National Health Surveillance Agency (ANVISA)

As per ResNo9 and ResNo255, 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 ResNo9 and ResNo255.

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 ResNo255 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 derivatives.

As indicated in LawNo9.782 and ResNo255, ANVISA is headed by a Collegiate Board of Directors composed of up to five (5) members, one (1) of whom serves as the Chief Executive Officer. Among the Collegiate Board’s key responsibilities are its role in defining ANVISA’s strategic guidelines and proposing governmental policies and directives to the Minister in support of the agency’s health surveillance objectives.

LawNo9.782 and ResNo255 further indicate that ANVISA has an Advisory Board. Per ResNo255 and BRA-36, the Advisory Board’s main objectives include requesting information and proposing guidelines and technical recommendations to the Collegiate Board to be addressed by ANVISA, and providing opinions on proposed governmental policies. Refer to LawNo9.782, ResNo255, and BRA-36 for detailed Collegiate Board and Advisory Board responsibilities.

As delineated in ResNo255, ANVISA’s General Management of Medicines and Biological Products (Gerência-Geral de Medicamentos e Produtos Biológicos (GGMED)) coordinates and supervises the organizational units responsible for the regulation of active pharmaceutical ingredients, medicines, and biological products, and manages the implementation of international cooperation activities aimed at regulating active pharmaceutical ingredients, medicines, and clinical research involving human beings. The Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is an administrative unit operating within GGMED that evaluates the processes and petitions related to clinical research on drugs and biological products, and issues technical opinions with the goal of granting approval to initiate clinical research in Brazil. See ResNo255 for detailed information on ANVISA’s organizational structure and administrative units.

Other Considerations

Per BRA-65, Brazil is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). BRA-73 and BRA-113 indicate that Brazil implemented the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) in 2019.

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-42, the following is ANVISA’s contact information:

ANVISA
Setor de Indústria e Abastecimento (SIA)
Trecho 5
Área Especial 57
CEP: 71.205-050
Brasília - DF

Phone: 0 800 642 9782 (Public Service Center for domestic inquiries)*

*Per BRA-99, while ANVISA does not have phone service to receive international calls, general inquiries may be sent via email using ANVISA’s Electronic Contact Form (BRA-68). In-country calls can be made to specific administrative offices posted on ANVISA’s Who’s Who website (BRA-39).

Per BRA-12, the medicines and biological products contact information is as follows:

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

Per BRA-18, the clinical research 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 and ZAF-9, the South African Health Products Regulatory Authority (SAHPRA) is the regulatory authority overseeing medicines and clinical research, as well as medical devices and radiation safety. As stated in the MRSA and GRMRSA, SAHPRA is responsible for clinical trial oversight, approval, and inspections in South Africa. The agency grants permission for clinical trials to be conducted in South Africa in accordance with the provisions of the GRMRSA.

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

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

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

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

Other Considerations

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

Contact Information

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

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

SAHPRA’s physical address is:

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

As provided in the G-CTA-Electronic and ZAF-36, the following are the SAHPRA Clinical Trial Unit emails:

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

See ZAF-47 for clinical evaluation and management contacts.

Overview

As delineated in ResNo9 and ResNo255, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications (referred to as Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs))) for drugs to be registered in Brazil. Per ResNo9, the G-DDCMManual, and BRA-8, the DDCM must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the application to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM, also known as Experimental Drug Dossiers. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. Per ResNo9 and BRA-8, while the DDCM may be submitted at any stage of development, Phase IV post-marketing trials are only subject to Clinical Trial Notification by ANVISA after obtaining ethical approvals. See ResNo506 for 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).

In addition, ResNo205 repealed the ResNo9 requirement that the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel. As indicated in ResNo9 and also noted in BRA-2, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))’s approval is required for certain studies (e.g., foreign studies), but ANVISA’s decision to approve the DDCM is not dependent on CONEP. Similarly, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory for all studies, but may be requested, according to BRA-1. However, per ResNo9, the EC (CEP) is required to approve substantial protocol amendments prior to implementation. Refer to the Ethics Committee topic for additional information on the CEP/CONEP System; CLNo038 for the criteria CONEP uses to process protocol amendments; and CLNo24 and CLNo24-Note for general guidelines on conducting clinical trials.

