National Health Surveillance Agency (ANVISA)

As delineated in ResNo945 and ResNo585, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspection of drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of ResNo945 and ResNo585.

LawNo9.782 states ANVISA is an independent administrative agency linked to the Ministry of Health (MOH) that is responsible for regulating, controlling, and supervising products and services involving public health risks. LawNo9.782 and ResNo585 explain that the goods and products under the agency’s purview include medicines for human use and their active ingredients; immunobiologicals and their active substances, and blood and blood products, and; advanced therapy products and their active components, and other inputs, processes, and technologies.

As indicated in LawNo9.782 and ResNo585, ANVISA is headed by a Collegiate Board of Directors which is responsible for defining ANVISA’s strategic management plans, ensuring compliance with and enforcing regulatory acts relating to health surveillance, and proposing governmental policies and guidelines to the Minister in support of the agency’s objectives.

Additionally, as delineated in ResNo585, with respect to active pharmaceutical ingredients and medicines, the General Management of Medicines (Gerência-Geral de Medicamentos (GGMED)), which operates within ANVISA’s Collegiate Board, coordinates and supervises the organizational units responsible for regulation; manages the implementation of international cooperation activities; improves regulations; assesses quality, safety, and effectiveness; supervises registration/post-registration; and cooperates with inspection activities.

Per ResNo585, the Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is another administrative unit operating within the Collegiate Board. COPEC is responsible for overseeing clinical research on medicines and biological products conducted for registration and post-marketing surveillance purposes; evaluating petitions; carrying out Good Clinical Practice (GCP) inspections; assisting with international cooperation activities related to the regulation of clinical research on medicines involving human beings; and issuing regulations for granting or denying petitions subject to approval for the clinical research of medicines and biological products and decisions resulting from GCP inspections. See ResNo585 for detailed information on GGMED, COPEC, and ANVISA’s organizational structure and administrative units.

International Alignment

Per BRA-65, ANVISA is a regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ResNo945 indicates that ANVISA has formally adopted the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. (Note: The ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025. However, per the ICH Efficacy Guidelines webpage, ANVISA has not yet implemented it in Brazil).

Please note: Brazil is party to the Nagoya Protocol on Access and Benefit-sharing (BRA-63), 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 BRA-81.

Contact Information

Per BRA-132, the following is ANVISA’s contact information:

ANVISA
Assessoria do Sistema Nacional de Vigilância Sanitária
Setor de Indústria e Abastecimento (SIA)
Trecho 5 – Guará
Brasília – DF
CEP: 71205-050

Phone: (61) 3462-4120 or (61) 3462-6921
E-mail: asnvs@anvisa.gov.br

ANVISA’s Digital Contact Us Form for International Users (BRA-120) may be used to clarify questions and request information.

Phone: 0 800 642 9782 (for general inquiries) (BRA-135). Calls can be made to specific administrative offices posted on BRA-39.

Per BRA-12, the GGMED contact information is as follows:

General Management of Medicines (GGMED)
Phone: (61) 3462-6724
Email: medicamento.assessoria@anvisa.gov.br

Per BRA-18, the COPEC contact information is as follows:

Coordination of Clinical Research in Medicines and Biological Products (COPEC)
Phone: (61) 3462-5599/5526
Email: pesquisaclinica@anvisa.gov.br

South African Health Products Regulatory Authority

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

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

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

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

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

Other Considerations

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

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

Contact Information

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

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

SAHPRA’s physical address is:

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

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

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

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

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

Overview

As set forth in ResNo945 and ResNo585, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs)) for drugs to be registered in Brazil. (Note: Applications are also known as petitions in Brazil). Per ResNo945 and the G-DDCMManual, clinical trials with drugs must have all or part of their clinical development in Brazil. ResNo945 also notes that the DDCM may be submitted at any stage of clinical drug development for one (1) or more phases of clinical trials. However, Phase IV post-marketing trials and non-interventional clinical research are not covered by this regulation and should be initiated after obtaining the relevant ethical approvals in accordance with specific standards to be issued by the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)).

Additionally, pursuant to LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is required to undergo prior ethical analysis by research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). According to ResNo945, clinical trial applications may be submitted in parallel; however, a drug clinical trial can only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

Clinical Trial Review Process

As described in ResNo585, ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is responsible for conducting the review and approval of clinical trial applications (DDCMs). Per ResNo945 and the G-DDCMManual, ANVISA’s technical analysis of a primary DDCM petition will only occur after the filing of at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)). A DEEC is defined as a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) in the DDCM. ResNo945 explains that the absence of the DEEC will result in the rejection of the DDCM without technical analysis. An exception applies to clinical trials involving more than one (1) experimental drug, with a primary DEEC petition that has already been linked to one (1) of the DDCMs of these drugs.

Per LawNo14.874 and ResNo945, ANVISA may request, on one (1) occasion through a technical requirement, clarifications and additional documents during its review of primary DDCM and DEEC petitions, as well as secondary petitions for substantial investigational product (IP) modifications or substantial clinical trial protocol amendments. This action suspends, but does not interrupt, the applicable review deadlines. If ANVISA does not issue a decision within 90 days of receipt, the DDCM and corresponding DEEC will be released upon expiration of the review period, and clinical development may begin after the required ethical approvals have been obtained. See the Timeline of Review section for ANVISA’s petition review timelines.

Pursuant to ResNo945, substantial IP modifications are changes that may affect the quality or safety of the experimental drug, active comparator, or placebo. Per ResNo945 and the G-DDCMManual, substantial IP modifications must be linked as secondary petitions to the corresponding DDCM. Non-substantial IP modifications must always be submitted to ANVISA in the next petition for substantial IP modification or as part of the drug development safety update (DSUR), whichever occurs first. ANVISA will issue a supplementary regulatory act regarding which IP modifications are considered substantial or non-substantial. Refer to the Submission Process and Submission Content sections for IP modification submission process and documentation requirements.

ResNo945 explains that a clinical trial protocol amendment is considered substantial if it meets at least one (1) of the following criteria:

• Protocol changes that interfere with the safety or physical or mental integrity of the participants, or
• A change that is likely to have an impact on the reliability or robustness of the clinical trial data

Per ResNo945 and the G-DDCMManual, substantial protocol amendments must be submitted as secondary petitions linked to the corresponding DEEC. ResNo945 further explains that non-substantial protocol amendments must be submitted to ANVISA in the next petition for a substantial amendment, or, if no substantial amendments by the end of the clinical trial, as part of the final clinical trial protocol monitoring report. ANVISA will issue a supplementary regulatory act to comply with these provisions. See the G-DDCMAmdmts for additional information on protocol amendments. Refer to the Submission Process and Submission Content sections for protocol amendment submission requirements and substantial protocol amendment documentation requirements.

Per BRA-134 and ResNo506, ANVISA also reviews requests for clinical trials using advanced therapy products, which are known as Clinical Development Dossiers for Advanced Therapies (Dossiês de Desenvolvimento Clínico de Produtos de Terapias Avançadas (DDCTA)). See ResNo506 for more information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products in Brazil (i.e., medicines for human use that are based on genes, tissues, or cells). Per ResNo945, in the case of clinical development involving genetically modified organisms (GMOs) or derivatives, an applicant must consult the responsible body, the National Technical Commission on Biosafety – CTNBio (Comissão Técnica Nacional de Biossegurança – CTNBio), in accordance with current legislation.

ResNo945 further delineates that DDCM, DEEC, and secondary petitions submitted to ANVISA prior to the publication of ResNo945 and still awaiting technical analysis will be assessed in accordance with the rules and requirements in force at the time of submission. Sponsors may also request that ANVISA review these petitions according to the optimized analysis procedure requirements described below in this section.

In addition, per ResNo997, ANVISA has established exceptional and temporary measures to optimize the analysis queue for clinical research approvals. Primary and secondary petitions for medicines and biological products that meet the criteria for the optimized analysis procedure based on regulatory reliance (Reliance) are assigned to a specific review queue, which may affect their processing order. Priority petitions that also meet these criteria are given priority over other petitions in the Reliance review queue. See below for more information on the optimized analysis procedure. See BRA-139 and BRA-136 for additional information on ANVISA’s exceptional and temporary review procedures and BRA-138 for frequently asked questions (FAQs) on ResNo997. Note: ResNo997 will remain in effect until December 31, 2026.

Pursuant to ResNo945, ANVISA may, at any time, cancel or suspend the DDCM, any associated clinical trial, or related secondary petitions if:

• It determines the approval conditions have not been met or receives reports of safety, quality, or efficacy issues that significantly affect the trial participants or the reliability or robustness of the clinical trial data
• It concludes that participants are being exposed to significant and unreasonable risks
• It determines that the sponsor has violated the requirements of ResNo945 or failed to comply with the good clinical practice (GCP) principles and IP good manufacturing practice (GMP) requirements

To comply with these provisions, per ResNo945, ANVISA will notify the sponsor of the suspension or cancellation of the DDCM or associated clinical trial and, where appropriate, initiate an administrative and/or investigative proceeding, in accordance with applicable legislation.

ResNo205 establishes specific approval procedures for clinical trials conducted to support the registration of new drugs intended to treat, diagnose, or prevent rare diseases. See the Submission Process section for rare disease clinical trial submission requirements.

Inspection

In accordance with LawNo14.874, ANVISA is authorized to conduct GCP inspections of clinical research centers, sponsors, and contract research organizations (CROs) (clinical research representative organizations (CRPOs) in Brazil). ResNo945 further specifies that ANVISA may inspect clinical trial centers, sponsors, CROs, laboratories, and other institutions involved in IP development to verify compliance with applicable Brazilian legislation and GCP. In addition to ANVISA’s GCP inspection standards, GCP inspections follow the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates, which Brazil has formally adopted. Refer to ResNo945 for more information on ANVISA’s GCP inspection requirements.

RegNo122 also provides guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with GCP. Per BRA-30, ANVISA’s COPEC conducts all clinical trial inspections in accordance with BRA-28. GuideNo35-2020 and GuideNo36-2020 further explain that GCP inspections of sponsors, CRO representatives, and clinical trial centers may be carried out before, during, or after a clinical trial and are classified as routine inspections or inspections based on complaints or suspected irregularities, per RegNo122. The guides also explain that inspections must involve at least two (2) ANVISA inspectors, one (1) of whom serves as the lead inspector and focal point for communication with the clinical trial center or sponsor/CRO(s). Inspections will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.

Priority Submissions

Per ResNo1001, primary DDCM and DEEC petitions, as well as secondary petitions for substantial IP modifications and substantial protocol amendments, may qualify for priority classification. Primary DDCM petitions and secondary petitions for substantial IP modifications are eligible for priority classification if they meet one (1) or more of the following criteria:

• New drug trial in any phase to be carried out in Brazil
• Vaccines of interest to the Ministry of Health (MOH)’s National Immunization Program
• The drug is the subject of an MOH Product Development Partnership or a Local Development and Innovation Program

Per ResNo1001, primary DEEC petitions and secondary petitions for substantial protocol amendments are eligible for priority classification if they meet one (1) or more of the following criteria:

• Clinical trials with drugs, including vaccines, for neglected, emerging, or reemerging diseases, and for medical emergencies in public health
• Clinical trials with drugs, including vaccines, for serious debilitating conditions in situations for which no prophylactic alternative exists
• Clinical trials conducted exclusively with the pediatric population
• Phase I clinical trials conducted exclusively in Brazil

According to ResNo1001, ANVISA must determine eligibility for the priority classification within 45 calendar days of the petition filing date. Once priority classification is granted, ANVISA has 45 days from the first business day after the priority petition is filed to issue its first technical response and 60 days from the applicable filing date to issue a final decision. If ANVISA’s technical area determines that the petition is not eligible for priority classification, the priority request will be denied. See the Submission Process and Timeline of Review sections for detailed priority submission procedures and review timelines.

Optimized Analysis Procedure Submissions

As delineated in ResNo945, ANVISA has adopted a technical evaluation mechanism known as the “optimized analysis procedure,” under which evaluations conducted by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) may be used as a sole or complementary basis for decision-making. AREEs are regulatory authorities whose practices are aligned with those of ANVISA and are therefore considered to be within the scope of regulatory reliance (Reliance). The optimized analysis procedure may be applied based on Reliance on AREE assessments or based on ANVISA-defined criteria regarding the risk or complexity of the clinical trial or the IP. See also BRA-137 for additional information on Reliance.

ResNo945 further states that clinical trials and/or IPs approved under the optimized analysis procedure—based on Reliance, experience with the use of the IP, or authorization by expiration of the review period—may be subject to on-site inspection. Such inspection may result in alteration of the decision, a request for additional evidence, or any other necessary sanitary measure, without prejudice to other applicable legal measures.

Reliance Reviews

ResNo945, RegNo338, and BRA-122 explain that the optimized analysis procedure based on Reliance may be applied, upon sponsor request, to the approval of primary DDCM and DEEC petitions, as well as secondary petitions for substantial modifications to the IP and substantial amendments to the clinical trial protocol. The documents required to support each type of petition or submission may be partially or fully exempted from technical review under the optimized analysis procedure by Reliance. ANVISA will also issue a supplementary normative act to establish the criteria and documents that may be partially or fully exempted from technical analysis under Reliance.

Pursuant to ResNo945, ANVISA will review the AREE documentation for compliance. Per ResNo945 and RegNo338, for the purposes of admissibility for analyzing primary and secondary petitions, the related documents must have been approved by at least one (1) of the AREEs recognized by ANVISA.

Per RegNo338, ANVISA has designated the following AREEs to review primary DDCM and DEEC petition requests, and secondary petition requests for substantial modifications to the IP and substantial amendments to the clinical trial protocol:

• European Medicines Agency (EMA) and its member countries
• Health Canada
• Swiss Agency for Therapeutic Products (Swissmedic)
• Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom
• US Food and Drug Administration (FDA)
• Pharmaceuticals and Medical Devices Agency (PMDA), Japan

ANVISA must be given the sponsor’s consent to communicate directly with the AREE about the clinical development process under analysis. ANVISA will also review any commitment terms or conditional approval assumed with the AREE and the details about the respective pending issues and referrals, if applicable.

According to RegNo338, following its evaluation under the optimized analysis procedure by Reliance, ANVISA will issue one (1) of the responses listed below:

• If the criteria for applying the optimized analysis procedure by Reliance are met, the status of the secondary petition request will be updated to "Approved"
• If the secondary petition submitted under the optimized analysis procedure by Reliance are not met, the status of the petition request will be updated to "Not Approved", and all documents linked to the petition will be subject to a full analysis, as described in ResNo945. In this case, an official letter will be sent to the company with the respective justification

ResNo945 and BRA-122 further state that the admissibility of the optimized analysis procedure based on Reliance does not presuppose prioritization of petition analysis, however, per ResNo945, ANVISA may create specific queues for the allocation and analysis of these petitions. BRA-122 also indicates that petitions will be analyzed in accordance with the chronological order of submission (issue date of the file), regardless of whether they fit into the optimized procedure. However, petitions prioritized under the terms of ResNo1001 and ResNo205 may also be included in the criteria for applying the optimized analysis procedure when requested by the applicant.

Additionally, per ResNo945 and BRA-122, ANVISA will be responsible for deciding whether to accept the request for analysis using the optimized procedure, including opting for the ordinary analysis of the petition, regardless of the decision issued by the AREE. Per ResNo945, ANVISA may carry out complementary monitoring actions, such as GCP audits or inspections to monitor DDCMs, DEECs, and secondary petitions approved by the optimized analysis procedure. Monitoring actions include the assessment of information regarding the safety profile, based on national and international alerts, and other duly justified actions, at ANVISA’s discretion, that may contribute to maintaining the approved conditions.

See the Submission Process and Submission Content sections for detailed submission requirements.

Risk and Complexity Based Reviews

As delineated in ResNo945, the optimized analysis procedure may also be applied based on the risk or complexity criteria of the clinical trial or IP. When requested by the sponsor, this type of technical analysis applies to DDCMs and substantial IP modifications. The required documents for each type of petition or submission may be partially or fully exempted from technical analysis according to the assessed risk and complexity of the clinical trial. ANVISA categorizes clinical trial risk as low, moderate, or high. Refer to RegNo338 for more information on risk assessment criteria.

ResNo945 further notes that in cases where the placebo, when used, is identical to the registered IP, differing from it only by the absence of the active pharmaceutical ingredient (API), and/or when the active comparator is identical to the registered drug, ANVISA’s evaluation of the documents present in the Investigational Medicinal Product Dossier (IMPD) or Investigational Product Dossier (DPI) may also be analyzed using the optimized analysis procedure based on risk assessment. Per RegNo338, ANVISA will provide a specific petition characterization form for the sponsor to complete for the proper identification of situations in which the optimized analysis procedure is supported by experience using the IP. BRA-122 further indicates that when ANVISA considers an AREE evaluation of an API and DPI, the Investigator's Brochure (IB) or a clinical protocol, the analysis of these documents may be partially or totally waived, as long as they are the same versions previously analyzed by the AREE, except when it concerns a complex clinical trial, prophylactic and therapeutic vaccines, and biosimilar products.

Overview

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

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

Clinical Trial Review Process

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

As stated in ZAF-36, the CTU completes a preliminary screening of the application and sends an official letter to the applicant with the outcome and follow-up questions on a screening checklist. As indicated in ZAF-23, incomplete documentation or sub-standard submissions will be rejected. Additionally, applications submitted without clinical trial insurance will be rejected. Applicants will be allowed a maximum of two (2) rounds of queries to respond to, and if the responses are not satisfactory, the application will be rejected. Per ZAF-36, if an application is rejected, no response is required; the screening checklist should be used as guidance for resubmission during the next review cycle. Next, the CTU’s Clinical Trial Committee (CTC) (which includes an expert committee of specialists, as needed) reviews the proposed clinical trials pursuant to the schedule on SAHPRA’s website. (See CTCDates for 2026 dates). Per ZAF-1, clinical trial reviews will result in one (1) of the following outcomes:

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

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

Other Considerations

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

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

National Health Surveillance Agency (ANVISA)

As set forth in ResNo857, the sponsor is responsible for paying a Health Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) to submit a clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). As per ResNo857 and BRA-47, once the sponsor has completed the process of submitting a primary DDCM petition, ANVISA’s Solicita Electronic Petition Request System (BRA-56) generates a document known as the Union Collection Guide (Guia de Recolhimento da União (GRU)). According to ResNo857, ANVISA uses the GRU as its primary method to generate TFVS fees. In addition to ResNo857, see also BRA-51 for detailed information on the GRU, and BRA-69 for information on the TFVS fee. See also BRA-38 and BRA-47 for additional information on accessing BRA-56.

