person from whom the sample originates.

Human Tissue Sample Consent Requirements

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

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

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

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

Human Stem Cell Consent Requirements

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

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

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

See ZAF-3 for an analysis of human tissue legislation and stem cell therapy in South Africa.

Human Genetic Research Consent Requirements

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

Waiver of Consent

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