Clinical Trial Review Process

As delineated in ResNo255, 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). ResNo9 and the G-DDCMManual explain that following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all the trials included in the DDCM that are permitted to initiate the clinical study. BRA-8 further explains COPEC experts conduct a preliminary review that includes a benefit-risk assessment based on various criteria such as drug registration status and drug status in other agencies (e.g., fast-track or breakthrough therapy). After this evaluation, the reviewer may release the dossier by the expiration deadline date so that the sponsor (applicant) may proceed with conducting the trial, requesting a meeting, or conducting a more detailed and complete dossier evaluation. See the Timeline of Review section for additional ANVISA timeline information. Also, see BRA-79 for additional information on ANVISA’s clinical trial review and approval framework, and BRA-40 for information on ANVISA drug registration requirements.

ANVISA has also released ServBltnNo104 to expedite the evaluation of clinical drug research development in Brazil without compromising the quality of the technical analysis. ServBltnNo104 provides detailed procedures for a simplified technical review of the following:

• DDCM petitions containing at least one (1) clinical trial protocol, at any stage of development, approved by at least one (1) regulatory authority of a member country of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) or by the United Kingdom’s (UK’s) Medicines and Healthcare products Regulatory Agency (MHRA). The protocol submitted to ANVISA need not be the same as the protocol approved by the member country.
• DDCMs for experimental drugs (also referred to as investigational products (IPs)) that are registered in at least one (1) ICH member country or the UK. This DDCM must be identical to the one (1) approved by the ICH member country or the UK, with the exception of the labels and secondary packaging models.
• Substantial quality changes approved by at least one (1) ICH member country or the UK (i.e., changes potentially impacting the quality or safety of the IP, active comparator, or placebo).

According to ServBltnNo104, the IP manufacturing process must also meet the criteria and recommendations described in the ICH guidelines, as applicable, according to the phase of clinical development. In addition, COPEC technical experts require DDCM petitions and substantial quality modifications to meet ServBltnNo104 criteria and be accompanied by the documentation required in ResNo9. COPEC will then analyze: the results of stability studies under accelerated and long-term conditions that support the proposed expiration date for the IP and, where applicable, for the modified placebo and comparator, when the storage recommendation is at room temperature (between 15 and 30 degrees Celsius); and the sample IP label for DDCM petitions.

In the event of non-compliance, COPEC will conduct a non-simplified analysis per ResNo9. ServBltnNo104 further explains that ANVISA may also at any time analyze all the documents required by ResNo9 relating to the IP risk analysis. Refer to the Submission Content section for DDCM petitions and substantial quality modifications documentation requirements.

See also BRA-19 and BRA-90 for guidance on scheduling pre-submission meetings with COPEC to discuss the clinical development of a drug (e.g., DDCM, an amended DDCM (secondary petition), or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted.

Priority Submissions

In addition to the previously stated DDCM requirements, ResNo204 establishes a priority category to register, amend previously registered, or request prior approval for drug submissions. ResNo204 states that the priority submission may be submitted as a DDCM or DEEC. A priority DDCM submission is required to meet one (1) or more of the following criteria: new drug trial in any phase to be carried out in Brazil, the drug is part of the Ministry of Health (MOH)’s National Immunization Program, or the product is determined to be of strategic public health interest and included under the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53). A priority DEEC submission is required to comply with the following: the drug is to be used for neglected, emerging, or reemerging diseases, health emergencies, or serious debilitating conditions for which there is no alternative; the trial is to be conducted exclusively with the pediatric population; or the drug will be used in a Phase I trial only to be manufactured in Brazil. The sponsor should specify at the time of submission that the new or amended protocol is a priority category request. If not confirmed prior to the technical review phase, the request for approval may be denied. ANVISA is required to first issue a written opinion letter within 45 calendar days from the first business day following protocol submission, a final opinion in 120 days for new drug registration requests, and a final opinion 60 days for post-registration petitions. See the Timeline of Review section detailed timeline information. Refer to ResNo204, ResNo811 (which partially amends ResNo204), and BRA-14 for detailed information on priority submission requirements.

See also BRA-2, BRA-1, and BRA-42 for additional information on priority submission.