Per BRA-69, ANVISA determines the TFVS fee based on the company’s size and the subject code assigned to the application request. Per the TFVS fee table provided in ResNo857 and OrdNo45, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval. Per BRA-69, users can also obtain their petition fee prior to submission by searching ANVISA’s Consultation System webpage (BRA-44) using the “Subject Consultation” (Consulta de Assuntos) tool. BRA-44 provides the fee value based on the petition description subject code. See BRA-69 for further fees information. See also BRA-129 for additional instructions on searching BRA-44.

Payment Instructions

As described in ResNo857, the TFVS fee must be paid by the GRU; the Federal Revenue Collection Document (Documento de Arrecadação de Receitas Federais (DARF)) (BRA-111), which is a document used to pay taxes, fees, or contributions; PagTesouro (BRA-114); or other methods that may be established. BRA-43 also states that bank payments may be completed at any financial institution participating in the bank clearing system, via the Internet, self-service (ATM) terminals, or directly at the cashier’s window. Per ResNo857 and BRA-43, payment must be made within 30 days after the GRU has been issued.

Per BRA-115, for payments made using ANVISA’s Solicita Electronic Petition Request System (BRA-56), users can select payment through the PagTesouro online payment system (BRA-114). As per BRA-47, users choosing to pay via PagTesouro (BRA-114) may do so by credit card, or by Pix, which is an instant payment method where a QR Code is generated to complete the payment. Per BRA-47 and BRA-115, users may also choose the “Generate Boleto” option in the Solicita system (BRA-56) to generate the GRU payment slip that can be used to pay via conventional banking methods, with confirmation within two (2) business days. See BRA-47 for further guidance on how to complete the payment process via the Solicita system (BRA-56). See also BRA-115 for additional information on PagTesouro (BRA-114).

South African Health Products Regulatory Authority

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

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

• Clinical trial application (safety and efficacy): South African Rand (R)33 700
• Clinical trial application (bioequivalence study): R31 700
• Clinical trial application (postgraduate study) with pharmaceutical company involvement: R11 200
• Phase 4 clinical trial application and any other clinical trial application, including university-involved postgraduate qualification and/or pre-consultation of clinical trials: R5 100

For amendments to clinical trials:

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

For licenses:

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

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

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

Payment Instructions

Per the G-SAHPRAFees, SAHPRA has initiated a process to phase in an electronic application system through various Application Portals that will create unique reference numbers for the application and relevant payment. When making payments, applicants should follow these guidelines:

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

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

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

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

Overview

As delineated in LawNo14.874, DecreeNo12.651, and ResNo466, Brazil has a decentralized process for the ethical review and approval of clinical trial research. Per LawNo14.874, investigators are required to submit the research documentation, including any amendments, to a research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) for approval. ECs (CEPs) operate under the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)) and are subject to the requirements established by LawNo14.874 and DecreeNo12.651, as well as National Health Council (Conselho Nacional de Saúde (CNS))-issued standards currently in force under the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)).

Note: Brazil is currently transitioning from the CEP/CONEP System under the CNS to SINEP. Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

LawNo14.874 establishes SINEP, and DecreeNo12.651 further defines its framework. SINEP is comprised of INAEP and includes an ethics review component, (Instância de Análise Ética em Pesquisa), which is carried out by the ECs (CEPs). ECs (CEPs) are overseen and credentialed, and where applicable, accredited by INAEP and are responsible for the ethical review of clinical trial protocols involving human beings.

In addition, LawNo14.874 and DecreeNo12.651 explain that the role of the ECs (CEPs) is defined according to the complexity of the ethical review and the degree of risk involved in the research, as follows:

• An EC (CEP) credentialed by INAEP, for the ethical review of low or moderate risk research
• An EC (CEP) credentialed and accredited by INAEP for the ethical review of high-risk research and for the review of low or moderate risk research

CEP/CONEP System (Pre-SINEP Framework)

As per ResNo466, ResNo446, and OSNo001, CONEP is the central body responsible for coordinating the network of institutional ECs (CEPs), and for registering and accrediting the ECs (CEPs). CONEP is a collegiate advisory body directly linked to the CNS, a permanent body within the MOH’s Health System (Sistema Único de Saúde (SUS)) (BRA-53).

Both the ECs (CEPs) and CONEP are responsible for evaluating the ethical aspects of all research involving human beings and for approving the research protocols when applicable, as explained in ResNo466, ResNo446, OSNo001, and ResNo706. ResNo466 further notes that institutions conducting research involving human beings may establish one (1) or more ECs (CEPs) according to their institution’s requirements. For those institutions lacking an EC (CEP), or in the case of an investigator without an institutional affiliation, CONEP is required to suggest an EC (CEP) to conduct the protocol review. Together, the ECs (CEPs) and CONEP represent the ethical review system in Brazil, known as the CEP/CONEP System, as described in ResNo466, OSNo001, G-ClinProtocols-FAQs, and ResNo706. See also BRA-50 and BRA-49 for useful information on CONEP and the CNS.

Ethics Committee Composition

National System of Ethics in Research Involving Human Beings (SINEP)

As stated in LawNo14.874 and DecreeNo12.651, the ECs (CEPs) should be composed of a collegiate and interdisciplinary team, of a consultative and deliberative nature, from medical scientific and non-scientific fields. LawNo14.874 specifies that EC (CEP) members should have the necessary qualifications and experience to analyze all aspects inherent to the research, including medical, scientific, ethical aspects and those related to good clinical practice (GCP). The EC (CEP) is also required to have in its composition one (1) Research Participant Representative (Representante de Participante de Pesquisa (RPP)).

DecreeNo12.651 further explains that the selection of representatives from the scientific community should be made through a public selection process, with criteria that prioritize representation and the promotion of regional, ethnic-racial, gender, and interdisciplinary diversity. These representatives must have academic training and professional experience in the areas of medicine, pharmacy, biotechnology, law, bioethics, or other areas of the human and social sciences, health, and other emerging fields for research involving human beings. An interdisciplinary composition that reflects technical knowledge should also be ensured. The selected specialists must hold a doctoral degree or at least 10 years of professional experience serving on ECs (CEPs) involving human beings or in the analysis, conduct, and development of human research protocols. See DecreeNo12.651 for additional details on the public selection process and appointment procedures.

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

As per OSNo001 and ResNo446, CONEP is an independent and multidisciplinary organization consisting of 30 appointed members and five (5) alternate members. Per ResNo446, CONEP also has an Executive Secretary appointed by the MOH’s Secretariat for Science, Technology and Strategic Inputs and an Assistant Secretary appointed by the CNS to coordinate CONEP’s work and to manage the technical and operational work to be carried out by the Executive Secretary. See ResNo466, OSNo001, and ResNo446 for detailed information on CONEP composition and responsibilities. See also BRA-50 for useful information on CONEP.

Research Ethics Committees (CEPs)

Within the CEP/CONEP System, OMREC indicates that an EC (CEP) should be composed of a minimum of seven (7) members having proven expertise in research. ResNo706, in turn, states the EC (CEP) must be composed of at least nine (9) members with at least two (2) RPPs. Additionally, OSNo001, OMREC, and ResNo706 indicate that the EC (CEP) should be multidisciplinary, represent a balanced gender and age composition, and consist of members embodying community interests and concerns.

OMREC and ResNo706 further state that not more than half of its members should belong to the same professional category. Additionally, per ResNo706, at least half of the members must demonstrate experience in research. Also, any changes to the infrastructure, composition of members or administrative employees must be communicated to CONEP. When there is a change in EC (CEP) member composition, at least one third of the members of the previous composition must be maintained. Changes in EC (CEP) coordination must also be communicated and approved by CONEP. See ResNo706 for additional information. Additional criteria for EC (CEP) membership are also available in Section 2 of OMREC.

ResNo647 also establishes standards and mandatory requirements for all ECs (CEPs) in Brazil to include RPPs who represent the interests of research participants. RPPs must be at least 18 years old; have a history of participation in a social and/or community movement in which the participation is not limited to health areas and can cover all segments of social movement activity; and must be able to express the viewpoints and interests of individuals and/or groups of research participants in order to represent the collective interests of different audiences in the CEP/CONEP System. See ResNo647 for detailed information on RPPs. See also BRA-29 for additional information.

Terms of Reference, Review Procedures, and Meeting Schedule

National System of Ethics in Research Involving Human Beings (SINEP)

Pursuant to OrderNo1, the internal regulations of the ECs (CEPs) must contain sufficient rules to ensure the regular functioning of the committees, the integrity of deliberations, and compliance with the legal deadlines applicable to the ethical analysis of research. ECs (CEPs) may implement certain administrative changes to their internal regulations immediately after formal notification to INAEP, accompanied by an update to the EC’s (CEP's) internal regulations, when applicable. However, ECs (CEPs) are required to obtain the approval of INAEP Coordination to establish changes that impact the composition, governance, or decision-making structure of the EC (CEP). See OrderNo1 for additional INAEP requirements.

As per LawNo14.874, ECs (CEPs) must adopt established procedures and be responsible for the following:

• Operating regularly
• Ensuring adequate infrastructure to carry out their activities
• Maintaining a publicly available list of their members with their respective professional qualifications
• Preparing a document describing their operational procedures
• Keeping written records of their activities and meetings

As described in LawNo14.874 and OrderNo1, EC (CEP) internal regulations and procedures must include at a minimum (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Previously scheduled meetings to deliberate on the ethical adequacy of the research
• Rules for convening and holding ordinary and extraordinary meetings
• Minimum quorum for the meeting to begin and for deliberations
• Rules regarding the composition of the board, disqualification, bias, and conflict of interest
• Rules for drafting minutes and recording resolutions
• Criteria for replacing full members with alternate members and expressly distinguishing between the roles of full member, alternate member, and alternate member acting as a substitute
• Frequency of meetings must be sufficient to ensure the regular functioning of the collegiate body, the timeliness of ethical analysis, compliance with the deadlines established in LawNo14.874, and the possibility of extraordinary meetings whenever necessary
• Description of the responsibilities of the coordinator and the deputy coordinator, if any, as well as the rules for substitution in case of absence
• Consultants or ad-hoc members who may be invited to contribute to the analysis of a specific matter are not part of the EC’s (CEP’s) deliberative body and do not have the right to vote

LawNo14.874 further states that only active EC (CEP) members are permitted to issue opinions and deliberate on the ethical adequacy of submitted research. Once duly credentialed, and where applicable, accredited, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP. ECs (CEPs) will also keep all project related documents on file for a period of five (5) years after the end of the research, with digital archiving permitted.

Also, per LawNo14.874, in the case of research involving a special group, to be established by regulation, the EC (CEP) must ensure, whenever possible, during the protocol discussion, the participation of one (1) representative of the special group as an ad-hoc member; and one (1) consultant familiar with the language, customs, and traditions of the specific community, when the research involves that community. EC (CEP) members may also invite external experts and representatives of vulnerable groups to issue an opinion on specific issues related to the research projects, but these individuals should not have the right to vote. See also the Vulnerable Populations section for requirements applicable to research involving special groups.

As stated in LawNo14.874, the institution hosting the EC (CEP) will promote and support the training of its committee members, with an emphasis on ethical and methodological aspects related to the rights of research participants. The EC (CEP)’s activities are subject to oversight and monitoring by INAEP. Failure by the EC (CEP) to comply with the provisions of LawNo14.874 will result in its de-accreditation by INAEP, in accordance with regulations.

See LawNo14.874 for additional EC (CEP) terms of reference and review procedure requirements.

CEP/CONEP System (Pre-SINEP Framework)

As set forth in OMREC, under the CEP/CONEP System, each EC (CEP) must have written standard operating procedures (SOPs), including a process for conducting reviews. The SOPs should include information on EC (CEP) 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. ResNo706 further specifies the EC (CEP) is responsible for the following:

• Maintaining adequate composition
• Choosing, for coordination, an EC (CEP) member that does not present a potential conflict of interest, by vote of the absolute majority (50% plus one) of the total number of full members
• Issuing opinions and sending CONEP reports on its activities within regulatory deadlines
• Maintaining confidentiality of all information regarding research protocols and the content of EC (CEP) meetings
• Preparing the internal regulations
• Analyzing research protocols of the proposing institutions, located only in the same Federative Unit as the EC (CEP) registration
• Ensuring periodic training of its members, through a permanent training plan on ethics in research involving human beings, including content targeted and accessible to RPPs
• Promoting educational activities in the area of research ethics involving human beings, with its members and the community in general
• Maintaining regular and effective communication with CONEP
• Receiving complaints and investigating ethical infractions, especially those that involve risks to research participants, communicating the facts to the competent bodies for investigation and, when appropriate, to the public prosecutor's office

ResNo706 further notes that an EC (CEP) is responsible for receiving and considering, from an ethical point of view, the research protocols indicated by CONEP. However, the committee may also refuse the ethical assessment of research protocols indicated by CONEP, upon justification. Per OMREC and ResNo706, the majority of committee members must be involved in the review and approval process, and the necessary quorum must be obtained to approve or deny permission to conduct a study as specified in each EC (CEP’s) SOPs. As per ResNo706, the term of office of EC (CEP) members is valid for four (4) years, with the possibility of reappointment, at the discretion of the CEP. At the end of the term of office, an EC (CEP) member may remain in this role up to 90 days, until a replacement or reappointment takes place.

See OMREC for detailed EC (CEP) procedures and information on other administrative processes. See CLNo25 for guidance on conducting virtual CEP/CONEP System meetings.

Overview

As stipulated in the NHA and ZAF-52, ethics committees (ECs) in South Africa are governed by the National Health Research Ethics Council (NHREC), which is a statutory body established under the NHA. NHREC determines guidelines for the functioning of ECs and registers and audits ECs, among other functions. Further, NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals.

As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCP, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study.

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

Ethics Committee Composition

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

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

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

The G-EthicsHR-ZAF states that it is important for ECs to have clear SOPs that clarify the expectations about EC members’ review responsibilities.

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

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

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

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

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

Overview

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

LawNo14.874 establishes SINEP, and DecreeNo12.651 further defines its framework. Within this system, ECs (CEPs), overseen by INEAP, are responsible for the ethical review of clinical trial protocols involving human beings.

As delineated in LawNo14.874 and DecreeNo12.651, the primary scope of information reviewed by ECs (CEPs) under SINEP relates to protecting the dignity, safety, and well-being of research participants throughout the conduct of research. ECs (CEPs) are responsible for acting independently and autonomously in the ethical analysis, review, and approval of research protocols and their amendments, as well as for evaluating the methods and materials used to obtain and document the free and informed consent of research participants.

As part of their ethical review, LawNo14.874 indicates that ECs (CEPs) are also responsible for requesting additional information for research participants when deemed essential to protect their rights, safety, and well-being. They must ensure research project and other documents adequately address relevant ethical issues and comply with applicable regulatory requirements, including those related to good clinical practice (GCP). ECs (CEPs) should also ensure that adequate means are provided for obtaining consent from the research participant or the legal representative and that they pay special attention to protecting the welfare of participants deemed to be vulnerable. DecreeNo12.651 further states that research involving special groups, due to their vulnerability or unique ways of life, may require differentiated ethical, methodological, or analytical treatment at all stages, as will be established in regulations to be issued by INAEP. (See the Vulnerable Populations and Pregnant Women, Fetuses & Neonates sections for additional information about these populations).

See OrderNo5 for INAEP's ethical guidance regarding bioequivalence, bioavailability, and other pharmacokinetic studies involving drugs with cytotoxic, genotoxic, teratogenic, mutagenic, or other high systemic toxicity risks.

In accordance with LawNo14.874 and DecreeNo12.651, the EC (CEP) review process must be guided by the following principles (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Protection of the dignity, safety, and well-being of the research participants
• Promotion of technical-scientific development and responsible innovation
• Guarantee of independence, transparency, and public disclosure in procedures and decisions
• Equality in the application of criteria and procedures for the review of research projects, based on the risk-benefit ratio, which must be favorable to the research participant and to society
• Efficiency, timeliness, and quality in the review and issuance of opinions
• Interdisciplinary and plural composition of the ECs (CEPs) as a qualifying element of ethical judgment
• Social oversight, with the participation of research participant representative(s)
• Respect for GCP

CEP/CONEP System (Pre-SINEP Framework)

ResNo466, ResNo251, and the G-ClinProtocols-FAQs state that the primary scope of information assessed by ECs (CEPs) and CONEP, jointly known as the CEP/CONEP System, relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in research.

Per ResNo466, ResNo251, and OSNo001, the CEP/CONEP System members must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). Detailed information on consent requirements for studies involving indigenous populations is available in the Vulnerable Populations section.

CEP/CONEP System members are also responsible for ensuring an independent, timely, and competent review of all ethical aspects of the research protocol, as stated in ResNo466 and OSNo001. Members must act in the interests of the potential research participants and the communities involved, evaluating the possible risks and expected benefits to participants; confirming the suitability of the investigator(s), facilities, and methods; and verifying the adequacy of confidentiality and privacy safeguards. Refer to ResNo466 and OSNo001 for detailed ethical review guidelines that govern the CEP/CONEP System.

Per ResNo466, ResNo446, and ResNo340, CONEP is required to review certain studies involving human genetics, human reproduction, invasive therapeutic procedures, indigenous populations, genetically modified organisms, embryonic stem cells, and the establishment and operation of biobanks for research. Refer to ResNo466, ResNo446, and ResNo340 for specific details on CONEP protocol review requirements for human genetics studies. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., protocols on the constitution and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically, and; CLNo041 for CONEP specimens consent instructions. See also ResNo506 for information on the role of CEP/CONEP System members in reviewing protocols submitted for clinical trials with advanced therapy products in Brazil (i.e., medicines for human use based on genes, tissues, or cells).

Exemption from Review

Pursuant to Article 26 of ResNo674, CLNo12 provides additional guidance on research that is exempt from ethical assessment by the CEP/CONEP System. Exempt research includes protocols that fall exclusively within the following categories: public opinion surveys with unidentifiable participants; research using publicly accessible or public domain information; census research conducted by government agencies; research using only information or data already available in aggregate form, without the possibility of individual identification; research conducted exclusively with scientific texts for literature review purposes; research that aims at the theoretical deepening of situations that emerge spontaneously in professional practice, provided no identifiable data are disclosed; education, teaching, extension or training activities conducted solely for instructional purposes by undergraduate students, technical course students, or professionals in specialization programs, without the purpose of scientific research; market research; scientific research carried out with cells, tissues, organs, and organisms of nonhuman origin, including their biological products, provided there is no interaction with research participants or the collection or use of human biological material; and activities intended solely to describe or analyze productive or administrative processes exclusively for organizational development purposes.

Role in Clinical Trial Approval Process

National System of Ethics in Research Involving Human Beings (SINEP)

Pursuant to DecreeNo12.651, the review of protocol authorization requests for clinical research may be carried out through an integrated ethical and sanitary assessment procedure established between INAEP and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). The procedure should prioritize studies involving products intended to address public health emergencies declared by a competent authority.