New Drugs for Rare Diseases

ResNo205 sets forth specific approval procedures for clinical trials to be conducted to register new drugs to treat, diagnose, or prevent rare diseases. The applications may be submitted as an initial DDCM, a secondary petition linked to the original DDCM, or a DEEC either linked to the original DDCM or for a new process. The sponsor must delineate at the time of submitting a new drug submission (DDCM), an amended DDCM (secondary petition), or DEEC, whether the DDCM is pertaining to a rare disease drug. If not confirmed prior to the technical review phase, the request for approval may be denied.

In addition, per ResNo763, which modifies 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, if the sponsor deems necessary, and ANVISA should hold the meeting within 60 days following this request. Refer to ResNo205 and ResNo811 (which partially amends ResNo205) for additional submission documentation requirements. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.

Equivalent Foreign Regulatory Authority Submissions

ResNo741 provides general criteria for the admissibility of the Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) regulatory documentation that ANVISA requires to conduct a technical evaluation using the “optimized analysis procedure”. ANVISA defines the optimized analysis procedure as a technical evaluation mechanism that uses the AREE’s documentation, which includes reports, opinions, or technical/legal documents used to issue an opinion, as a sole or complementary reference. The optimized analysis procedure is facilitated by regulatory trust practices that are based on collaborative work and recognition, mutual or unilateral, among regulatory authorities or international entities. Among other requirements, in order for ANVISA to adopt the optimized analysis procedure, the health product covered in the AREE’s documentation must be essentially identical to the one submitted for ANVISA’s evaluation; and the products authorized for distribution should also have been adequately evaluated, and meet recognized standards of quality, safety, and efficacy. The specific criteria and procedures for defining the AREEs will be established in normative acts in a phased approach, according to each type of health surveillance process or product category. RegNo289 and RegNo292 are the initial normative acts adopted by ANVISA to define these processes/categories.

In accordance with ResNo741, ANVISA approved RegNo289, which establishes the criteria and procedures for ANVISA’s technical evaluation, known as the optimized analysis procedure, of one (1) or more AREE assessments to analyze registration and post-registration authorization requests for medicines, vaccines, biological products, and their active substances that are already approved in the reference country. ANVISA will issue a Letter of Adequacy of Active Pharmaceutical Ingredient Dossier (Carta de Adequação de Dossiê de Insumo Farmacêutico Ativo (CADIFA)) to certify the AREE has regulatory practices aligned with those of ANVISA and has ensured that products authorized for distribution have been adequately evaluated and meet recognized standards of quality, safety, and effectiveness. Additionally, RegNo289 also provides procedures for regulatory authorities to be designated as AREEs and a list of the currently approved AREEs.

Pursuant to RegNo289, ANVISA has designated the following foreign agencies as AREEs:

• European Medicines Agency (EMA)
• Health Canada
• European Directorate for the Quality of Medicines & HealthCare (EDQM)
• Swiss Agency for Therapeutic Products (Swissmedic)
• MHRA, UK
• US Food and Drug Administration (FDA)
• Therapeutic Goods Administration (TGA), Australia

Refer to RegNo289 for detailed requirements on submitting a request for ANVISA authorization via the optimized analysis procedure. See also BRA-26 for additional background information on RegNo289. See ResNo741 for additional information on the optimized analysis procedure and AREE related requirements. See also the Manufacturing & Import section for additional information on RegNo292.

Overview

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

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

Clinical Trial Review Process

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

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

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

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

Other Considerations

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

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

National Health Surveillance Agency (ANVISA)

As set forth in ResNo9 and 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 (Dossier 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 DDCM request (“petition” in Portuguese), 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, BRA-69 for information on the TFVS fee, and BRA-10 for additional information on TFVS requirements. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

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 BRA-11, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval. BRA-8 further notes that ANVISA charges a fee for substantial amendments to the clinical protocol. Additionally, 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 information.

Payment Instructions

As described in ResNo857, the TFVS fee must be paid by 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 explained in BRA-115, PagTesouro (BRA-114) is programmed to allow the payment of all fees related to ANVISA petitions in the Solicita system (BRA-56). 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 the MRSA-Fees and ZAF-37, applicants are responsible for paying several non-refundable fees to submit a clinical trial application. MRSA-Fees delineates the following fees:

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

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

For amendments to clinical trials:

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

For licenses:

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

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

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

Payment Instructions

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

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

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

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

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

Overview

As per ResNo466, ResNo446, and OSNo001, Brazil has a centralized registration process for research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) and requires institutional level EC (CEP) approval for each trial site. The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs (CEPs), and for registering and accrediting the ECs (CEPs). ResNo466, ResNo446, and OSNo001 state that CONEP is a collegiate advisory body directly linked to the National Health Council (Conselho Nacional de Saúde (CNS)), a permanent body within the Ministry of Health (MOH)’s Unified 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 participants may establish one (1) or more ECs (CEPs) according to their particular 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, BRA-16, and BRA-49 for useful information on CONEP and the CNS.

Ethics Committee Composition

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. The members represent a balanced gender composition; eight (8) members must equally represent various segments of the CNS. In addition, according to BRA-16, five (5) members must have a background in ethical research and health, and eight (8) members must represent the theological, legal, health management, and other related professions. 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, ResNo446, and BRA-16 for detailed information on CONEP composition and responsibilities. See also BRA-50 for useful information on CONEP.

Research Ethics Committees (CEPs)

As per the PANDRH-GCPs, an institutional EC (CEP) must have at least five (5) members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. By comparison, the OMREC requires the EC (CEP) to 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) Research Participant Representatives (Representantes de Participante de Pesquisa (RPPs)).

The PANDRH-GCPs, the OSNo001, OMREC, and ResNo706 also indicate that the EC (CEP) should be multidisciplinary, represent a balanced gender and age composition, and consist of members embodying community interests and concerns. The OMREC and ResNo706 further state that not more than half of its members should belong to the same professional category. ResNo706 also notes that at least half of members must demonstrate experience in research. In addition, as per the PANDRH-GCPs, in communities where minority ethnic populations predominantly reside, the EC (CEP) should include a member, alternate, or consultant from that group. The EC (CEP) may also designate alternate members whose functions are delineated in the EC’s (CEP’s) standard operating procedures (SOPs). Per ResNo706, any changes to the infrastructure, composition of members or administrative employees must be communicated to CONEP. When there is a change in CEP member composition, at least one third of the members of the previous composition must be maintained. Changes in CEP coordination must also be communicated and approved by CONEP. See ResNo706 for additional information. Additional criteria for EC (CEP) membership is also available in Section 3.2 of the PANDRH-GCPs and Section 2 of OMREC.

ResNo647 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

As set forth in the PANDRH-GCPs and OMREC, each EC (CEP) must have written 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

Also, as noted in ResNo706, 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 the PANDRH-GCPs, 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’s (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.

The PANDRH-GCPs also state that the EC (CEP) must retain all relevant records (e.g., SOPs, member lists, member affiliations and occupations, documents presented, meeting minutes, and correspondence) for three (3) years after the study’s conclusion, and make them available to the regulatory authorities upon request.

For detailed EC (CEP) procedures and information on other administrative processes, see Sections 3.3 and 3.4 of the PANDRH-GCPs and the OMREC. Also, see CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up EC (CEP) accreditation and renewal processes and maintain regular functioning of ECs (CEPs), and CLNo25 for guidance on conducting virtual CEP/CONEP system meetings.

Overview

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

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

Ethics Committee Composition

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

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

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

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

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

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

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

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

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

Overview

As set forth in ResNo466, the PANDRH-GCPs, ResNo251, and the G-ClinProtocols-FAQs, the primary scope of information assessed by research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (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 a clinical trial.

Per ResNo466, the PANDRH-GCPs, 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). ResNo304 further establishes specific ethical requirements for research studies involving indigenous populations. Detailed information on documentation and consent requirements for studies involving indigenous populations is available in the Documentation Requirements, Vulnerable Populations, and Consent for Specimen sections.

The CEP/CONEP System members are also responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol as stated in ResNo466, the PANDRH-GCPs, and OSNo001. It 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, the PANDRH-GCPs, and OSNo001 for detailed ethical review guidelines that govern the CEP/CONEP System.