Per LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is required to undergo prior EC (CEP) ethical review. According to ResNo945, clinical trial applications may be submitted in parallel; however, a drug clinical trial can only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

In addition, ResNo945 requires the EC (CEP) to review and approve any protocol amendments prior to those changes being implemented. There is no stated expiration date for an EC (CEP) approval in ResNo945. LawNo14.874 further notes that the EC (CEP) research ethics review process will be conducted using the information and documents to be established in specific regulations. All documents requested by the EC (CEP) must be specified in an act issued by the MOH, in EC (CEP) regulations or rules, and be relevant to the matter analyzed.

As explained in OrderNo2, LawNo14.874 establishes two (2) timeframes in the EC (CEP) ethical review process: verification of the completeness of the documentation within 10 working days from the date of protocol submission, and issuance of the ethical opinion within 30 days from the date of accepting all of the research documentation. Before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor or require adjustments to the research documentation. EC (CEP) review will be suspended during this time, and the investigator will be given time to respond to the requests made by the EC (CEP). However, the investigator’s failure to respond within the EC (CEP) deadline may result in cancellation of the study's review process. Per LawNo14.874, at the discretion of the EC (CEP), the investigator may participate in the meeting to provide clarification about the research, but the investigator is prohibited from attending the meeting while the final decision is being made. See the Timeline of Review section for detailed timeline information.

Upon completion of EC (CEP) review, LawNo14.874 indicates that the EC (CEP) opinion will be one (1) of the following: approval of the research; non-approval of the research; or, suspension, when approved research that is already in progress needs to be interrupted for safety reasons. The investigator may initially appeal the decision to the EC (CEP) that issued the opinion, and appeal one (1) final time to INAEP. All those involved in conducting, monitoring, evaluating, or approving the research with direct access to the study records to verify compliance with the procedures and applicable legislation, as well as the validity or integrity of the data, must ensure the preservation of data confidentiality and the anonymity of the research participant, in accordance with current legislation.

Per LawNo14.874, after the research begins, if there is a need for a change that interferes with the risk-benefit balance or the approved documentation, the EC (CEP) that initially reviewed the research must analyze and issue an opinion for an amendment to the research project submitted by the coordinating investigator. The amendment may only be implemented after approval by the EC (CEP), in accordance with this law, except when the safety of the research participant depends on its immediate implementation. The provisions for the initial research project review are also applicable to amendments to the research project.

In addition, LawNo14.874 provides that research conducted involving human beings that does not comply with the provisions of this law constitutes an ethical infraction and subjects the offender to disciplinary sanctions provided for in the legislation of the professional council to which the sponsor or the contract research organization (CRO) is affiliated, without prejudice to applicable civil and criminal sanctions. For the purpose of applying these disciplinary sanctions, the EC (CEP) or INAEP will notify the competent professional councils of the ethical infraction committed. Failure to comply with the provisions of LawNo14.874, and failure to comply with the GCP standards per ResNo945, constitutes a health infraction and subjects the offender to the penalties provided for in LawNo6.437, and in specific health regulations, without prejudice to applicable civil and criminal sanctions.

Risk-Based Framework

Decree No. 12.651 further provides that EC (CEP) ethical reviews under SINEP use a risk-based approach from which the degree of risk is classified, considering various factors, including:

• The nature of the intervention or procedure adopted in the research
• The degree of invasiveness and the potential for harm to the research participant
• The population involved, with particular attention to groups in situations of vulnerability
• The use of emerging technologies, sensitive data, or artificial intelligence in healthcare
• The degree of scientific uncertainty regarding the effects of the object of study
• The existence of direct benefits from the research to the participant and to the community
• The complexity of the study design
• The stage of clinical development of the product or technology being evaluated
• Clinical research conducted on a multicenter or international basis

Based on risk classification, per DecreeNo12.651, simplified procedures may be adopted for the submission of documentation, as well as for the review and authorization of clinical research studies. Research protocols are also processed according to their risk level. BRA-143 further clarifies that risk classification must stem from a multidimensional analysis that balances the risks and benefits to the health, safety, dignity, and well-being of the participants with the legitimate interest in the advancement of scientific knowledge.

Additionally, LawNo14.874 and DecreeNo12.651 delineate that the role of ECs (CEPs) is defined according to the complexity of the ethical review and the degree of risk involved in the research, distinguishing between INAEP-credentialed ECs (CEPs), which review low- and moderate-risk research, and INAEP-credentialed and accredited ECs (CEPs), which are authorized to review high-risk research as well as studies involving low or moderate risk levels. Within this framework, and in accordance with the review workflow indicated in DecreeNo12.651, CONEP serves as the appellate body until INAEP members take office. BRA-142 further specifies that, pending further INAEP guidance, responsibility for the ethical review of low- and moderate-risk research protocols should rest with credentialed ECs (CEPs) affiliated with the MOH (e.g., foundations, institutes, hospitals, etc.), while the responsibility for the ethical review of high-risk protocols, specifically those listing the MOH as the proposing institution, should rest with credentialed and accredited ECs (CEPs), as described in DecreeNo12.651. See also BRA-143 and BRA-142 for additional guidance.

High-Risk Research Protocols

Under the SINEP system, per BRA-143, eight (8) accredited ECs (CEPs) are responsible for reviewing all high-risk protocols (see BRA-143 for a list of accredited ECs (CEPs)). Exceptions to this workflow requirement include biobank development protocols, which have been temporarily suspended per BRA-142, as well as certain categories of protocols for which the MOH serves as the proposing institution.

In addition, per BRA-143, high-risk protocols that have already been reviewed and approved by an accredited EC (CEP) should be returned to the original EC (CEP) that conducted the review, thereby preserving the ethical opinion issued and the validity of the decision rendered by the competent body. Protocols that do not fall under the high-risk classification should be returned to the researchers, thereby retaining the opinion previously issued by the originating EC (CEP). BRA-141 also notes that accredited ECs (CEPs) will conduct ethical reviews of high-risk protocols, in accordance with ResNo466 and CLNo172, until INAEP issues specific regulations on risk classification.

Priority Review for SUS Strategic Research

Per LawNo14.874 and DecreeNo12.651, research of strategic interest to the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53) and relevant to responding to public health emergencies is given priority in ethical analysis and is subject to special analysis procedures, including deadlines. These procedures will be further delineated in a separate act to be issued by INAEP, as provided in DecreeNo12.651.

DecreeNo12.651 also specifies that clinical research intended for the sanitary registration of medicines or medical devices is prioritized within SUS when the research is:

• Funded, in whole or in part, with public resources derived from government agencies or from funds for the promotion of science, technology, and innovation
• Aimed at the treatment, prevention, or diagnosis of socially determined, emerging, or re-emerging diseases; severe or debilitating clinical conditions for which no therapeutic or prophylactic alternative is available; and rare diseases
• Targeting the pediatric population, for which no therapeutic or diagnostic alternative is available
• The subject of the MOH Productive Development Partnership, a Local Development and Innovation Program, or related initiatives within the scope of the Health Economic-Industrial Complex
• The active pharmaceutical ingredient is manufactured domestically
• Involves new medicines, medical devices, and advanced therapies for which clinical development and production are carried out domestically
• Involves vaccines of interest to the MOH’s National Immunization Program

See the Timeline of Review section for detailed SUS timeline information.

Multicenter Research

Pursuant to LawNo14.874, DecreeNo12.651, OrderNo3, and BRA-141, multicenter research conducted across different research centers by more than one (1) researcher follows a single protocol. The ethical review of multicenter research is conducted by a single EC (CEP), preferably the EC (CEP) linked to the coordinating research center, which issues the opinion and notifies the other participating center ECs (CEPs) of its decision. Per OrderNo3, the EC (CEP) responsible for the initial approval has formal decision-making authority over the ethical review and monitoring of multicenter research, as well as the authority to assess amendments to the original project. OrderNo3 further recommends that the coordinating EC (CEP) provide participating center ECs (CEPs) with at least five (5) working days to submit comments on local population vulnerabilities, regional particularities, or local institutional arrangements before issuing the final ethical opinion, while ensuring compliance with the 30-working day ethical review period.

OrderNo3 further provides that participating center ECs (CEPs) may not conduct a parallel ethical review of an approved protocol or independently suspend the approved multicenter protocol. However, if serious irregularities or unforeseen imminent risks to research participants within its institution are identified, the participating center EC (CEP) must issue a technical recommendation to the management of the institution or research center to adopt measures to immediately halt research activities at that site. It must also, preferably within 24 hours, communicate the matter and forward the technical recommendation to the EC (CEP) responsible for the ethical review and to INAEP so that those bodies may take the appropriate measures. Additionally, participating center ECs (CEPs) act as local ethical protection bodies and conduct material and institutional monitoring of research at their respective centers. Their responsibilities include receiving complaints from research participants at their institutions; receiving local serious adverse event notifications; recording and promptly forwarding the information received to the coordinating EC (CEP) and INAEP; and monitoring compliance with the approved single protocol at their institutions. See OrderNo3 for additional guidance regarding the implementation of the single ethical review process for multicenter research.

BRA-141 further explains that the single ethical review process does not eliminate local responsibilities or authorizations. Participating centers are still obligated to ensure adequate conditions for the execution of the study, including verifying technical and physical infrastructure, organizing logistics and recruitment in a manner compatible with local realities, and maintaining ongoing institutional responsibility for the protection, integrity, and well-being of participants under their supervision.

Additionally, BRA-141 states that, provided there is a favorable ethical opinion from the responsible EC (CEP), an additional opinion from a local CEP is not required to validate the commencement of activities at centers already included in the approved protocol. However, the participating center must verify the scope of the opinion to ensure that the center and the activities to be conducted at that specific site are included in the protocol. See also BRA-141 for additional INAEP guidance on single EC (CEP) reviews. See the Submission Process section for submission requirements for single EC (CEP) reviews.

CEP/CONEP System (Pre-SINEP Framework)

As per ResNo466, the EC (CEP) (and CONEP, if applicable) must approve a protocol before research may begin. Per OSNo001, the EC (CEP) must also review and approve protocol amendments before they are implemented. If applicable, CONEP may also review protocol amendments. (See CLNo038 for the criteria CONEP uses to process protocol amendments.) ResNo466 and OSNo001 specify that research development and submission, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via Platforma Brasil (BRA-34). See CLNo24 and CLNo24-Note for CONEP’s general clinical trial guidelines for investigators and ECs (CEPs).

Additionally, CLNo040 specifies that if investigational brochure (IB) updates result in modifications to the detailed protocol and/or the informed consent form (ICF), then a protocol amendment must be submitted. The EC (CEP) will analyze the updated IB together with the amendment and supporting documents and, if necessary, request amendments and/or clarifications.

Per CLNo29, in the case of an appeal, only the responsible investigator who received a substantiated opinion of non-approval may appeal through the CEP/CONEP System via Platforma Brasil (BRA-34). The appeal must be filed within 30 calendar days, counting from the first day following issuance of the non-approval opinion. The EC (CEP) must review submitted appeals and issue a substantiated opinion within 30 calendar days following receipt. If the EC (CEP) determines that the requirements and justifications presented in the appeal are sufficient to continue the ethical analysis, the appeal will be approved or remain pending if the protocol requires adjustments prior to approval. If the EC (CEP) does not approve the appeal, the investigator may appeal to CONEP. CONEP must issue a substantiated opinion of approved, pending, or not approved within 45 days of receiving the appeal. If CONEP does not approve the appeal, the investigator, upon receiving the non-approval opinion from CONEP, may file an appeal directly to CONEP. Based on its analysis of the appeals submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal following the final appeal request, the appeal process is terminated, the research protocol is archived, and no further appeal requests are permitted. There is no stated expiration date for an EC (CEP) approval in ResNo466 or OSNo001. See the Timeline of Review section for detailed timeline information.

CONEP Review Pathways

ResNo674 provides review criteria and corresponding timelines to classify research and the processing of research protocols involving human beings in the CEP/CONEP System based upon study type and level of intervention in the human body. The regulation divides research into two (2) groups: 1) studies seeking to describe or understand phenomena that has happened or happen in the research participant’s daily life; and 2) studies that aim to verify the effect of an investigational product (IP) or technique used in research, deliberately applied to the participant, prospectively monitored, and which may or may not involve a control group. The studies are further characterized according to procedure and whether it involves intervention in the human body and if it is invasive.

Classification by study design and procedure is as follows: Type A – observational research; Type B – observational research involving human body intervention; and Type C – investigational research designed to verify the effect of an IP (including a medicine, drug, biological product, or health device) or an investigational technique used in research, deliberately applied to the participant, prospectively monitored, with or without a control. Type C studies are further divided into two (2) subtypes: C1 studies, in which the object of investigation is not an IP in the health area, and C2 studies, in which the object of investigation is an IP in the health area.

EC analysis varies according to the type of research and modulation factors (i.e., consent process, confidentiality, and/or research methods), and requires the reviewer to verify the documentation the investigator submits in Plataforma Brasil (BRA-34). See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.

There are four (4) ways of processing protocols in the CEP/CONEP System: express, simplified, collegiate, and special collegiate; the modulation factors per Annex II of ResNo674 provides additional characteristics to further modify the protocol processing method to be used. See ResNo674 and BRA-4 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures.

High-Risk Research Protocols

As per ResNo674, the CNS has published protocol risk classification and processing guidelines for use in the CEP/CONEP System to provide criteria for assessing the risk level of research protocols. Per ResNo466, ResNo446, and CLNo172, CONEP determined that protocols falling within special thematic areas—such as human genetics, human reproduction, indigenous populations, genetically modified organisms, and the establishment and operation of biobanks—are considered high risk. Refer to ResNo466, ResNo446, and ResNo340 for a complete list of the special thematic areas. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., protocols on the establishment and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically; and CLNo26 for information on submitting research protocols involving human bodies and/or anatomical parts. ResNo674 also notes that CONEP is solely responsible for the registration of biobank development protocols, and the research classification and modulation factors used to further characterize protocols in BRA-34 will not be applicable.

Priority Review for SUS Strategic Research

Per ResNo580, the MOH’s Secretary of Science, Technology and Strategic Inputs refers protocols to CONEP that are determined to be of strategic public health interest for SUS (BRA-53). ResNo580 recognizes strategic research protocols as those studies that may contribute to public health, justice, reduction of social inequalities and technological dependencies, and those that address public health emergencies.

Multicenter Research

Per ResNo346, for multicenter research protocols, the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. CONEP will only evaluate the first protocol submitted and then send its final opinion to the original EC (CEP) and the other participating institutions. ResNo674 similarly explains that the initial analysis of the research protocol using the research classification procedure will occur at the EC (CEP) of the coordinating center or the accredited EC (CEP), when applicable, and will be subsequently forwarded for analysis by the EC (CEP) of the other co-participating centers and/or institutions, after approval. See ResNo346 for additional multicenter protocol processing information.

Foreign Research

As delineated in ResNo292, ResNo446, and ResNo466, applications with coordination and/or sponsorship originating outside of Brazil require additional review by CONEP. Per ResNo446, an exception applies to studies conducted entirely outside Brazil that have been approved by an EC (CEP) or equivalent body in the country of origin.

ResNo292 also explains that the scope of research from abroad or with foreign participation includes collaboration between public or private foreign individuals or legal entities; sending and/or receiving biological materials from humans; sending and/or receiving data and information collected to aggregate research results; and international multicenter studies. For protocols within this thematic area, per ResNo292, special attention should be given to ensuring the EC or equivalent institution within the originating country has issued an approval. If not, the Brazilian EC (CEP) and CONEP must approve the protocol. Refer to ResNo292 and the G-ClinProtocols-FAQs for additional guidance on research studies submitted from abroad.

Overview

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

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

Role in Clinical Trial Approval Process

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

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

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

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

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

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

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

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

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

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

Expedited Review

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

Rapid Review

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

Joint Review

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

Foreign Research Collaboration

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

Artificial Intelligence

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

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

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

National System of Ethics in Research Involving Human Beings (SINEP)

Under the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)), LawNo14.874 and DecreeNo12.651 do not specify fees for research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) under the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)).

CEP/CONEP System (Pre-SINEP Framework)

According to ResNo466, OMREC, and ResNo706, under the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System, which is composed of the CEPs and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), CONEP does not permit ECs (CEPs) to charge a fee to review clinical trial protocols. OMREC further explains that financing to support ethical reviews should come from a specific scientific committee budget designated within each institution.

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

Overview

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising ECs (CEPs) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will also continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

LawNo14.874 establishes the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)), and DecreeNo12.651 further defines SINEP’s framework. Within this system, research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)), overseen by the Ministry of Health (MOH)’s INAEP, are responsible for the ethical review of clinical trial protocols involving human beings.

In accordance with DecreeNo12.651 and per OrdNo85, the MOH, through the Secretariat of Science, Technology, and Innovation and the Health Economic-Industrial Complex (SECTICS/MS), established a temporary working group (Grupo de Trabalho Temporário (GTT)) to support the drafting of complementary and regulatory procedures regarding the functioning of INAEP and the implementation of SINEP. The group is also responsible for:

• Assisting in providing guidance on operational decisions and contributing to the continuity of ethical evaluations during the transition of CONEP’s activities to INAEP
• Conducting a survey of current regulations on ethics in research with human beings that require adaptation
• Proposing supplementary regulations to support the operation of SINEP and INAEP
• Proposing courses of action related to the transition of CONEP's activities to INAEP

In addition, per OrdNo8, the Secretariat of Science, Technology and Innovation in Health of the MOH (SCTIE/MS) established the MOH’s Technical Monitoring Committee of the National Research Platform Involving Human Beings to make recommendations, provide information, and develop proposals to improve the development process of the National Research Platform Involving Human Beings. The committee will have a duration of 12 months, which may be extended for another 12 months, if justified. See OrdNo8 for detailed committee information. See also the Submission Process and Initiation, Agreements & Registration sections for additional information on the National Research Platform, also referred to as the human research platform in DecreeNo12.651.

National Research Ethics Authority (INAEP)

Per LawNo14.874, DecreeNo12.651, and ResNo1, INAEP, an interdisciplinary and independent collegiate body, established within the scope of the MOH, is responsible for the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Issuing regulatory standards on research ethics
• Evaluating the effectiveness of the SINEP
• Credentialing and accrediting ECs (CEPs) to ensure they are qualified to perform the ethical review of research, according to the degree of risk involved
• Monitoring, supporting, and overseeing the ECs (CEPs) in relation to the review of research protocols and in compliance with the pertinent standards
• Promoting and supporting the training of EC (CEP) members, with special emphasis on ethical and methodological aspects
• Acting as an appeals court for decisions issued by ECs (CEPs)
• Contributing to a culture of ethical responsibility in research and in scientific, technological, and innovative development to reconcile the protection of research participants with process efficiency—particularly regarding emerging technologies—and in compliance with ethical standards
• Formulating and approving its internal regulations

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

As per ResNo466, OSNo001, and ResNo446, CONEP was created by the MOH to provide ethical oversight of clinical research and to safeguard the rights and welfare of human beings involved in clinical studies. CONEP reports to the CNS, the advisory body to the MOH.

As delineated in ResNo466, OSNo001, and ResNo446, CONEP’s core responsibilities center on:

• Examining the ethical aspects of research involving human beings
• Analyzing and monitoring research protocols and issuing opinions on applications with coordination or sponsorship originating outside Brazil, unless the co-sponsor is the Brazilian Government and applications are related to specialized thematic areas (i.e., human genetics, human reproduction, vaccines, and human biological materials)
• Preparing and updating relevant ethical standards
• Registering, auditing, accrediting, and training ECs (CEPs)
• Monitoring EC (CEP) processes
• Promoting and participating in educational EC (CEP) activities

See also the Scope of Review section for detailed EC (CEP) and CONEP review requirements associated with protocols originating outside of Brazil.

Registration, Auditing, and Accreditation

LawNo14.874 and DecreeNo12.651 transferred responsibility for EC (CEP) accreditation from CONEP to INAEP. Because EC (CEP) accreditation under the former CEP/CONEP framework remains relevant during the transition to the SINEP framework, both the current INAEP accreditation provisions and the former CONEP accreditation procedures are summarized below.

National System of Ethics in Research Involving Human Beings (SINEP)

National Research Ethics Authority (INAEP)

Pursuant to LawNo14.874 and DecreeNo12.651, INAEP is responsible for accrediting and certifying ECs (CEPs) to ensure that they are able to conduct ethical research reviews in accordance with the degree of risk involved. Per DecreeNo12.651, until INAEP completes a new evaluation, ECs (CEPs) already accredited and certified to conduct ethical reviews of research involving human beings are deemed accredited and certified by INAEP. See BRA-143 for additional guidance on the responsibilities of accredited ECs (CEPs) and a current list of INAEP-accredited ECs (CEPs).

Additionally, BRA-142 establishes an automatic extension, granted on an exceptional basis, for a period of one (1) year for accredited ECs (CEPs) whose accreditation expired during the 2025 fiscal year. The extension is calculated from the original expiration date to ensure the regular and uninterrupted continuity of EC (CEP) operations. The extension does not waive or supersede the accreditation renewal process. Sponsoring institutions must continue to comply with the renewal requirements in ResNo706.

Per DecreeNo12.651, INAEP will establish criteria, requirements, and procedures for suspension and cancellation.

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

Under the CEP/CONEP framework, ECs (CEPs) were required to register with and obtain accreditation from CONEP in accordance with ResNo466 and ResNo706. ResNo706 established the eligibility requirements and procedures for CEP registration, accreditation, and renewal. See ResNo706, CNSResNo506, and SP006REC for additional information on the former CONEP accreditation process.

ResNo706 also established the procedures governing the suspension and cancellation of EC (CEP) accreditation. Suspension temporarily interrupted an EC's (CEP's) receipt of new research protocols while requiring continued oversight of protocols already under its responsibility. Cancellation revoked the EC's (CEP's) registration in the CEP/CONEP System and provided for the transfer of its protocols to another EC (CEP). See ResNo706 for additional information on the former CONEP suspension and cancellation procedures.

Overview

As stipulated in the NHA, ethics committees (ECs) in South Africa are governed by the National Health Research Ethics Council (NHREC), which is a statutory body established under the NHA. NHREC determines guidelines for the functioning of ECs and registers and audits ECs, among other functions. The NHREC was created by the Minister of Health to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. According to ZAF-52, NHREC gives direction on ethical issues relating to health and develops guidelines for the conduct of research involving humans and animals. Further, NHREC oversees and supports ECs across the country, ensures that health research involving human participants upholds the highest ethical standards, and promotes alignment with international best practices through global collaboration.

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

• Determine guidelines for the functioning of ECs
• Register and audit ECs
• Set norms and standards for conducting research on humans including clinical trials
• Adjudicate complaints about the functioning of ECs
• Refer professional misconduct to the relevant statutory councils
• Recommend disciplinary action for violations of ethical research standards
• Advise the national department and provincial departments on any ethical issues concerning research

Registration, Auditing, and Accreditation

As delineated in the NHA, the G-EthicsHR-ZAF, and the SA-GCP, all ECs are required to register with the NHREC in order to undertake the ethical review of a clinical study. As indicated in the ECRegstrn, applications from ECs whose scope does not align with the mandate of the NHREC, as defined by the NHA, will not be accepted. The application form requires a clear description of the types of health or health-related research the EC reviews, or will review and monitor. The submission must demonstrate how these activities fall within the mandate of the NHREC. Only applications that clearly align with the NHA and the NHREC's scope will be considered for registration.

Registration information is available on the NHREC webpage (ZAF-12), and a list of ECs currently registered with NHREC is available at ZAF-13. The application to register an EC is at ZAF-53. ZAF-54 states that the EC registration is recorded and publicly listed by the NHREC.

Per the G-EthicsHR-ZAF, the criteria for the NHREC registration assessment and the eligibility audit for ECs are based on the G-EthicsHR-ZAF and other internationally recognized guidelines. ZAF-12 indicates that ECs must comply with the NHA and the G-EthicsHR-ZAF to be eligible for NHREC registration. As required in the G-EthicsHR-ZAF, members of the NHREC undertake the assessment and auditing to ensure that ECs comply with capacity and operational requirements. After the first pre-registration audit, guidance and recommendations for improvement are provided with specific timelines for improvements. Before the registration is completed and a registration number is issued, NHREC conducts a follow-up audit to ensure that required revisions have been completed. Voluntary deregistration can occur when an EC is no longer active and closes. Per ZAF-12, once approved, the EC is formally recognized as a NHREC-registered research EC. To maintain registration, RECs must submit annual reports (ZAF-54), implement any required improvements, and respond to audit outcomes.

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

Overview

As stated in ResNo945 and the G-DDCMManual, the sponsor, the designated contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or the sponsor-investigator must apply to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to obtain clinical trial approval by submitting a Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)) for a drug that will have all or part of its development in Brazil for registration purposes. (Note: Applications are also known as petitions in Brazil).

Pursuant to LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is required to undergo prior ethical analysis by research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). ResNo945 explains that clinical trial applications can be submitted in parallel, however, a clinical drug trial may only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

As delineated in ResNo466 and OSNo001, the National Health Council (Conselho Nacional de Saúde (CNS))’s National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))/CEP system is responsible for the ethical analysis of research protocols involving human beings. Per ResNo466, the principal investigator (PI) is responsible for submitting the protocol to the EC (CEP) or CONEP and obtaining ethical approval prior to initiating the research.

Note: Brazil is currently transitioning from the CEP/CONEP system under the CNS to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will also continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available.

Regulatory Submission

Primary Petitions

As per ResNo945, a primary DDCM petition may be submitted to ANVISA at any stage of clinical drug development for one (1) or more clinical trial phases. ResNo945 and the G-DDCMManual further note that a DDCM must also be filed with at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) for analysis. A DEEC is a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) within the DDCM. Each DEEC must be filed as a separate process for an individual clinical trial and linked to the corresponding DDCM. Per the G-DDCMManual, DEECs are submitted as primary petitions and assigned a case number and specific subject for each clinical trial to be conducted in Brazil that has not been previously submitted to ANVISA. Only DEECs from clinical trials conducted in Brazil may be submitted. ResNo945 further indicates that the sponsor, CRO, or sponsor-investigator may link additional DEECs to a submitted DDCM at any time after the initial submission.

ResNo945 provides the following additional DDCM submission requirements:

• The person responsible for submitting the DDCM to ANVISA must also submit all subsequent petition submissions related to the DDCM
• A CRO may only submit a DDCM if the sponsor does not have a head office or branch in Brazil
• A DDCM submission by a sponsor-investigator must be done through the primary sponsor, and
• If a sponsor-investigator wishes to conduct a clinical trial involving a drug with an approved DDCM, the sponsor-investigator may, with the initial DDCM owner’s permission, use the information previously submitted to ANVISA without resubmitting all of the required documentation. If the sponsor-investigator does not obtain authorization from the initial DDCM owner, all the required information supporting the proposed development rationale must be submitted to ANVISA through updated, indexed literature

Additionally, ResNo205 establishes specific approval procedures for clinical trials conducted to support the registration of new drugs intended to treat, diagnose, or prevent rare diseases. Petitions may be submitted as an initial DDCM, a secondary petition linked to the original DDCM, or a DEEC linked to the original DDCM or submitted as a new process. Sponsors must determine, when submitting an initial DDCM, a secondary DDCM petition, or a DEEC, whether the petition pertains to a rare disease drug. See ResNo205 for detailed rare disease clinical trial submission requirements.

Per OrdNo54, applicants may request in-person or virtual hearings with ANVISA to clarify matters that, due to their complexity, cannot be resolved through the service channels established and publicized on the ANVISA website. BRA-90 further specifies that applicants may request pre-submission meetings with ANVISA's Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., a DDCM, secondary petition, or DEEC) or a clinical trial application previously submitted to ANVISA. However, according to BRA-146, ANVISA has replaced the Parlatório System referenced in OrdNo54 and BRA-90 with the ANVISA Hearing System for scheduling hearings. See BRA-146 and BRA-147 for additional information on scheduling a hearing.

In addition, per ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, but if the sponsor deems it necessary, then ANVISA should hold the meeting within 60 days of the request.

ResNo903 further states that when a sponsor or CRO transfers responsibility for submitting a DDCM petition and the linked specific clinical trial processes for an investigational product (IP) to ANVISA, the succeeding company must update the related clinical trial registration data via a petition for global transfer of responsibility for the clinical trial. See ResNo903 for additional information. See also the Submission Content section for specific documentation requirements, and the Insurance & Compensation and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

See ResNo506 for more information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products (i.e., medicines for human use that are based on genes, tissues, or cells).

Secondary Petitions

As explained in the G-DDCMManual, secondary petitions must be linked to the corresponding process. Secondary petitions related to a DDCM must also be filed with the Petition Consent Form (BRA-21). Examples of DDCM petitions include: Substantial Modification to the Investigational Product (BRA-127); Investigational Drug Development Safety Update Report (DSUR); Cancellation of DDCM on Request; Global Transfer of Responsibility for DDCM; Temporary Suspension of DDCM; Reactivation of Suspended DDCM; Investigational Drug Development Plan (PDME) Update Notification; and Investigator’s Brochure (IB) Update Notification.

Similarly, per the G-DDCMManual, secondary petitions related to a DEEC must be linked to the corresponding clinical trial process. Examples of DEEC petitions include: Alteration of the Clinical Trial Submission Form (FAEC) (BRA-22); substantial amendment to clinical protocol; Annual Report on Clinical Trial Protocol Monitoring; Cancellation of Clinical Trial Protocol on Request; Global Transfer of Responsibility for Clinical Trial Protocol; Temporary Suspension of Clinical Trial Protocol; and Reactivation of Suspended Clinical Trial Protocol.

As stated in ResNo945 and the G-DDCMManual, sponsors must submit substantial IP modifications to ANVISA as secondary petitions linked to the corresponding DDCM. ResNo945 indicates that non-substantial IP modifications must be submitted to ANVISA in the next petition for substantial IP modification, or as part of the DSUR, whichever occurs first. The G-DDCMAmdmts further notes that these modifications may be made at any time after initial DDCM submission, including before ANVISA issues its final decision. See the G-DDCMAmdmts for detailed submission instructions, the G-ResNo945-FAQs for technical procedures for submitting DDCM and DEEC petitions, including secondary petitions, and the Submission Content section for documentation requirements.

As per ResNo945 and the G-DDCMManual, petitions for substantial amendments to clinical trial protocols must also be filed as a secondary petition linked to the corresponding DEEC. ResNo945 further explains that non-substantial clinical trial protocol amendments must always be submitted to ANVISA in the next substantial amendment petition, or as part of the final clinical trial protocol monitoring report, in cases where there are no substantial amendments by the end of the clinical trial. See the G-DDCMAmdmts for detailed submission instructions for protocol modifications. See also BRA-125 for the Substantial Amendment to Clinical Trial Protocol form. Refer to the Submission Content section for DEEC petition content requirements and substantial protocol amendment documentation requirements.

ResNo1001 further provides that primary DDCM and DEEC petitions and secondary petitions for substantial IP modifications and substantial protocol amendments may be classified as priority if they meet the applicable criteria. Priority classification may be requested upon submission of these petitions or at any time following submission through a specific petition for that purpose. These requests may only be submitted by the company recognized by ANVISA (i.e., the sponsor) as responsible for the respective petition. If ANVISA’s technical area does not confirm priority classification, the request will be denied. When filing or submitting a specific prioritization request, the company must attach a document indicating which criterion(s) established in ResNo1001 justify priority classification. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections.

See ResNo742, G-ResNo945-FAQs, BRA-6, and BRA-7 for requirements related to submitting DEECs linked to DDCMs for comparative bioavailability/bioequivalence studies and comparative pharmacokinetic studies with biosimilar products.

In addition, for regulatory submission purposes, the G-SUSARs indicates that DSURs must be submitted as secondary electronic petitions linked to the DDCM process using petition subject 10825 – CLINICAL TRIALS – Safety Update Report of the Development of the Investigational Drug. See also the Safety Reporting section for additional DSUR reporting requirements.

As delineated in ResNo945, RegNo338, the G-DDCMManual, and BRA-122, the sponsor may request the optimized analysis procedure based on regulatory trust practices (Reliance) or the risk or complexity criteria of the clinical trial or the IP. The request must be submitted as a secondary petition before ANVISA begins its technical analysis of the corresponding DDCM petition. Per ResNo945 and RegNo338, for primary and secondary petitions to be considered under Reliance, the related documents must have been approved by at least one (1) of the Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) recognized by ANVISA. The AREE-approved documents must be the same versions as those submitted to ANVISA. The G-DDCMManual further explains that under the Reliance procedure, certain documentation may be exempt from technical analysis if the applicable criteria are met. However, all documents required for the applicable petition or process must still be submitted.

Per ResNo945, RegNo338, the G-DDCMManual, BRA-122, and BRA-123, applicants must submit a secondary petition requesting analysis under the Reliance procedure using one (1) of the following subject codes:

• 12102 – Clinical Trials – Optimized analysis procedure for DEEC
• 12103 – Clinical Trials – Optimized analysis procedure for Substantial Amendment to the Clinical Protocol
• 12104 – Clinical Trials – Optimized analysis procedure for Approval in the Process of the DDCM
• 11634 – Clinical Trials – Optimized Analysis Procedure for Substantial Modification to IP

In addition, per the G-DDCMManual and BRA-122, separate requests for analysis under Reliance must be submitted for each DDCM or DEEC petition because the petitioning system does not permit one secondary petition to be linked to another. Refer to the G-DDCMManual and BRA-122 for additional information. See also the Scope of Assessment section for detailed optimized analysis procedure requirements by Reliance or the risk assessment of the clinical trial or IP.

For requests to ANVISA to apply the optimized analysis procedure based on risk assessment using IP experience, the G-DDCMManual indicates that there is no specific subject code. Therefore, a company may request the application of the optimized analysis procedure by either one (1) of these options:

• In the Clinical Trial Submission Form (FAEC) (BRA-22), marking the option "(X) to the question, “We request the application of the optimized analysis procedure, pursuant to Article 8 of IN No. 338/2024", or answering "yes" to the question "Request for the application of the optimized analysis procedure (based on the risk assessment supported by the experience of using the investigational product).” (Note: Per BRA-123, BRA-22 should be completed electronically in ANVISA’s Solicita Electronic Petition Request System (BRA-56)).
• In the Petition Form for Substantial Modification of the Investigational Product (BRA-127), answering "yes" to the question "Request for the application of the optimized analysis procedure (based on the risk assessment supported by the experience of using the IP), pursuant to Article 8 of IN No. 338/2024".

Electronic Filing

Per ResNo945 and the G-DDCMManual, the original DDCM and all related processes and petitions (e.g., secondary petitions and DEEC(s)) must be submitted electronically. ResNo947 also notes that documents to be filed with ANVISA must be submitted exclusively via the agency’s electronic petitioning systems for filing documents, except in specified cases. BRA-38 specifies electronic petitioning is carried out via the Solicita Electronic Petition Request System (BRA-56). See BRA-47 and BRA-38 for instructions on how to login to the Solicita System.

The G-DDCMManual explains that when the DDCM has been submitted, the sponsor must electronically file all the documents corresponding to the initial DDCM petition’s subject code. Per BRA-123, due to the simplification in the DDCM and DEEC subject codes, the sponsor or the CRO should use the following to submit DDCM and DEEC documentation: 12405 – Clinical Trials - Approval in process of the Clinical Drug Development Dossier (DDCM) - Medicines and Biological Products; and 12406 – Clinical Trials - Approval in process of the Specific Clinical Trial Dossier (DEEC) - Medicines and Biological Products. For secondary petitions, subject codes 10820 and 10824 should be used.

ResNo945 also specifies that the submitted documentation must support textual searches, copying, and contain bookmarks and hyperlinks that facilitate navigation. Refer to BRA-47 for instructions for submitting DDCM checklist documents and clinical drug research forms via BRA-56. See the G-DDCMManual and BRA-47 for additional DEEC petition submission instructions. See also ResNo947 for further details on ANVISA’S electronic filing requirements.

As per ResNo857, BRA-47, and BRA-43, once the sponsor has completed the process of submitting a DDCM request, ANVISA’s Solicita Electronic Petition Request System (BRA-56) generates a document known as the Union Collection Guide (Guia de Recolhimento da União (GRU)). The GRU is the primary method used to generate the Health Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)). ResNo857 explains that petitions subject to TFVS will only be eligible for filing after confirmation of full corresponding payment. Once the full TFVS payment is confirmed, the electronic petitions will be automatically filed. (See the Regulatory Fees section for detailed information on the payment process.)

ResNo857 further states that if a petition is filed without due payment of the TFVS fee, the request and the documentation will be returned to the sponsor. BRA-43 specifies that ANVISA will accept the following documents as proof of payment from the sponsor:

• Presentation of the original GRU receipt collected electronically, which must be accompanied by the original electronic banking network payment receipt
• Presentation of the original GRU receipt collected from the banking network, which must contain the original receipt stamp for authentication
• The transaction number issued by ANVISA’s Solicita Electronic Petition Request System (BRA-56)

See also BRA-47 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition Consent Form. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

As indicated in the G-DDCMManual, ANVISA recommends that the DDCM and associated documents (especially the clinical protocol, the PDME, and the IB) be submitted in Portuguese. If a translated version of the submission is not provided, ANVISA’s technical area reviewer may issue a requirement for the sponsor to provide a free translation of the submitted documentation. ResNo947 also states that documents filed with ANVISA must be presented in Portuguese, however, documents submitted in English and Spanish will also be accepted, and a request for translation of the documents may be submitted. When translation is necessary, in the absence of a specific rule requiring translation in the sworn version, a free translation may be accepted.