National Research Ethics Commission (CONEP)-Designated Protocol Reviews

Per ResNo580, the Ministry of Health (MOH)’s Secretary of Science, Technology and Strategic Inputs refers protocols to CONEP that are determined to be of strategic public health interest for the Unified Health System (Sistema Único de Saúde (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. Refer to the Oversight of Ethics Committees section for additional information on CONEP’s review requirements for this type of protocol. A working group was also created to support the MOH’s assessment of research involving human beings when carried out in the SUS sphere, per OrdNo552. The interagency working group includes National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), CONEP, and the National Health Council (Conselho Nacional de Saúde (CNS)), and is coordinated by an MOH representative.

In addition to conducting public health and international project reviews, 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. 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).

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 with 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). Per BRA-93, Plataforma Brasil is a national and unified database of human subjects research records that represents the entire CEP/CONEP System. The platform is also used to track research applications from submission to final approval by the EC (CEP), and when necessary, by CONEP. 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, BRA-4, and BRA-5 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures. (Please note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor the Plataforma Brasil webpage for any developments.)

Role in Clinical Trial Approval Process

As delineated in ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, ANVISA and the EC (CEP) (and CONEP, if applicable) must approve a clinical trial application before a trial is permitted to commence. However, ResNo205 repealed the ResNo9 requirement that EC (CEP) approval must be submitted as part of the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel.

In addition, as indicated in ResNo9, and also noted in BRA-2, CONEP’s approval is not a requirement for ANVISA to approve the DDCM. However, the PANDRH-GCPs, ResNo9, and OSNo001 state that the EC (CEP) must review and approve any protocol amendments prior to those changes being implemented. According to BRA-1, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory, but may be requested. In these cases, only the EC (CEP) is required to approve the amended protocol prior to implementation and ANVISA should be notified. Per ResNo9, the EC (CEP) is required to approve substantial protocol amendments prior to implementation. See ResNo9 and the G-DDCMManual for additional information on preparing DDCMs, and CLNo038 for the criteria CONEP uses to process protocol amendments.

ResNo466 and OSNo001 specify that the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via BRA-34. Also see the Timeline of Review section for additional EC timeline information. There is no stated expiration date for an EC (CEP) approval in ResNo466, the PANDRH-GCPs, ResNo9, or OSNo001. However, in the event that an EC (CEP) revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator and ANVISA.

Per CLNo29, in the case of an appeal, only the researcher 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 researcher 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 researcher, upon receiving the non-approval opinion from CONEP, may file an appeal directly to 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.

Following the review process, the PANDRH-GCPs also states that the sponsor must receive the following information prior to the trial’s commencement:

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

Per the PANDRH-GCPs, the sponsor should also obtain documentation and dates relating to any EC (CEP) re-evaluations, re-approvals, withdrawals, or suspensions of approval from the investigator. (See the Submission Content section for additional details on the EC review process).

Additionally, CONEP has published a number of circular letters to clarify protocol review and processing procedures, submission instructions, and investigator responsibilities related to the following:

• Classifying protocol thematic areas requiring CONEP review (CLNo172)
• Processing protocol amendments (CLNo038)
• Providing general clinical trial guidelines (CLNo24 and CLNo24-Note)
• Presenting documentation required for CONEP analysis (CLNo062)
• Conducting virtual CEP/CONEP System meetings (CLNo25)
• Updating the informed consent form (ICF) (CLNo17)
• Additional clarifications on ICF text (CLNo51)
• Obtaining consent for human specimens (CLNo041)
• Using medical records data for research purposes (CLNo039)
• Submitting requests for research center inclusion/exclusion (CLNo046)
• Processing biobank development protocols electronically (CLNo34)
• Linking investigator/institutions to the responsible EC in submissions (CLNo183)
• Standardizing consent and electronic assent for research participants and biobanks (CLNo23)
• Submitting research protocols with human bodies and/or anatomical parts (CLNo26)
• Processing adverse events for Brazil and abroad (CLNo13)
• Submitting the Serious Adverse Event (SAE) form and instructions (CLNo008)
• CEP protocol processing timeline and responsibility to researchers/research participants in the event of a temporary strike or institutional recess (CLNo10)
• Submitting appeals to the CEP/CONEP System (CLNo29)
• Obtaining consent from research participants under 18 years old and people with “absence of autonomy” (CLNo11)

The above circulars are described in more detail where appropriate across the Brazil profile.

Foreign Research

As delineated in ResNo292, ResNo446, and ResNo466, applications with coordination and/or sponsorship originating outside of Brazil require additional EC review by CONEP. Per ResNo446, an exception to the required CONEP review applies to studies that have been fully carried out abroad and have been approved by an EC or equivalent body in the country of origin. ResNo580 also amends the ResNo466 requirements related to co-sponsored research projects and those involved with shipping human biological materials. This regulation states that when the MOH’s Secretariat of Science, Technology and Strategic Health Inputs issues an official agreement for a specific research project, the EC (CEP) for the proposing institution may conduct its review without the need for additional review by CONEP.

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 insuring 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.

Multicenter Research

ResNo346 establishes the submission process for multicenter research protocols and indicates that the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. Per OSNo001, the principal investigator is also required to submit a list of the participating institutions and associated protocols, the coordinating center, and the EC (CEP) designated to monitor the study’s progress as part of the research protocol package sent to the EC (CEP) for review. ResNo346 further notes that 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 and OSNo01 for detailed information on the coordinating center’s role in this process.

Exemption from Review

Pursuant to Article 26 of ResNo674, CLNo12 provides further guidance on research that is exempt from ethical assessment by the CEP/CONEP system. Research that is exempt includes protocols that fall exclusively into the following categories: public opinion surveys with unidentifiable participants; research that uses publicly accessible information; research that uses public domain information; census research carried out by government agencies; research carried out exclusively with information or data already available in aggregate form, without the possibility of individual identification; research carried out exclusively with scientific texts to review the scientific literature; research that aims at the theoretical deepening of situations that emerge spontaneously and contingently in professional practice, as long as it does not reveal data that can identify the individuals; activity carried out with the sole purpose of education, teaching, extension or training, without the purpose of scientific research, of undergraduate students, technical course, or professionals in specialization; 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 imply the collection or use of human biological material to obtain them; and, activity whose purpose is to describe or analyze the productive or administrative process exclusively for organizational development purposes.

Overview

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

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

Role in Clinical Trial Approval Process

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

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

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

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

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

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

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

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

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

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

Expedited Review

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

Rapid Review

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

Joint Review

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

Foreign Research Collaboration

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

Artificial Intelligence

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

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

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

National Research Ethics Commission (CONEP)

According to ResNo466, OMREC, and ResNo706, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit research ethics committees (ECs) (Comitês de Ética em Pesquisas (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 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

As per ResNo466, OSNo001, and ResNo446, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central statutory body responsible for the registration, audit, and accreditation of research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)). CONEP was created by the Ministry of Health (MOH) to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. CONEP reports to the National Health Council (Conselho Nacional de Saúde (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 participants
• 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.

LawNo14.874, which comes into force on August 27, 2024, establishes the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos), which consists of a national research ethics body and an ethical analysis research body, represented by the ECs (CEPs). The national research ethics body, an interdisciplinary and independent collegiate body that is part of the MOH, is responsible for the following:

• Issuing regulatory standards on ethics research
• Evaluating the effectiveness of the National System of Ethics in Research with Human Beings
• Accrediting and certifying the ECs (CEPs) so that they are able to perform the function of ethical analysis in research, according to the degree of risk involved
• Monitoring, supporting, and supervising the ECs (CEPs) in relation to the analysis of research protocols and 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 made by ECs (CEPs)

The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

Registration, Auditing, and Accreditation

As per ResNo466, SP006REC, OSNo001, ResNo446, and ResNo706, all ECs (CEPs) must be registered and accredited by CONEP. CONEP’s Executive Secretariat who performs a documentation review to ensure compliance with the requirements delineated in ResNo446 carries out accreditation. ResNo706 further states that CEP registration and accreditation may only be requested by health, teaching, or research institutions headquartered in Brazil, without potential conflict of interest, and in good standing with competent bodies. The granting of EC (CEP) registration and accreditation is prohibited to research centers maintained or linked to Representative Clinical Research Representative Organizations (Organização Representativa de Pesquisa Clínica (ORPCs)) and professional category associations.

CNSResNo506 states that accreditation is valid for three (3) years. ResNo706, in turn, indicates that the term of validity of EC (CEP) accreditation is four (4) years.