Ethics Review Submission

National System of Ethics in Research Involving Human Beings (SINEP)

According to LawNo14.874, the investigator is responsible for submitting a research project to the EC (CEP) for approval. The submission should include the research documentation and any amendments.

DecreeNo12.651 also states, for multicenter research, studies conducted in different research centers by more than one (1) investigator should be submitted as a single protocol to one (1) EC (CEP). BRA-141 further provides that the submission of documents (e.g., infrastructure, recruitment, etc.) specific to each institution is still required. See also BRA-141 for additional INAEP guidance for institution-specific requirements for single EC (CEP) reviews.

In addition, per BRA-143 and BRA-142, research protocols previously submitted to CONEP that fall within special thematic areas traditionally considered high-risk, as defined in ResNo466 and ResNo446, must be forwarded to accredited ECs (CEPs) for ethical review in accordance with DecreeNo12.651. BRA-143 further states that this requirement applies to both protocols that have already been filed and those to be submitted prior to INAEP’s issuance of new guidelines. All high-risk protocols must be submitted to one (1) of the eight (8) accredited ECs (CEPs) listed in BRA-143. Exceptions to this workflow requirement include biobank development protocols, which have been temporarily suspended per BRA-142, as well as certain categories of protocols for which the MOH serves as the proposing institution.

CEP/CONEP System (Pre-SINEP Framework)

Per ResNo466, the PI must obtain ethical approval from the EC (CEP), and, if applicable, from CONEP. The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil EC (CEP) and investigator manuals. Please refer to Scope of Review and Oversight of Ethics Committee sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. See also CLNo183 for instructions on linking investigator/institutions to the responsible EC (CEP) in submissions; CLNo062 for guidance on submitting documentation required for CONEP analysis; and CLNo046 for instructions on submitting requests for inclusion/exclusion of research center(s).

Per OSNo001, the investigator is required to submit the research protocol in Portuguese to the CEP/CONEP System via BRA-34, and when applicable, accompanied by the originals in the foreign language.

OSNo001 further states that, in the event of a multicenter clinical trial, the PI is required to submit a list of the participating institutions and the associated protocols as part of the research protocol package sent to the EC (CEP) for review.

Additionally, per ResNo580, for co-sponsored or cooperative research projects as described in ResNo466, the protocol submission must include a referral document from the Secretary of the MOH’s Secretariat of Science, Technology and Strategic Health Inputs. When this document is included, the EC (CEP) of the proposing institution may conduct its review without the need for additional CONEP review.

Overview

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

Regulatory Submission

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

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

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

Per the ZAF-40, during a public health emergency, applicants should use the modified clinical trial application form in ZAF-40. This form recognizes the constraints on the availability of information posed by the emergency. SAHPRA may accept clinical trial applications with reduced information together with a commitment to update and complete the required information as soon as possible. However, all documents submitted must be organized with zipped folders according to the checklist in ZAF-40 and correctly labelled to ensure easy validation by SAHPRA (See the Submission Content and Emergencies sections for more details).

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

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

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

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

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

Ethics Review Submission

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

Regulatory Authority Requirements

Clinical Drug Development Dossier (DDCM)

As delineated in ResNo945 and the G-DDCMManual, the following documentation must be submitted to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to file a clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) via the Solicita Electronic Petition Request System (BRA-56) (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• DDCM Petition Consent Form (BRA-21)
• Investigational Drug Development Plan (PDME)
• Investigator’s Brochure (IB)
• Investigational Medicinal Product Dossier (IMPD) (including information on active pharmaceutical ingredient (API), investigational drug, and placebo and modified comparator drug)
• DEEC (see detailed requirements listed below)
• Declarations on compliance with Good Clinical Practice (GCP), Good Laboratory Practice (GLP), and Good Manufacturing Practice (GMP)
• GCP Certificate or equivalent document for the completed or ongoing clinical trials must be attached to the DDCM, if applicable
• Declaration of commitment to distribute and use IPs only after DDCM and corresponding initial and subsequent Specific Clinical Trial Dossiers (Dossiês Específicos de Ensaio Clínico (DEECs)) authorization. This declaration should only be attached to the DDCM if the sponsor is interested in receiving the Import Document (DI) before completion of the DDCM review and approval. If the declaration is submitted with the DDCM, the DI will be issued to allow early importation for both the initial DEECs submitted with the DDCM, and any subsequent DEECs submitted after DDCM approval.

Additionally, per ResNo903, when a sponsor or contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) transfers responsibility for submitting a DDCM and its linked specific clinical trial processes for an IP, the succeeding company must update the related clinical trial registration data via a petition for global transfer of responsibility for the clinical trial. The petition must be accompanied by the following documents:

• Petition Consent Form duly completed and signed (BRA-21)
• Declaration of the corporate or commercial transaction carried out (see Declaration form in Annex I of ResNo903)

See ResNo903 for additional information. See also the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

Specific Clinical Trial Dossier (DEEC)

Per ResNo945 and the G-DDCMManual, the DEEC petition submission should include the following:

• Clinical Trial Submission Form (FAEC) (BRA-22)
• Clinical trial protocol containing the minimum information described in the International Council for Harmonisation’s Guideline E6(R2) (BRA-28) and its updates
• Statistical analysis plan (PAE), at least in draft version, for phase 3 and adaptive clinical trials
• Opinion of the relevant country/region's scientific advisory board on the clinical trial, if applicable
• Pediatric investigation plan of the relevant country/region, if applicable
• Sample investigational drug label
• Proof of clinical trial registration, in the same version of the clinical protocol submitted to ANVISA, in the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE) (Note: The Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.) If proof of registration is unavailable at the time of DEEC submission, it must be submitted with the notification of clinical trial commencement.)

Substantial IP Modifications

Per ResNo945 and the G-DDCMManual, for substantial IP modifications, the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM that must include the following (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Copy of the previously approved IMPD or Investigational Product Dossier (DPI), with the proposed modifications highlighted (track changes format), and a table comparing the current situation with the proposed changes, including the justification for each change and an assessment of its impact on clinical development
• GMP certificate or equivalent document for the IP, if applicable
• Petition Form for Substantial Modification to the Product under investigation (BRA-127)
• Other information in accordance with each proposed modification

See the G-DDCMAmdmts for detailed submission instructions. ResNo945 also indicates that non-substantial IP modifications must be submitted to ANVISA in the next petition for substantial IP modification, or as part of the drug development safety update report (DSUR), whichever occurs first.

Substantial Protocol Amendments

As per ResNo945 and the G-DDCMManual, for substantial clinical trial protocol amendments, the sponsor must submit to ANVISA an electronic secondary petition linked to the corresponding DEEC (see BRA-125 for the Substantial Amendment to Clinical Trial Protocol form) that must include the following: (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Copy of the previously approved clinical protocol with the proposed modifications highlighted (track-changes format), and a table comparing the current situation with the proposed changes, including the justifications for each change and an assessment of the impacts on clinical development
• Updated Clinical Trial Submission Form (FAEC) (BRA-22), in both clean and track changes versions, together with the new clean version of the clinical protocol. (Note: Per BRA-123, BRA-22 should be completed electronically in ANVISA’s Solicita Electronic Petition Request System (BRA-56)).

See the G-DDCMAmdmts for detailed submission instructions for protocol amendments. See also G-ResNo945-FAQs for additional guidance on substantial protocol amendments.

ResNo945 further explains that non-substantial clinical trial protocol amendments must always be submitted to ANVISA in the next substantial amendment petition, or as part of the final clinical trial protocol monitoring report, in cases where there are no substantial amendments by the end of the clinical trial.

Optimized Analysis Procedure (Reliance) Submissions

Pursuant to ResNo945, to request the optimized analysis procedure by Reliance, the sponsor must submit official proof issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) of approval of the clinical protocol, clinical protocol amendment, official proof of the DDCM, or substantial IP modification of the IMPD or DPI, as applicable. If official proof is unavailable, a declaration signed by the sponsor's legal and technical representatives (see BRA-124) must be presented with due justification and additional information, if applicable.

Per RegNo338, ANVISA will provide a specific petition characterization form for the sponsor to complete for the proper identification of situations in which the optimized analysis procedure is supported by experience using the IP. For each type of petition, the optimized analysis procedure based on risk assessment may be applied to the documents listed below:

• IB, for low-risk clinical trial categories involving medicine used as registered in Brazil or by an AREE, without substantial modifications; and fixed-dose combinations with registered APIs already used concomitantly in medical practice, for the same indication, target population, and dosage regimen (without clinically significant pharmacokinetic and/or pharmacodynamic interaction)
• IMPD or DPI, for low-risk clinical trial categories and moderate risk clinical trial categories involving a new therapeutic indication, target population, and/or dosage regimen

RegNo338 further specifies that, under the optimized analysis procedure by Reliance, ANVISA will review the following documents:

• IB, except for complex clinical trials, prophylactic and therapeutic vaccines, and biosimilar products
• API and IMPD or DPI
• Clinical trial protocol, except for complex clinical trials, prophylactic and therapeutic vaccines, and biosimilar products

Ethics Committee Requirements

National System of Ethics in Research Involving Human Beings (SINEP)

According to LawNo14.874, investigators are responsible for submitting research documentation, including any amendments, for research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval.

No other information is currently available regarding specific EC (CEP) submission documentation requirements. However, LawNo14.874 states that the information and documents required for the ethical review process will be established in specific regulations.

CEP/CONEP System (Pre-SINEP Framework)

As per OMREC and OSNo001, in accordance with CEP/CONEP System requirements, researchers are required to submit the following documentation online via BRA-34 for review by an EC (CEP) (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Cover Sheet for Research Involving Human Beings (completed by investigator in Plataforma Brasil (BRA-34))
• Clinical research protocol (in Portuguese)
• Background, justification, and registration in the country of origin for drug and device health products
• Description of materials, methods, rationale, expected results, and bibliography
• Critical risk and benefit analysis
• Duration
• Responsibilities of investigator, institution, and sponsor
• Criteria for project suspension or termination
• Location of implementation of various project steps
• Necessary infrastructure and agreement of the institution
• Statement of Commitment from the principal investigator (PI)
• Informed consent form (ICF) (See Informed Consent topic for additional information)
• Detailed research financial budget and investigator remuneration
• Ownership of information
• Characteristics of the participant population, and justification for the use of vulnerable groups
• Number of participants locally and globally (multicenter)
• Description of methods that affect research participants
• Sources of material and details of the specific collection
• Recruitment plans, inclusion and exclusion criteria
• PI/investigator(s) Curriculum Vitaes (CVs)
• List of the participating institutions and associated protocols
• Coordinating center
• EC (CEP) designated to monitor the study’s progress
• Research project schedule
• Foreign Research or Foreign Cooperation documentation (commitments and advantages for research participants and the country; identification of the national investigator and co-responsible institution; EC approval document in the country of origin or justification; response to the need for personnel training in Brazil; and lists of participating centers abroad and in Brazil)
• Research with new drug, vaccine, and diagnostic test document requirements (current clinical trial phase and demonstration of compliance with previous clinical trial phases; drug substance registration in the country of origin and status of research; IB; clinical information from previous trial phases; justification for using placebo or wash out period; access to the drug, if its superiority is proven; investigator’s statement of commitment; justification for inclusion of healthy participants; forms of recruitment)

See OMREC and OSNo001 for detailed CEP/National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) System submission requirements. See also BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.

Clinical Protocol

As delineated in OMREC and OSNo001, the clinical protocol should include the following elements:

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

For complete protocol requirements, refer to OMREC and OSNo001.

Regulatory Authority Requirements

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

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

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

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

Per the ZAF-40, SAHPRA states that during a public health emergency, new and experimental treatments may become necessary and clinical trials are essential to provide the evidence to develop appropriate policies for patient treatments. Under these circumstances, there may be limited information available. However, applications need to contain a certain minimum of information to enable a meaningful evaluation and regulatory decisions. To address this, SAHPRA provides an information grading system in the ZAF-40 wherein required information is labelled. Applicants must attempt to provide the information listed below and justify when this is not available. The required information is graded as follows:

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

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

Ethics Committee Requirements

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

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

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

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

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

Clinical Protocol

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

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

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

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

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

Overview

As stated in ResNo945, clinical trial applications may be submitted in parallel, however, a drug clinical trial may only be initiated after approval is obtained by both the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).

Regulatory Authority Approval

As set forth in LawNo14.874, ANVISA must complete its review of a primary clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento de Medicamentos Clínico (DDCM)), within 90 business days. If ANVISA does not issue a response within that period, clinical development may be initiated, provided that the DDCM petition contains the relevant ethical approvals. ResNo945 further specifies that, upon receipt of the DDCM and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions, ANVISA has 90 business days from the date of issuance of the DEEC document to evaluate the application. If ANVISA fails to issue a response within 90 days of receipt, the DDCM and corresponding DEEC are deemed released, and clinical development may begin once the relevant ethical approvals have been obtained. The 90-day review period also applies to primary petitions for new DEECs subsequently linked to the DDCM, and to secondary petitions for substantial investigational product (IP) modifications and substantial protocol amendments. See Scope of Assessment section for detailed DDCM and DEEC submission requirements.

Additionally, per ResNo945, ANVISA will begin technical review of the DDCM only after at least one (1) DEEC has been filed. The DEEC must be filed within 15 business days of the DDCM’s issuance date. If no DEEC is filed within this period, the DDCM with be rejected without technical review, except for clinical trials involving more than one (1) IP, where the DEEC has already been linked to one (1) of the corresponding DDCMs.

LawNo14.874 and ResNo945 further explain that ANVISA may, on a single occasion, request additional clarifications and documents through a technical requirement during the analysis of primary DDCM and DEEC petitions, as well as secondary petitions for substantial IP modification or substantial clinical protocol amendment. ANVISA’s technical requirement suspends, but does not interrupt, the applicable analysis deadlines. ResNo945 also notes that the sponsor must comply with the technical requirement within 30 business days of ANVISA’s confirmation of receipt. See also G-ResNo945-FAQs for additional guidance on submitting DDCM and DEEC petitions.

Under RegNo457, when a sponsor uses the continuous submission procedure to file specified Investigational Medicinal Product Dossier (IMPD) quality documents, the clinical trial may begin (or a substantial IP modification may be implemented) if ANVISA does not respond within 30 calendar days after the pending documents are filed, provided all other applicable ethical and regulatory requirements have been met.

BRA-122 also explains that petitions submitted to request ANVISA evaluation under the optimized analysis procedure based on regulatory trust practices (Reliance) that have not been analyzed within ANVISA’s 90-day review period will be released due to the expiration of the review period, in accordance with ResNo945 and LawNo14.874. The status of these petitions will be updated to “Added to process”. See BRA-122 for additional information. See the Scope of Assessment and Submission Process sections for detailed criteria and procedures to submit optimized analysis procedure petitions.

In addition, per ResNo997, ANVISA has established exceptional and temporary measures to optimize the analysis queue for clinical research approvals. Certain primary and secondary clinical research petitions for medicines and biological products that meet the criteria for applying the optimized analysis procedure by Reliance will be assigned to a specific queue, which may affect their processing order. Priority petition submissions that also meet these criteria will be analyzed before other petitions in the specific queue. See the Scope of Assessment section for details. See also BRA-139 and BRA-136 for additional information on ANVISA’s exceptional and temporary review procedures and see BRA-138 for frequently asked questions related to ResNo997.

Refer to BRA-60 for details on the median analysis timelines for ANVISA to complete its technical review of prioritized and ordinary petitions.

Priority Submissions

Pursuant to ResNo1001, priority classification may be requested upon submission of a primary DDCM and DEEC petition, a secondary petition for substantial IP modifications and substantial protocol amendments, or at any time following submission through a specific petition for that purpose. ANVISA must determine eligibility for priority classification within 45 days of the filing date of the relevant petition. If priority classification is requested through a separate petition after the original petition is filed, ANVISA must determine eligibility within 45 days of the filing date of the prioritization request.

ResNo1001 further states that once priority classification is granted, ANVISA has 45 days, counted from the first business day after submission of the priority petition, to issue its first technical response and 60 days from the applicable filing date to issue a final decision. When priority classification is requested through a separate petition after the original petition is filed, the 45-day and 60-day review periods are counted from the filing date of the prioritization request. For secondary petitions filed for substantial IP modifications and substantial protocol amendments, the deadlines are also counted from the respective filing date. ANVISA requests for clarification or additional technical information suspend these review periods until the requested information is submitted. The 60-day review period may be extended once, by up to one-third of the original deadline (20 days), through a reasoned decision issued at least 15 working days before the original deadline expires. See the Scope of Assessment and Submission Process sections for additional information on priority classification requirements and submission procedures.

In addition, as set forth in ResNo205, for a clinical trial with medicines for rare diseases to be conducted in Brazil, ANVISA must evaluate a DDCM, DEEC, or substantial modification due to inclusion of a clinical trial protocol within 30 days after submission, and will issue a notification requesting additional information or a statement of conclusion. ANVISA will evaluate secondary petitions referring to a DDCM, DEEC, or substantial modification due to inclusion of a clinical trial protocol according to the same timeline. Refer to ResNo205 for detailed submission requirements and deadlines.

See the Scope of Assessment section for further information on priority submissions. See also G-ResNo945-FAQs for additional guidance on submitting priority petitions.

Ethics Committee Approval

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising ECs CEPs and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will also continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available.

National System of Ethics in Research Involving Human Beings (SINEP)

As explained in OrderNo2, LawNo14.874 establishes two (2) timeframes in the EC (CEP) ethical review process: verification of the completeness of the documentation within 10 working days from the protocol submission date, and issuance of the ethical opinion within 30 days from the date of accepting all of the research documentation. Before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor or require adjustments to the research documentation. Such requests may suspend the ethical review period for up to 20 business days. LawNo14.874 specifies that the investigator will have 10 working days, extendable for an additional 10 working days upon justification, to respond to the requests made by the EC (CEP), and the study analysis process may be canceled in case of non-compliance with the deadline. See OrderNo2 for additional details regarding the calculation, suspension, and continuation of ethical review timelines.

LawNo14.874 further states that the investigator may initially appeal the decision to the EC (CEP) that issued the opinion within 30 business days and may file a final appeal to INAEP within 30 business days. The EC (CEP) must decide the initial appeal within 30 business days, and INAEP must decide the final appeal within 30 business days. See the Scope of Review section for details on the EC (CEP) review processes. See also BRA-117 for additional information.

Additionally, per LawNo14.874 and DecreeNo12.651, the EC (CEP) opinion regarding research of strategic interest to the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53) and relevant to responding to public health emergencies will be issued within a period of 15 business days from the date of receipt of the authorization request. DecreeNo12.651 further specifies that the 15-day period may be extended in instances duly justified by the technical complexity of the subject matter or by the need for supplementary documentation.