ResNo706 specifies that registration and accreditation of the EC (CEP), as well as its renewal, will be carried out upon submission of the following documents:

• Application sent by the supporting institution, signed by its legal guardian, containing the description of this institution and the commitment to ensure the minimum operating conditions of the EC (CEP)
• Proof of the minimum operating requirements of the supporting institution, in accordance with specific standards
• Request form, according to the model provided by CONEP
• Letters of appointment of Research Participant Representatives (RPPs), in accordance with the specific resolution
• Act of designation of the EC (CEP)
• EC (CEP) internal regulations

Additionally, per ResNo706, to begin activities, the EC (CEP) must, within 90 days after the announcement of registration and accreditation approval, prove the adequate training of its members. The approval of registration and accreditation of the EC (CEP) that does not begin its activities will be revoked within 120 days after approval of its registration. The renewal of the EC (CEP) accreditation must be initiated 90 days before the expiration date of its validity and be completed before it expires. An extension of the deadline for renewal may be requested once for a maximum period of 90 days when justified.

CNSResNo506, by comparison, states that to apply for accreditation, as well as renewal, an EC (CEP) is required to submit the following documentation along with a proposal for accreditation:

• Formal application justifying the EC (CEP)'s accreditation request
• Current EC (CEP) internal regulations
• Description of the EC (CEP)’s current functioning and infrastructure
• Proposal of the minimum number of high-risk protocols of other institutions that the EC (CEP) undertakes to evaluate on an individual basis, after obtaining the accreditation certificate
• Report of EC (CEP) activities for the three (3) years prior to the date of publication of the public call

See CNSResNo506 for additional documentation requirements.

As noted in CNSResNo506 and SP006REC, the renewal application must be submitted within the window of 60 days before to 60 days after the accreditation’s expiration date. Once the deadline has elapsed, and no renewal has been requested, the accreditation certificate will be canceled automatically. Additionally, per CNSResNo506, the accreditation certificate may be canceled, at any time, at the request of the EC (CEP), upon presentation in writing, without prejudice to the loss of its registration. In the absence of compliance with current CNS norms, CONEP will cancel the accreditation certificate, consubstantiating its decision in opinion. In case of cancellation of the accreditation by CONEP, the EC (CEP) may appeal. During the review period, the accredited CEP will maintain the rights conferred by the accreditation certificate. SP006REC also notes that if communication with CONEP during the pending renewal process is interrupted by the EC (CEP) for more than 60 days, the EC (CEP) registration will be automatically cancelled and the EC (CEP) will be notified by official letter.

See SP006REC, CNSResNo506, and ResNo706 for additional details on CONEP’s accreditation process. See CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up EC (CEP) accreditation and renewal processes and maintain regular functioning of ECs (CEPs).

High-Risk Research Protocols

In addition to being accredited by CONEP per the earlier stated requirements, CNSResNo506 explains that ECs (CEPs) may also be certified for their role in the ethical analysis of high-risk research protocols. As per ResNo674, the CNS has published protocol risk classification and processing guidelines to be used in the CEP/CONEP System to provide criteria to assess the risk level of research protocols.

Per CNSResNo506, until ResNo674 becomes operational, CONEP has determined that protocols falling within the special thematic areas of human genetics, human reproduction, indigenous populations, genetically modified organisms, and the establishment and operation of biobanks must be considered high risk. Refer to ResNo466, ResNo446, and ResNo340 for a complete listing of the special thematic areas. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., including protocols on the constitution and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically; and CLNo26 for information on submitting research protocols with human bodies and/or anatomical parts.

CNSResNo506 further states that at the time of obtaining accreditation, the EC (CEP) should submit a statement signed by the EC coordinator that commits the EC (CEP) to evaluating high-risk protocols at least equal to the protocol submitted to CONEP. This process also supports CONEP’s plan to decentralize the CEP/CONEP System and delegate more high-risk protocol reviews to certified ECs (CEPs). If the number of high-risk protocols exceeds the EC’s (CEP’s) operational capacity to review, then CONEP will evaluate the outstanding protocols. BRA-2 also provides helpful information on this process.