CEP/CONEP System (Pre-SINEP Framework)

As delineated in OSNo001 and BRA-91, the EC (CEP) is required to issue an initial report in 30 days from the date the principal investigator (PI) submits an application for review. The EC (CEP)’s review of the protocol documentation for completeness should be accomplished within 10 days following submission. Per BRA-91, the review period must be counted from the date the project entered “Ethical Assessment” (i.e., after going through the validation of documents which takes around 10 days and when the Certificate of Presentation for Ethical Assessment (Certificado de Apresentação de Apreciação Ética (CAAE)) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment. If these deadlines have expired, BRA-91 further suggests that the investigator responsible for the research project, contact the EC (CEP) to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation. Additionally, per CLNo040, if an amended project needs to go through CONEP’s appraisal, the deadline for document validation is 15 days and for ethical review, 45 days.

Per CLNo10, in the event that EC (CEP) activities are temporarily suspended due to a strike or institutional recess, the EC (CEP) must notify CONEP of measures to be adopted to ensure the continuity of protocol processing for ethical assessment according to the deadlines delineated above per OSNo001, specifically, 10 days for document checking for completeness and 30 days to release the opinion.

Per CLNo29, in the case of an appeal, only the investigator responsible for the protocol, which had a substantiated opinion of non-approval, may submit a request to the CEP/CONEP System via Platforma Brasil (BRA-34). The appeal must be filed within 30 calendar days, counting from the first day following the issuance of the substantiated opinion of non-approval. Appeals submitted to the EC (CEP) will be reviewed and a substantiated opinion analyzing the appeal will be issued within 30 calendar days following receipt. If the EC (CEP) considers the requirements and justifications presented in the appeal to be appropriate in order to continue the ethical analysis, the appeal will be approved, or pending approval, if the protocol requires adjustments prior to approval. However, if the appeal is not approved by the EC (CEP), the investigator may appeal to CONEP. CONEP, in turn, has a deadline of up to 45 days after receiving the appeal to issue a substantiated opinion of approved, pending, or not approved, when evaluating the appeal in relation to the substantiated opinion issued by the EC (CEP). If CONEP does not approve the appeal, the investigator, upon receiving the non-approval opinion from CONEP, may file an appeal directly with CONEP itself. From an analysis of the resources submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal, the processing of the appeal is terminated, the research protocol is archived, and no other appeal requests will be permitted.

See the Submission Process section for CEP/CONEP System submission requirements.

Overview

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

Regulatory Authority Approval

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

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

Next, the CTC reviews the proposed clinical trials. CTCDates provides the dates of the 2026 CTC meetings and the SAHPRA submission due dates. It is advisable to submit clinical trial applications before these due dates. Once the reviewer approves the application, the CTC presents the committee’s/reviewer’s recommendations to SAHPRA. ZAF-1 states that applicants receive a response within 10 working days from the CTC meeting, and they must send an answer within seven (7) working days after receipt of comments. If an applicant would like to request a meeting with the CTC, the request should be submitted through the SAHPRA Chief Executive Office pursuant to the procedures in the G-ConsultMtg.

Ethics Committee Approval

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

Overview

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS))'s CEP/CONEP System—comprising research ethics committees (ECs) (Comitê de Ética em Pesquisa (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available.

Per LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is subject to prior ethical analysis by ECs (CEPs). According to ResNo945, clinical trial applications (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs)) may be submitted in parallel by the sponsor, the designated contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or the sponsor-investigator; however, a clinical trial can only be initiated after approval is obtained by both the EC (CEP) and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).

Also, according to ResNo466 and OSNo001, applications with coordination or sponsorship originating outside Brazil require an additional review and approval by CONEP, unless the co-sponsor is the Brazilian Government. See the Scope of Review and Oversight of Ethics Committees sections for detailed information on INAEP and CONEP responsibilities and other studies requiring CONEP approval. No waiting period is required following the sponsor’s receipt of these approvals.

In addition, per ResNo945 and G-DDCMManual, the sponsor or the designated CRO is required to obtain an import license from ANVISA for the shipment of the investigational product (IP) to be used in the trial. (See the Manufacturing & Import section for additional information).

ResNo945 and the G-DDCMManual also specify that clinical trials should be conducted in compliance with the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. LawNo14.874 and ResNo466 also state that the ethical analysis of research involving human beings should comply with good clinical practice (GCP) and ethical and scientific principles. Further, per ResNo945 and the G-DDCMManual, clinical trials must be conducted in accordance with Good Laboratory Practice (GLP) or equivalent standards, including the Organisation for Economic Co-operation and Development (OECD)’s Principles on GLP (BRA-15). Refer to BRA-15 for additional information on GLP requirements.

ResNo945 further states that the clinical trial start date form in Brazil (BRA-25) must be filed as a secondary petition to the corresponding Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) within 30 business days after each start date.

Clinical Trial Agreement

As per LawNo14.874, the sponsor is responsible for establishing the contract between the parties involved in the research.

In addition, per ResNo945, any trial-related functions that are transferred to a CRO must also be specified in writing in a document signed by the sponsor and CRO. In the case of delegating responsibilities and activities, a written document must also be signed between the parties.

Clinical Trial Registration

As per ResNo945 and the G-DDCMManual, the sponsor must register the clinical trial in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE). According to BRA-52, the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)) (BRA-45) is a primary registry in the ICTRP network. See also BRA-45 and BRA-46 for further information about ReBEC. If proof of registration is not available at the time of the DEEC submission, it must be submitted together with the Start of Clinical Trial Notification Form in Brazil (BRA-25).

In addition, per BRA-32, ANVISA’s Clinical Trials (Ensaios Clínicos) tool, accessed via ANVISA’s Consultation System webpage (BRA-44), provides public information about the status of each clinical trial, the trial location, and the investigators responsible for conducting the trial. See BRA-32 and BRA-129 for additional instructions on searching BRA-44.

Pursuant to DecreeNo12.651, the MOH, under the SINEP framework, will also establish an integrated online system, referred to as a human research platform, for the registration, submission, evaluation, and monitoring of research involving human beings. See DecreeNo12.651 and LawNo14.874 for additional information.

Overview

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

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

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

Clinical Trial Agreement

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

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

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

Clinical Trial Registration

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

Governance

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

Safety Reporting Definitions

In accordance with LawNo14.874, the ResNo945, the G-SUSARs, and CLNo13, the following definitions provide a basis for a common understanding of Brazil’s safety reporting requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event/Experience (AE) – Any undesirable experience occurring to a participant during a clinical trial, whether or not considered related to the investigational product(s) (IP). An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the IP
• Adverse Drug Reaction or Adverse Reaction (ADR) – A harmful and unintentional response attributed to a drug and which occurs at doses normally used for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any adverse medical occurrence with an IP that at any dose results in death, risk of death, persistent or significant disability, congenital anomaly/birth defect and situations that require or extend patient hospitalization
• Suspected Serious, Unexpected Adverse Drug Reaction (SUSAR) – An adverse reaction that is simultaneously serious and unexpected, with the reasonable possibility of a causal relationship between the investigational drug and active comparator. One whose nature or severity is inconsistent with the IP (i.e., the investigator’s brochure (IB), Safety Information Summary (SIR) or package insert)

Safety Reporting Requirements

Investigator Responsibilities

As set forth in LawNo14.874, the investigator should promptly communicate all serious or unexpected AEs to the sponsor, the health authority, the research ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)), and the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)). ResNo945, and the G-SUSARs, specify that the investigator must inform the sponsor within 24 hours of all SAEs from the date of knowledge of the event. ResNo945 further explains that investigators must monitor and report to the sponsor, in accordance with good clinical practice (GCP) and the study protocol, the occurrence of all AEs, including those that come to their attention after the end of the clinical trial. The investigators must also provide any requested information and express their opinion regarding the causality between the AE and the IP. Per the G-SUSARs, upon becoming aware of an AE, the investigator should classify it for causality, severity, intensity, and expected/unexpectedness as per Annex 1 in the G-SUSARs. Further, if the investigator becomes aware of an AE after the completion or termination of the clinical trial, and there is suspicion of a possible causal relationship with the IP, the sponsor should be informed as soon as possible.

As explained in the G-SUSARs, the investigator is also responsible for adopting immediate safety measures to protect the clinical trial participant against any imminent risk, and for reporting the occurrence of all AEs to the sponsor. The participant affected by an AE should receive appropriate care and safety measures until resolution or stabilization of their clinical condition, as described in the clinical protocol. Upon becoming aware of an AE, the investigator must classify it regarding causality, severity, intensity, and expectedness, in accordance with the AE classification criteria delineated in Annex 1 in the G-SUSARs.

LawNo14.874 further specifies that the confidentiality of technical research information must be lifted when necessary for the analysis of SAEs. In the event of an SAE, the participant, their legal representatives, or their successors may disclose details relating to the former's participation in the research. Also, per the G-SUSARs, in the event of a possible SUSAR, the investigator should only break the concealment of treatment assignment for safety reasons, if the breaking of blinding is relevant to the safety of the trial participant, when immediate action needs to be taken.

CLNo13 also establishes specific CEP/National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) System processing requirements for SAEs occurring in Brazil and outside the country. As delineated in CLNo13, only SAEs should be reported to the CEP/CONEP System; it is optional for the investigator or sponsor to report an AE. SAE ethical analysis is the exclusive responsibility of CEPs, and CONEP prefers not to be involved in the review, except when at the CEP’s discretion, it is deemed necessary.

Per CLNo13, CEPs must present SAE notifications about a participant’s SAE index (initial SAE) and subsequent events in a single document, in tabular format, and submit it online to the CEP/CONEP System via Plataforma Brasil (BRA-34) using the “notification” function. This document must also be updated with each occurrence of a subsequent SAE. The document must contain the study identification research title and Certificate of Presentation of Ethical Appreciation (Certificado de Apresentação de Apreciação Ética) (CAAE)) number, name of the research center, name of the responsible investigator, coded identification of the participant and description of the index and subsequent events. Per BRA-91, the CAAE is the number generated by Plataforma Brasil (BRA-34) to identify the research project when it is received by CEP for ethical review.

CLNo13 explains that each SAE must be characterized according to the following:

• Date of SAE occurrence
• Participant number or code
• SAE number or code
• SAE classification (index or subsequent)
• Breakdown of the occurrence (e.g., febrile neutropenia, pneumonia, etc.)
• SAE type (death, life threatening, need for hospitalization, prolonged hospitalization, significant damage, permanent damage, congenital anomaly, at the investigator’s discretion, others)
• Participant status on the date of the last update (in progress, recovered without sequelae, recovered with sequelae, and death)
• Description of research participant withdrawal(s)

Additionally, in the case of multicenter studies, the investigator at the coordinating center must prepare the consolidated report (partial and final reports) containing information on SAEs from all of the participating research centers and submit it to the CEP to which it is linked via Plataforma Brasil (BRA-34) using the “notification” functionality. CLNo13 also explains that for SAEs occurring outside the country, it is the responsibility of the coordinating research center investigator to prepare the consolidated SAEs report. If the CEP is linked to the coordinating center, CONEP will also evaluate the SAEs if the protocol is included in item IX.4 of ResNo466.

Refer to CLNo008 for detailed instructions and the CONEP form to report SAEs to the CEP/CONEP System for review, and CLNo13 for information on processing AEs for Brazil and abroad.

Sponsor Responsibilities

In accordance with LawNo14.874, the sponsor is responsible for:

• Promptly notifying the investigator, the institution, the competent ethical review entities, and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), about discoveries that may adversely affect the safety of the research participant, compromise the conduct of the research or affect the approval granted by the EC (CEP)
• In the case of clinical trials, issuing reports on serious or unexpected ADRs to the IPs, notifying the institutions and investigators involved and ANVISA
• Promptly notifying ANVISA of all serious or unexpected AEs whose causality is possible, probable, or defined in relation to the IP

ResNo945 and the G-SUSARs also state that the sponsor is required to report SUSARs to ANVISA and is permitted to delegate the reporting responsibility to the contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil). In the case of sponsor-reported SUSARs, where the investigator’s interpretation differs from that of the sponsor, both reports should be submitted with their respective justifications. Per ResNo945, SUSAR notifications to ANVISA must be made independently of the submission of the IB, amendments, reports, or early termination of the clinical trial. The G-SUSARs further notes that the sponsor must also inform the investigators involved in the clinical trial about the SUSARs and adopt the necessary measures to update the safety documents, such as the IB, drug package insert (in the case of a registered drug), and other related documents. Additionally, the sponsor must notify ANVISA about additional occurrences (follow-ups) of SUSARs until the IB is updated. (See Quality Requirements section for detailed IB requirements)

ResNo945 and the G-SUSARs also state that in the event of a possible SUSAR, the sponsor must break the blinding only for the participant who was affected by the SUSAR to notify ANVISA. Where possible, the blinding should be preserved for those responsible for the analysis and interpretation of study results and those responsible for continuing the clinical trial, such as study managers, monitors, and investigators. Therefore, these professionals must continue to receive SUSARs blindly.

As per ResNo945, when an event is related to the disease and represents a primary efficacy outcome of a clinical trial, the protocol must clearly define the event and indicate that it is not subject to notification.

As per ResNo945, when an event is related to the disease and represents a primary efficacy outcome of a clinical trial, the protocol must clearly define the event and indicate that it will not be subject to notification. If the event described is characterized as a SUSAR, it must be reported, as it may require a possible change in the safety profile. Medication errors, pregnancy, or uses not foreseen in the protocol, including misuse and abuse of the product under investigation, are subject to the same reporting obligations as ADRs. In the case of pregnancy, the investigator and the sponsor must accompany the mother and child. The G-SUSARs also state that any pregnancy that occurs in a participant during a clinical trial should be followed until its outcome, and the baby should be followed for the necessary period. See the Pregnant Women, Fetuses & Neonates section for additional information on this population.

As per ResNo945, the sponsor should ensure all relevant information pertaining to SUSARs occurring in Brazil is documented and electronically reported to ANIVSA within a maximum of seven (7) calendar days after first knowledge. ResNo945 indicates that additional information on the monitoring of SUSAR events should be included in the assessment within eight (8) calendar days from the notification date. Additionally, per ResNo945, the sponsor must notify ANVISA of any other SUSARs which are not fatal or life-threatening, within 15 calendar days from the date of first knowledge. Per the G-SUSARs, for clinical studies that are already in progress and have been previously approved, the notifications must be adequate to the requirements set forth in ResNo945.

In addition, per ResNo945 and the G-SUSARs, the sponsor must systematically collect, monitor, and evaluate all AEs, including non-serious AEs, that occur throughout clinical development and be responsible for the safety of clinical trial participants. The G-SUSARs also notes that the results of these evaluations must be submitted to ANVISA in the Drug Development Safety Update Report (DSUR) or whenever requested.

ResNo945 explains that safety information originating from other countries where clinical development is taking place must be communicated to ANVISA if it implies a change in the benefit-risk profile of the experimental drug, including safety actions taken by other agencies. The sponsor must also inform the investigators involved in the clinical trial about SUSARs and adopt procedures for updating the IB, in addition to reassessing the risks and benefits for the participants.

Further, per the ResNo945 and the G-SUSARs, the sponsor must establish a monitoring plan to manage AEs that occur following a trial’s completion/termination. ResNo945 further explains that the plan should justify the proposed period, which takes into account the IP(s), the participants, and the clinical trial. Throughout the clinical development of the IP, the sponsor and the investigator must adopt immediate safety measures to protect the trial participants in the event of a SAE/SADR. The trial participant suffering from an AE must receive care and appropriate safety measures must be taken until their clinical condition is resolved or stabilized, as described in the clinical protocol.

Per BRA-73, Brazil has also implemented the ICH Guideline E2B (R3) on Electronic Transmission of Individual Case Safety Reports (ICSRs) - Data Elements and Message Specification - Implementation Guide (BRA-88).

See ResNo506 for detailed information on AE and SAE safety reporting requirements involving investigational advanced therapy products.

Other Safety Reports

As described in ResNo945 and the G-SUSARs, DSURs must be sent annually to ANVISA, until the end of the clinical development of the IP in Brazil. Each DSUR must be filed within 60 calendar days of either the annual anniversary of ANVISA’s approval of the clinical trial application, or the annual anniversary of the date established in the international development program, as applicable. ResNo945 and the G-SUSARs also note that the DSURs must be prepared in accordance with the format described in the current version of the ICH Harmonised Tripartite Guideline: Development Safety Update Report (E2F) (BRA-72). The SAE/AE data collected by the sponsor that occur throughout clinical development must be submitted to the Independent Data and Safety Monitoring Committee (IDMC or Data Safety Monitoring Board (DSMB)), if established, and the results of this assessment must be forwarded to ANVISA in the DSUR, in English, and upon request by ANVISA. See also the Site/Investigator Selection section for additional DSMB requirements.

Further, per the G-SUSARs, the sponsor must submit a single document containing data pertinent to all dosage forms and concentrations, all indications, and study participant populations associated with the IP. If this is not possible, a justification must be provided in the introductory section of the DSUR report. For concomitantly administered medicinal products, the sponsor may refer a single DSUR encompassing the IP and the other concomitantly administered therapies; or file separate reports for each IP product. For fixed-dose combinations, the sponsor must request a single DSUR covering all IPs. All safety-related modifications to the DDCM that are considered insubstantial must be also submitted to ANVISA as part of the DSUR.

For investigational advanced therapy products, SAEs must be reported through the Online Adverse Event Notification Form for Advanced Therapy Products (BRA-101).

Form Completion & Delivery Requirements

As per BRA-83, VigiMed (BRA-83) is ANVISA’s online system for citizens, health professionals, drug registration holders, and study sponsors to report suspected SAEs related to drugs and vaccines. In accordance with ResNo945, BRA-37 indicates that upon registration with BRA-83, companies (sponsors) must submit SUSARs exclusively via BRA-83. In addition, ResNo945 states that SUSAR notifications should be submitted individually and contain all the information requested in the fields present in the electronic notification system and as provided in the ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (BRA-66) and its updates.

In addition, per the G-SUSARs, any relevant safety events that alter the benefit-risk ratio of the IP or clinical trial(s) must be reported to ANVISA as soon as possible, using submission subject code 12378 - CLINICAL TRIALS - Safety monitoring linked to the respective process (DDCM or DEEC), and concurrently sending an email to vigimed.pesquisa@anvisa.gov.br, communicating the submission of the documents.

Per BRA-37, sponsors of clinical trials with medicines and biological products that have not yet been registered with VigiMed-Pesquisa Clínica should complete VigiMed’s Registration/Change of Registration form (BRA-131) and send it to this email address: vigimed.pesquisa@anvisa.gov.br. See also BRA-130 for the VigiMed Company User Manual, and BRA-145 for general instructions on using VigiMed.

Safety Reporting Definitions

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

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

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

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

Sponsor Responsibilities

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

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

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

The G-SafetyRpt delineates the following reporting timeframes:

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

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

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

Form Completion & Delivery Requirements

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

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

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

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

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

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

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

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

Interim and Annual Progress Reports

As per ResNo945 and the G-CTReptsManual, the sponsor must file a progress report, known as an annual clinical trial protocol monitoring report, to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) in the form of a secondary petition electronically attached to the respective protocol to which it is linked. The G-DDCMManual also specifies that the annual clinical trial monitoring report should be linked to the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)).

ResNo945 states that the report should be filed within 60 calendar days of the start date of the clinical trial in Brazil. The annual report should contain the following information for each clinical trial protocol, in tabulated form, exclusively from Brazilian centers:

• Clinical trial title and protocol code
• Recruitment status and breakdown of the number of participants recruited by center in Brazil and worldwide
• Number/description of deviations and protocol violations by center
• Number of centers in Brazil and worldwide and their respective status, and
• Number of serious adverse events (SAEs) per participant and per center in Brazil, including the description of SAEs related to the investigational drug or comparator, adverse drug reactions (ADRs), Suspected Serious and Unexpected Adverse Reactions (SUSARs), and whether or not the blinding was broken

Per ResNo945, the annual clinical trial monitoring reports should contain all information through the end of the clinical trial in Brazil. Afterwards, only the final clinical trial report needs to be submitted. Additionally, the annual report may be waived in the year in which the final report is filed.

As stated in LawNo14.874, the investigator is responsible for submitting partial reports with information on the progress of the research, annually and whenever requested, to the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) that analyzed the study.

Final Report

ResNo945 and the G-CTReptsManual state that the sponsor should submit a final report to ANVISA in the form of a secondary petition electronically attached to the respective protocol to which it is linked. The final report must be filed within 12 months of the clinical trial end date. ResNo945 also specifies that the report should be submitted after completing the activities of a clinical trial in all participating countries, for whatever reason. The final report should contain, at a minimum, the following:

• Clinical trial title and protocol code
• Final recruitment status and breakdown of the number of participants recruited by center in Brazil and worldwide
• Final number of centers in Brazil and worldwide
• Final number of SAEs per participant and per center in Brazil, including the description of SAEs related to the investigational drug or comparator, ADRs, SUSARs, and whether or not the blinding was broken
• Reason for termination of the study and rationale for premature termination of development in Brazil or worldwide, when applicable

Per G-CTReptsManual, the annual and final reports for each clinical protocol may also be submitted using the International Council for Harmonisation (ICH)’s Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports (E3) format (BRA-27).

Other Reporting Requirements

As stated in ResNo945 and the G-CTReptsManual, in addition to submitting a final report, the sponsor is also responsible for submitting clinical trial start and end date forms for trials conducted in Brazil. The forms with the trial start and end dates must be filed as a secondary petition to the corresponding trial dossier within 30 calendar days after each start and end date. Per ResNo945, the secondary petition should be submitted to ANVISA corresponding to the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) process. See Submission Process section for secondary petition submission requirements. See BRA-56 to access ANVISA’s Solicita Electronic Petition Request System website that allows users to submit these forms electronically, and BRA-25 and BRA-24 for links to the notification forms. See also BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

Interim and Annual Progress Reports

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

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

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

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

Final Report

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

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

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

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

As per LawNo14.874 and ResNo945, a sponsor is defined as a natural or legal person, under public or private law, that supports research through financing, infrastructure, human resources, or institutional support. ResNo466 defines a sponsor as an individual, company, institution, or organization that supports research through the initiation, management, or financing of a clinical trial.

LawNo14.874 further explains that a sponsor may authorize a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) to perform one (1) or more trial-related tasks and functions. ResNo945 specifies that a CRO is any company regularly installed in Brazil contracted by the sponsor or by the sponsor-investigator, which partially or totally assumes, together with the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), the sponsor's responsibilities. Any trial-related functions that are transferred to a CRO must also be specified in writing in a document signed by the sponsor and CRO. Per LawNo14.874 and ResNo945, although the sponsor may transfer their trial-related functions, the sponsor still has definitive responsibility for the quality and integrity of the clinical trial data.

ResNo945 also defines a sponsor-investigator as the natural person responsible for conducting and coordinating clinical trials, alone or in a group. The sponsor-investigator uses their own financial and material resources from national or international research funding entities or by private entities and other non-profit entities, while maintaining immediate and independent control over the study. When a clinical trial is developed by a sponsor-investigator, the institution with which the individual is linked is the primary sponsor. The primary sponsor may delegate responsibilities to the investigator, who will be responsible for conducting the clinical trial at the institution, and the sponsor-investigator will serve as the secondary sponsor. In the case of delegating responsibilities and activities, a written document must be signed between the parties.

In addition, per ResNo903, when a sponsor or CRO transfers responsibility to another company for submitting a clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) and the associated clinical trial processes for an investigational product (IP) to ANVISA, the succeeding company must update the relevant clinical trial registration data via a petition for global transfer of responsibility. See ResNo903 for additional information. See BRA-96 for more information on the global transfer of responsibility clinical trial request process. See also the Submission Content section for specific documentation requirements, and the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

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

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

Overview

As set forth LawNo14.874, the sponsor is responsible for selecting the investigator(s) and the institution(s) that will carry out the research, taking into account the qualifications necessary for conducting and supervising the research.

In addition, per ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for guidance on sponsor responsibilities related to site/investigator selection.

See also CLNo046 for the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidance on submitting requests for inclusion/exclusion of research center(s).

Foreign Sponsor Responsibilities

As specified in the ResNo945, the sponsor may transfer any or all of the sponsor’s study related duties and functions to a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil). However, the sponsor is ultimately responsible for the study data’s quality and integrity. Any study related duties, functions, or responsibilities transferred to and assumed by a local representative or CRO must be specified in writing. However, as per ResNo945, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or branch in Brazil.

Data Safety and Monitoring Board

LawNo14.874 states that, whenever possible, an independent data monitoring committee (Data Safety Monitoring Board (DSMB)) should be established to periodically evaluate the progress of the research, safety data, and critical points of efficacy and recommend to the sponsor whether to continue, modify, or interrupt a research study. In addition, ResNo945 indicates that it is desirable that an Independent Data and Safety Monitoring Committee (IDMC) (DSMB) be established by the sponsor to evaluate, at defined intervals or as needed in an emergency, the progress of the clinical trial, the safety data and the critical efficacy endpoints, and recommend to the sponsor whether to continue, modify, interrupt, or suspend a trial. The G-SUSARs also suggests that a DSMB be established, regardless of the clinical phase. The decision on the need to set up a DSMB must consider several factors including:

• Clinical and scientific relevance to the clinical trial
• Potential acceptable benefits and risks for the protection of participants
• Type of population
• Trial design, including objective(s) and outcome(s)
• Relevance of the committee to the integrity of the research

See also G-DSMB-BRA for DSMB operational guidelines.

Multicenter Studies

Refer to BRA-28 for sponsor guidance on conducting multicenter studies.

Overview

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

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

Capacity Building & Training

As described in the G-Monitor, the sponsor should consider previous experience with the investigator or site, workload of the investigator, and resource availability at the study site during investigator and site selection. Per the G-Capacity, clinical trial applications should include evidence and activity plans to build capacity at each study site as well as enhancing research activities and skills of professionals from historically disadvantaged groups. Mandatory training in Good Clinical Practice (GCP) forms a part of capacity building. To support transformation and capacity building, the South African Health Products Regulatory Authority (SAHPRA) states that the sponsor must have a policy on “Capacity Building and Transformation in Clinical Research in SA” in place, and preferentially select sites that are compliant. See G-Capacity, for detailed information on actions that will comply with this requirement.

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

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

Management of Investigators

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

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

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

Foreign Sponsor Responsibilities

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

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

Data and Safety Monitoring Board

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

Multicenter Studies

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

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

Insurance

As indicated in ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for guidance on sponsor responsibilities related to insurance coverage.

Compensation

Injury or Death

As specified in the LawNo14.874 and ResNo945, the sponsor is responsible for providing compensation and health assistance to research participants who have suffered as a result of their participation in the research. ResNo945 further specifies that the sponsor is responsible for all expenses related to procedures and examinations, especially those related to diagnosis, treatment, monitoring, and hospitalization of the clinical trial participant, and should take other actions necessary to resolve adverse events related to the clinical trial.

Additionally, per ResNo466, the investigator, the sponsor, and the institutions and/or organizations involved in the different phases of the research must provide immediate assistance, as well as be responsible for providing full assistance to research participants with regard to complications and damages arising from the research. Research participants should also be ensured that the conditions for monitoring, treatment, comprehensive assistance and guidance, including in-screening studies, will be in place as long as necessary. LawNo14.874 also notes that the institutions and organizations involved in the research will be jointly responsible for its conduct and will provide full assistance to the participants for complications and damages arising from the research.

Trial Participation

LawNo14.874 delineates that remuneration of the participant, or the granting of any type of advantage for their participation in research, is prohibited. However, the following do not constitute remuneration or advantage for the research participant:

• Reimbursement of transportation, food expenses, or provision of material supplies in advance
• Other types of reimbursement required, depending on the research project

LawNo14.874 further states that compensation is permitted for healthy volunteers participating in Phase I clinical trials or bioequivalence studies, when the participant is registered in a national registry of volunteers for bioequivalence and Phase I studies, and provided that the participant is not simultaneously enrolled in more than one (1) research study.

Also, as specified in ResNo466, compensation to participants is only provided for transportation costs and meals for the participants or their legal representative/guardian during the trial.

See BRA-29 for additional information on participant compensation rights.

Post-Trial Access

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising research ethics committees (ECs) (Comitê de Ética em Pesquisa (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—under the CNS to SINEP. Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

Pursuant to DecreeNo12.651, and in accordance with LawNo14.874, under SINEP, the sponsor must submit a post-trial access plan to the EC (CEP)) before the clinical trial begins. The plan must present and justify the need to provide participants with free access to the investigational product (IP) after completion of the trial. LawNo14.874 further states that, when post-trial access to the IP is required, the sponsor must prepare a post-trial supply program in accordance with the regulations. To guarantee continued access to the IP after the trial concludes, the program must provide for ongoing participant safety monitoring. The program should only be initiated after regulatory approval. The request for such approval must be submitted in a timely manner to ensure the research participant can transition to the post-trial period without interruption of treatment.

Additionally, per LawNo14.874, at the end of the clinical trial, the investigator, following consultation with the sponsor and the research participant, must carry out an individualized assessment to determine the need to continue the IP for each participant. DecreeNo12.651 further specifies that the sponsor must ensure free supply of the IP whenever the responsible researcher considers it to be the best therapeutic alternative for the participant’s clinical condition, based on available evidence and a favorable assessment of the risk-benefit ratio, in accordance with LawNo14.874. See also BRA-141 for additional INAEP guidance on post-trial access.

LawNo14.874 further explains that assessment of the need for continued IP supply after the clinical trial must be carried out in accordance with the following criteria:

• The severity of the disease and its threat to the participant's continued life
• The availability of satisfactory therapeutic alternatives for the participant’s treatment, considering their location
• If the experimental drug addresses an unmet clinical need
• If the evidence of benefit to the participant outweighs the evidence of risk with the use of the experimental drug

Per LawNo14.874, the free supply of the IP within the scope of the post-trial supply program may be interrupted, upon submission of justification to the EC (CEP), for assessment, only in any of the following situations:

• The research participant chooses to stop participating, or the participant cannot freely and validly express their consent
• A cure has been identified for the disease or health problem targeted by the clinical trial, or a satisfactory therapeutic alternative has been introduced, a fact duly documented by the investigator
• The lack of benefit from the participant’s continued use of the IP, considering the risk-benefit relationship outside the trial context or the emergence of new evidence of risks related to the IP’s safety profile, a fact duly documented by the investigator
• The occurrence of an adverse reaction that, at the investigator’s discretion, makes it impossible to continue using the IP, even in the face of potential benefits
• The impossibility of obtaining or manufacturing the IP for technical or safety reasons, duly justified, and provided that the sponsor provides an equivalent or superior therapeutic alternative available on the market
• A lapse of five (5) years, counted from the commercial availability of the experimental drug in the country
• The availability of the IP in the public health network

LawNo14.874 further notes that in the case of reactions arising from the study itself, the sponsor must ensure appropriate and necessary health care or measures for the research participant.

CEP/CONEP System (Pre-SINEP Framework)

Under the CNS' CEP/CONEP System, at the end of the study, the sponsor much ensure free and indefinite access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective. Access must also be guaranteed to participants between the time they stop participating in the trial and the end of the study, as delineated in ResNo466.

Further, ResNo563 states that for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining ANVISA registration. ResNo38 also indicates that the sponsor or the contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) should guarantee access to the post-trial drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the CNS. The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Trial Medicine Supply Programs (see BRA-126 for form).

In addition, per ResNo903, the global transfer of sponsor or CRO responsibility for clinical trials is also applicable to expanded access programs, compassionate use programs, and post-trial drug supply. See ResNo903 for additional information. See also the Submission Content section for specific documentation requirements, and the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

Insurance

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

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

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

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

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

Compensation

Injury or Death

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

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

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

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

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

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

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

Trial Participation

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

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

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

Post-Trial Access

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

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

Quality Assurance/Quality Control

As set forth in LawNo14.874, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems based on standard operating procedures (SOPs), to ensure that research is conducted and data is generated, documented, and reported in compliance with the protocol, good clinical practices (GCP), and other applicable regulatory requirements. The sponsor is responsible for QC during each stage of data processing to ensure its reliability and correct handling, and for maintaining the quality and integrity of research data, even if some or all functions have been transferred to a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil).

In addition, per ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for guidance on sponsor responsibilities related QA and QC systems throughout the conduct of the trial.

ResNo945 also notes that in the case of a clinical trial initiated by the investigator, the institution to which the investigator is linked will be the primary sponsor. While the primary sponsor cannot delegate the quality assurance, auditing, and monitoring activities of clinical trials to the sponsor-investigator, the primary sponsor may delegate these responsibilities to a CRO. The primary sponsor must present its own or outsourced structure with QA and monitoring.

Monitoring Requirements

LawNo14.874 notes that the investigator is responsible for providing, when requested, direct access to research records and documents for the monitor, the auditor, other representatives of the sponsor, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)), and ANVISA; allowing the sponsor to monitor and audit the research; and allowing ANVISA, INAEP, and the EC (CEP) to conduct inspections.

Additionally, in the event of a routine inspection by ANVISA, RegNo122 states that the agency will notify the institution at least 15 calendar days in advance of the visit. Both the sponsor and/or the CRO are responsible for preparing for the inspection. ANVISA must also notify the principal investigator (PI) of the scheduled visit to the center to be inspected, when applicable, by means of a GCP Inspection Notification Letter. For more detailed information on ANVISA’s inspection process, refer to RegNo122. See also Scope of Assessment section for detailed ANVISA inspection requirements. See GuideNo35-2020 and GuideNo36-2020 for additional guidance on GCP inspection requirements.

See ResNo926 for information on ANVISA’s inspection requirements for research centers to obtain a Certification of Good Practices to conduct bioavailability/bioequivalence drug studies. See also BRA-28 for additional sponsor monitoring requirements.

Premature Study Termination/Suspension

Pursuant to LawNo14.874, the sponsor is responsible for promptly communicating the reasons for the suspension or premature termination of the research to the investigators involved, the executing institution, ANVISA, and the EC (CEP) that approved the study, where applicable. Within 30 business days, the coordinating researcher must submit to the EC (CEP), the discontinuation notification, the technical-scientific justifications underpinning the decision, and a detailed report containing the results obtained up to the time of the study’s interruption. In the case of a clinical trial, in addition to the documentation specified, the coordinating researcher and the sponsor are required to submit a plan for the follow-up and assistance necessary for the participants in the discontinued study. The discontinuation of research for reasons the EC (CEP) deems non-substantive will be considered an ethical infraction and will subject the offender to the sanctions delineated in LawNo14.874. See LawNo14.874 for additional details related to sanctions. DecreeNo12.651 also provides that INAEP will regulate the plan for monitoring and assisting participants in discontinued trials in accordance with the provisions delineated above per LawNo14.874.

ResNo945 further explains that the sponsor may, at any time, suspend or cancel a Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)) or approved clinical trial, provided that the appropriate justifications are submitted, as well as a plan for monitoring the participants, if the trial has already been initiated. Per ResNo945 and the G-DDCMAmdmts, once a DDCM has been cancelled, no clinical trials related to it may be continued in the country. Per ResNo945 and the G-DDCMManual, suspensions and cancellations must be filed with ANVISA, in the form of a secondary petition attached to the corresponding DDCM. ResNo945 and the G-DDCMAmdmts also note that the petition must be submitted within 15 business days following the decision to suspend or cancel a DDCM or clinical trial.

In addition, ResNo945 and the G-DDCMAmdmts state that in cases where the sponsor temporarily suspends the DDCM or clinical trial, as an immediate safety measure, the sponsor must notify ANVISA within seven (7) calendar days from the date of suspension. ResNo945 also notes that the reasons, scope, interruption of treatment, and suspension of participant recruitment must be clearly explained in the temporary suspension notification. The request for reactivation of a suspended clinical trial protocol or DDCM must be accompanied by the appropriate justifications, and the sponsor must await authorization from ANVISA to restart the clinical trial. As per the G-DDCMAmdmts, the temporary suspension can be reactivated with the submission of a secondary petition to ANVISA. Refer to the Submission Content section for instructions on submitting a secondary petition to suspend or cancel a DDCM or clinical trial.

Per ResNo945, the sponsor may, at any time, request that ANVISA discontinue its analysis of the DDCM, the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)), and secondary petitions. The withdrawal request must be accompanied by the appropriate justifications and applies only to petitions in which ANVISA’s decision has not yet been published in the Official Gazette of the Union (Diário Oficial da União (DOU)). Temporary suspension, cancellation, reactivation, and withdrawal of DDCM, DEEC, and secondary petitions may only be implemented after ANVISA has issued a statement, which must be issued within 30 business days, by means of publication of its decision in the DOU. However, in the case of a temporary DDCM or clinical trial suspension as a safety measure, ANVISA’s implementation must be immediate, and the analysis carried out within 10 calendar days.

See also BRA-28 for guidance on sponsor responsibilities related to premature trial termination/suspension.

Quality Assurance/Quality Control

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

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

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

Monitoring Requirements

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

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

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

Premature Study Termination/Suspension

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

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

Electronic Data Processing System

As specified in ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28), and its subsequent updates for use with this regulation. Refer to BRA-28 for sponsor requirements when using electronic trial data processing systems.

Records Management

As delineated in ResNo945, the sponsor must be responsible for storing clinical trial data for a period of five (5) years after the last approval of a registration request for registration in Brazil. The sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, or a marketing application receives the last approval.

Additionally, per LawNo14.874, investigators are responsible for storing under their custody, in physical or digital media, essential research data and documents for a period of five (5) years after a project’s formal end or discontinuation, and for a period of 10 years in the case of advanced therapy products.

Electronic Data Processing System

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

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

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

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

Records Management

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

Responsible Parties

The LGPD delineates that the “controller” is responsible for decisions regarding the processing of personal or sensitive personal research data. Within this context, the controller may carry out studies as a research body, guaranteeing, whenever possible, the anonymization of personal data.

Per CD-ANPD-No18, which regulates the performance of the person responsible for processing data, the “person in charge” is appointed by the controller and operator to act as a communication channel between the controller, data subjects, and the National Data Protection Authority (Autoridade Nacional de Proteção de Dados (ANPD)). The person in charge may be a natural person, member of the organizational structure of the processing agent or external to it, or a legal entity, and must be able to communicate with the holders and with the ANPD, clearly, precisely, and in Portuguese. Additionally, the exercise of activity of the person in charge does not presuppose registration with any entity or any specific certification or professional training. See CD-ANPD-No18 for details on the activities and duties of the person in charge and how conflicts of interest are handled. Refer to G-CD-ANPD-No18 for additional guidance and good practices for data processing agents.

Data Protection

As set forth in C-AmndtNo115, the protection of personal data is a guaranteed fundamental right in Brazil. The LGPD further delineates data protection principles (e.g., purpose, adequacy, necessity, free access, data quality, transparency, security, prevention, non-discrimination, and accountability) with which the controller must comply. The protection and anonymity of the personal data of research participants is also regulated by LawNo14.874, and applied subsidiarily to the LGPD.

Per the LGPD, the data quality principle is fulfilled when the controller can guarantee to the data subjects that their personal data is processed with accuracy, clarity, and relevance, and is updated as required to meet the compliance requirements for the stated purpose. The controller must keep a record of the personal data processing operations carried out, especially when the processing operation is for an official purpose. The controller must also provide instructions to the operator, the person responsible for processing the personal data on the controller’s behalf, to check compliance with the specified instructions and rules. Additionally, the controller is required to protect the confidentiality of the personal data holder and their background. The holder is defined as the person whose personal data are being processed.

The LGPD also provides a definition for sensitive personal data or information that encompasses health related considerations. Sensitive personal data refers to personal data about racial or ethnic origin; religious belief; political opinion; union membership or organization of a religious, philosophical, or political nature; data relating to health or sexual life; and genetic or biometric data, when linked to a natural person. See also LGPD for guidance on implementing a privacy governance program, and see the LGPD and BRA-76 for detailed information on data protection requirements in Brazil.

As per OrdNo1.184, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has established a personal data protection policy to comply with the provisions in Article 23 of the LGPD, which define personal data processing requirements for legal entities governed by public law. OrdNo1.184 specifically delineates internal guidelines for ANVISA for the protection of personal data, and for compliance with legislation, standards, guidelines, and other acts related to privacy, personal data protection, transparency, access to public information, and the protection of freedoms and fundamental rights of individuals. The guidelines are applicable to employees, collaborators, outsourced workers, interns, suppliers, service providers, and everyone who carries out activities that involve, directly or indirectly, the processing of personal data held by ANVISA. See OrdNo1.184 for details, and BRA-77 for additional background information.

In addition, per ResNo738, which aims to standardize the use of databases for the purpose of scientific research involving human beings, database information is protected to preserve the dignity and fundamental rights of research participants, especially as it relates to their informational self-determination, freedom, privacy, honor, and image. Researchers, sponsors, and institutions involved in the creation and use of databases must act with integrity and responsibility when processing data, and are responsible for:

• Respecting the rights of participants
• Guaranteeing the confidentiality of information
• Preserving the freedom, privacy, intimacy, honor, and image of participants, especially when there is identifying or sensitive data
• Applying information security measures
• Keeping the database in a safe place, where access is restricted, controlled, and traceable
• Adopting measures to reduce the risk of damage, tampering, or loss of data
• Respecting the principles of research integrity

ResNo738 further explains that research protocols, which involve the creation of a database or the use of existing databases, must be processed in accordance with the type of research and the modulation factors established in ResNo674. The research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP))/National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), jointly known as the CEP/CONEP System, is responsible for this review process. (See Scope of Review section for detailed information on research classification and protocol review pathways.) Personal data processing may be carried out to execute studies by a research body that guarantees, whenever possible the anonymization and security of personal data. Unless the participant or legal representative/guardian provides a signed consent that is approved by the CEP/CONEP System, personal identifying data must also be removed when the data is deposited, partially or completely, in national or international banks, with public or restricted access. Refer to ResNo738 for additional details on the management and use of database information for research purposes.

In the event of a security incident, per CD-ANPD-No15, the controller must communicate to the ANPD and the data holder the occurrence of a security incident that could cause significant risk or damage to the holders in compliance with Article 48 of the LGPD. CD-ANPD-No15, which defines a security incident as any confirmed adverse event, related to the violation of the confidentiality, integrity, availability, and authenticity properties of personal data security, and involves at least one (1) of the following criteria:

• Sensitive personal data
• Data on children, adolescents, or elderly people
• Financial data
• Authentication data in systems
• Data protected by legal, judicial, or professional secrecy
• Large-scale data

Per CD-ANPD-No15, the controller must communicate the incident to the ANPD and to the personal data holder within three (3) working days from the date of first awareness. The controller must also keep a record of the security incident for a minimum of five (5) years, counting from the date of registration, unless additional obligations are established that require a longer period of record maintenance. See CD-ANPD-No15 for detailed reporting requirements. See also BRA-61 and BRA-62 for additional background information.

In addition, per CD-ANPD-No19, international data transfer may be carried out to countries or international organizations recognized by the ANPD as providing a level of personal data protection equivalent to that provided for under the LGPD. Alternatively, transfers may be based on the controller’s verification of compliance with the LGPD’s principles, data subject rights, and data protection requirements through specific contractual clauses for a given transfer, standard contractual clauses, or global corporate standards as provided for in the LGPD and CD-ANPD-No19. See Chapter V of the LGPD, CD-ANPD-No19, and BRA-118 for detailed international data transfer requirements. See also CD-ANPD-No32 regarding ANPD’s recognition of the European Union (EU) as providing an adequate level of personal data protection for purposes of international data transfers.

CD-ANPD-No19 further explains that if the international data transfer involves sensitive personal data, the parties will apply additional safeguards, including specific security measures proportionate to the risks of the processing activity, the specific nature of the data and the interests, rights, and guarantees to be protected. Also, if international data transfer involves the sensitive personal data of children and adolescents, the parties will apply additional safeguards, including measures to ensure that the processing is carried out in their best interests, in accordance with national legislation and international law. The parties must adopt security measures and provide information on measures taken which consider the nature of the information processed, the specific characteristics and purpose of the processing, the current state of technology, and the risks to the rights of the holders, especially in the case of sensitive personal data and of children and adolescents. The measures may include, among others, the governance and supervision of internal processes, and technical and administrative security measures, including measures to ensure the security of the operations carried out, such as the collection, transmission, and storage of data.

Consent for Processing Personal Data

Per LGPD, the processing of personal data can only be carried out in the following cases:

• By providing consent by the holder
• For the fulfillment of a legal or regulatory obligation by the controller
• By the public administration, for the treatment and shared use of data necessary for the implementation of public policies provided for in laws and regulations or supported by contracts, agreements, or similar instruments per Chapter IV (LGPD)
• To carry out studies by a research body, guaranteeing, whenever possible, the anonymization of personal data
• When necessary for the execution of a contract or preliminary procedures related to a contract to which the holder is a party, at the request of the data subject
• For the regular exercise of rights in judicial, administrative, or arbitration proceedings

The LGPD further specifies that the processing of sensitive personal data may only be carried out when the holder or the holder’s legal guardian consents, in a specific and obvious way, for the purpose of processing sensitive personal data. The consent must be provided in writing or by another means that demonstrates the holder’s intention. If the consent is provided in writing, it must be included in a separate clause of the other contractual clauses. The sponsor bears the burden of proving that the consent was obtained in accordance with the provisions of this law. The processing of personal data is prohibited by the absence of consent. The consent must refer to specific purposes; generic authorizations for the processing of personal data will be voided. The consent can be revoked at any time by express statement of the holder, by a free and facilitated procedure. If the information is changed, the sponsor must inform the holder and specifically highlight the content of the amendments. In cases where the holder’s consent is required, the holder can revoke consent if opposed to the changes.

Further, per the LGPD, the processing of sensitive personal data may occur without the holder’s consent in those cases where it is indispensable for:

• Compliance with legal or regulatory obligations by the controller
• Shared processing of data necessary for the execution, by the public administration, of public policies provided for in laws or regulations
• Carrying out studies by a research body, guaranteeing, whenever possible, the anonymization of sensitive personal data
• Regular exercise of rights, including in contract and in judicial, administrative, and arbitration proceedings
• Protection of the life or physical safety of the holder or third party
• Guardianship of health, exclusively, in a procedure performed by health professionals, health services, or health authority
• Guarantee of fraud prevention and security of the holder, in the processes of identification and registration authentication in electronic systems, safeguarding the rights mentioned in Article 9 of this law, and, except in the event that the fundamental rights and freedoms of the holder prevail that require the protection of personal data

Data holders also have the right to be informed about the collection and use of their personal data. The data holder is entitled to obtain from the sponsor access to their treated data at any time and upon request. Treatment is defined as any operation performed with personal data. See Chapter III of the LGPD for additional information on the rights of data holders.

See CLNo1-2021 for CONEP guidelines for investigators and CEPs related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. See also CLNo039 for CONEP guidance on accessing and using a participant’s medical records for research purposes while ensuring compliance with privacy and confidentiality standards. The guideline also states that all participants should be treated with dignity, respect for their autonomy, and ensure protection for vulnerable populations. See also BRA-29 for additional resources on participant rights to data privacy. Refer to the G-PDP-Acad for recommendations and good practices to support the processing of personal data for academic purposes and for performing studies and research in compliance with the LGPD.

In addition, as indicated in ResNo738, participants in research databases are the owners of their data and must be guaranteed fundamental rights to access their stored information at any time. Participants may request corrections or updates to their database information that they believe to have been entered incorrectly. They may request the partial or total removal of their information, with the cancellation valid from the date they first communicated their concern. Participants also have the right to request compensation if there is damage resulting from the misuse or breach of security or confidentiality of their stored data.

ResNo738 further explains in research that proposes the creation of a database, the informed consent form (ICF) (also known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil) must contain the following:

• Research justification and objectives, risks and benefits of data storage including information about the future use of data, when applicable
• Description of the procedures adopted to guarantee the secrecy and confidentiality of information, ensuring the preservation of the intimacy, honor, and image of the participants
• Description of strategies for controlling access to data and information
• Information about the future use of data and information for research, in a specific and highlighted way, when there is this intention, presenting alternatives that indicate the need or not for new consent
• Justification for sharing bank data and information, in a specific and prominent way, when there is this intention, presenting alternatives that indicate the participant's authorization or not
• Information on the irreversible anonymization of data, when any, with explanations of the consequences of such a procedure
• Information about the right to request correction, partial withdrawal, or complete removal of the participant’s data and information

Consent for Processing Personal Data of Children/Adolescents

Per the LGPD, the processing of personal data of children and adolescents must be carried out in their best interest with specific and highlighted consent given by at least one (1) of the parents or the legal guardian. However, the sponsors are permitted to collect personal data from children without the consent of a parent or legal guardian when collection is necessary to contact the parent or legal guardian, used only once and without storage, or for their protection, and in no case may be passed on to a third party without the consent of at least one (1) parent or the legal guardian.

The sponsor must make all reasonable efforts to verify that the consent was given by the individual responsible for the child, considering the available technologies. Additionally, information on the processing of the personal data of children and adolescents must be provided in a simple, clear, and accessible manner, considering the physical-motor, perceptual, sensory, intellectual, and mental characteristics of the user, using audiovisual resources when appropriate, in order to provide the necessary information to the parents or legal guardian, and that is appropriate to the child’s level of understanding.

To facilitate the processing of personal data of children and adolescents, the ANPD-No1 states that processing may be based on the legal hypotheses delineated in Article 7 (personal data) or in Article 11 (sensitive personal data) of the LGPD, provided that the best interest of the children and adolescents prevails, as evaluated in the specific case.

Responsible Parties

For the purposes of data protection requirements, the POPIA provides that the “responsible party” is a public or private body or any other person that, alone or in conjunction with others, determines the purpose of and means for processing personal information. In addition, an "information officer" is the designated head or deputy of a public or private body responsible for fulfilling the duties and functions related to personal information.

Data Protection

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

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

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

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

The POPIA establishes a duty requiring a public or private body to register its Information Officer with the Information Regulator (South Africa) on the eServices platform (ZAF-14). Per the POPIA, the Information Officer is responsible for compliance with lawful processing of information and working with and responding to requests by the Regulator. Per the POPIA-Regs, the Information Officer has further responsibilities to:

• Develop, implement, monitor, maintain, and continually improve a compliance framework
• Conduct a personal information impact assessment to ensure compliance with the conditions for the lawful processing of personal information
• Develop internal measures and systems to process requests for information or access
• Conduct internal awareness sessions on protection of personal information requirements

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

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

See ZAF-4 for voluntary guidance on complying with the POPIA, and ZAF-28 for more background on information officers. For additional guidance on processing personal data, including guidance on “special personal information” (e.g., health history) and personal information of children, see the Information Regulator website.

Consent for Processing Personal Data

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

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

Consent for Processing Personal Data of Minors

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

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

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

Obtaining Consent

In all Brazilian clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in LawNo14.874 and ResNo466. Per LawNo14.874 and OMREC, the informed consent form (ICF) is known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.

As per LawNo14.874, the ResNo466, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by a research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). CLNo51 further clarifies that the ICF should be written as an invitation rather than as a statement as this may reduce the participant’s autonomy. Refer to CLNo51 for detailed information. See the Required Elements section for details on contents to be included in the form.

LawNo14.874 and OMREC state that the investigator, or their designated representative, must fully inform the participant or their legal representative/guardian of all relevant aspects of the research, including the EC (CEP)’s approval. As delineated in LawNo14.874, ResNo466, OMREC, and the G-ClinProtocols-FAQs, the ICF content should be presented in clear and objective language that is easy to understand to ensure the participant or the legal representative(s)/guardian(s) completely understands the research. Further, per LawNo14.874, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive their legal rights. Per LawNo14.874, the research participant or their legal representative/guardian may withdraw their consent at any time, regardless of justification, without any burden or loss being incurred. ResNo466 further notes that the investigator must bear in mind that the prospective participant’s ability to understand the information required to give consent depends on their maturity, ethics, intelligence, education, and cultural beliefs. Per LawNo14.874 and the G-ClinProtocols-FAQs, the information should be in both written and oral form. Also, per the G-ClinProtocols-FAQs, the participant and the legal representative/guardian should also be given adequate time to consider whether to participate. See BRA-29 for additional information on informed consent.

In addition, per ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for additional consent guidelines.

Re-Consent

According to LawNo14.874, the ICF must be updated and submitted for EC (CEP) consideration whenever new relevant information arises that could alter the research participant’s decision regarding their participation. CLNo17 also notes that the EC (CEP) should approve any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits before such changes are implemented. Per CLNo51, the investigator must ensure that the participant or legal representative/guardian sign the revised ICF and any other updated information. CLNo17 further notes that changes made to the ICF through separate documents are not considered acceptable. The update requires the investigator to generate a single and complete version of the new document, free of addenda and/or other documents associated with it. The investigator or their delegated representative should also emphasize the changes contained in the updated ICF. The clarifications delineated in CLNo17 also apply to assent forms. See also BRA-28 for additional guidance on re-consent.

Language Requirements

As earlier stated, LawNo14.874, ResNo466, and the G-ClinProtocols-FAQs, require the ICF to be presented orally and in writing at a level that the participant is able to understand. The G-ClinProtocols-FAQs further notes that the ICF must be adequately adapted and be fully revised in Portuguese to ensure that the document is properly translated.

Documenting Consent

LawNo14.874 and OMREC state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. In addition, LawNo14.874 explains that if the participant or legal representative/guardian is illiterate, an impartial witness should be present throughout the informed consent process. At this time, the participant or legal representative/guardian will give verbal, and, if possible, written consent, and the witness should sign and date the form, certifying that the written information was explained accurately and understood.

For multicenter research conducted under the single ethical review process, OrderNo3 requires the ICF to include the address, telephone number, and email address of the EC (CEP) responsible for the ethical review of the single protocol.

Before participating in the study, per OMREC, the participant should receive a copy of the signed and dated ICF, and any other written information provided during the informed consent process. ResNo466 and the G-ClinProtocols-FAQs specify that two (2) original copies of the ICF should be prepared with all pages initialed and signed by the participant or legal representative/guardian, and the investigator(s) or person(s) overseeing the consent process.

Waiver of Consent

No information is currently available regarding consent waivers for research participants. See the Consent for Specimen section for information on waivers pertaining to a participant’s stored genetic materials.

Obtaining Consent

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

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

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

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

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

Re-Consent

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

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

Language Requirements

According to the SA-GCP, the ICF should be provided in a participant’s preferred written language. The G-GPHlthCare states that the researchers should provide information to the participants in a language that the participant understands and in a manner that takes into account the participant’s level of literacy, understanding, values, and personal belief systems.

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

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

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

Documenting Consent

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

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

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

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

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

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

Waiver of Consent

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

Based on ResNo466 and OMREC, 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):

• Study justification, objectives, and procedures, including details of the methods to be used
• Identification of any experimental aspects of the study, if applicable
• Clarification of methodology before and during the research
• Explanation of possible discomforts and risks to the participant
• Description of any expected benefits to the participant, including information on the measures and precautions to be taken to avoid and/or reduce adverse effects and conditions that may cause harm, considering the research participant’s characteristics and context
• Explanation of existing alternative therapeutic methods, when applicable
• Clarification, when relevant, of the possibility of including the participant in control group or placebo, with a clear explanation of what this means
• Description of the monitoring and assistance to which research participants will be entitled, including the benefits and monitoring after the study ends and/or interruption of the research
• Statement guaranteeing full freedom to the research participant, to refuse to participate or withdraw their consent, at any stage of the research, without any penalty
• Statement guaranteeing maintaining the confidentiality and privacy of research participants during all phases of the research
• Statement confirming the research participant will receive a copy of the ICF
• Explanation of the reimbursement guarantee and how the expenses incurred by the participants and the resulting reimbursement will be covered
• Explanation of compensation for any damages arising from the research
• Statement that the participants are not required, under any condition, to waive the right to compensation for damages
• Statement from the responsible researcher confirming compliance with the ICF requirements
• Contact information for the responsible party (researcher's name and phone number and postal code) for questions and assistance