Additionally, ResNo674 notes CONEP will be solely responsible for the registration of biobank development protocols, and the research classification and modulation factors used to further characterize the protocols in BRA-34 will not be applicable. (Note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor the Plataforma Brasil webpage for any developments.)

Suspension and Cancellation of Accreditation

As indicated in ResNo706, an EC (CEP) or the supporting institution may request suspension of the EC’s (CEP’s) accreditation for a maximum period of 90 days, upon reasoned justification, and the suspension may be extended once, for an additional 90-day period.

Per ResNo706, the suspension of EC (CEP) accreditation consists of the temporary interruption of the receipt of new research protocols for ethical assessment. The suspended EC (CEP) must maintain monitoring of the protocols under its responsibility, whether approved or in progress, while the suspension remains. New protocols, submitted for consideration by the suspended EC (CEP), will be directed to another EC (CEP), as indicated by CONEP. CONEP’s decision to suspend the EC (CEP)'s accreditation may be appealed to CONEP within 30 days. An extension of the deadline for appeal may be requested, once, for a maximum period of 30 days, upon justification.

ResNo706 further explains that the cancellation of EC (CEP) accreditation consists of revoking the registration and removing the EC (CEP) in the CEP/CONEP System. If cancelled, CONEP will transfer the protocols to another EC (CEP) for due monitoring. Cancellation, at the request of the supporting institution, will be assessed by means of a request addressed to the CONEP Coordination, containing the reasons for the request. The cancellation decision may be appealed to CONEP within 30 days. An extension of the deadline for appeal may be requested once, for a maximum period of 30 days, upon justification. In case of cancellation, requests for new registration by the supporting institution within a period of 12 months are prohibited. See ResNo706 for detailed information on EC (CEP) accreditation suspensions and cancellations.

Overview

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

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

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

Registration, Auditing, and Accreditation

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

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

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

Overview

As stated in ResNo9, the G-DDCMManual, and BRA-8, the sponsor, the designated contract research organization (CRO), or the sponsor-investigator must apply to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to obtain approval for a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) for a drug to be registered in Brazil that will have all or part of its development in Brazil. Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside of Brazil require additional EC review by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. ResNo205 repealed the ResNo9 requirement that EC (CEP) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel.

Regulatory Submission

Per ResNo9, the G-DDCMManual, and BRA-8, the DDCM must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the DDCM to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM, also known as the Experimental Drug Dossier. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. ResNo9 further notes that DDCM submissions to ANVISA can only be made by a CRO when the sponsor has no headquarters or subsidiary in Brazil. See also BRA-42 for additional information on ANVISA protocol filing requirements.

As indicated in the G-DDCMManual and BRA-8, ANVISA recommends that the DDCM and associated documents (including the protocol, investigator’s brochure, informed consent form, and sponsor and institutional declarations) be translated into 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.

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA, as stated in ResNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial DDCM submission. If the modification has occurred following ANVISA’s issuance of the authorizing document known as a Special Notice (Comunicado Especial (CE)), per BRA-8, ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version. While sponsors are required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, they are only required to submit substantial protocol amendments via a secondary petition whereas non-substantial DDCM protocol amendments should be submitted as part of the annual clinical trial report. Non-substantial amendments that do not impact the protocol should be presented to ANVISA as part of the drug development safety update report. See BRA-13 for updated ANVISA application forms.

See ResNo742, BRA-8, BRA-6, and BRA-7 for requirements associated with submitting DEECs for comparative bioavailability studies and comparative pharmacokinetic studies for biosimilars.

As described in the G-DDCMManual and BRA-8, all DDCM petitions (both initial and secondary) should be submitted electronically to ANVISA via the Solicita Electronic Petition Request System (BRA-56). Per BRA-58, once the DDCM has been submitted, the sponsor is then required to electronically file all the documents corresponding to the initial DDCM petition’s subject code checklist. As explained in BRA-75, the sponsor must electronically attach all the documents required in the related DDCM checklist (accessed online via BRA-56) that corresponds to one (1) of the following related subject codes: 10748, 10749, 10750, 10751, 10752, 10753, 10754, and 10755. BRA-59 provides detailed instructions for submitting the DDCM checklist documents via BRA-56.

As per ResNo857, BRA-47, and BRA-43, once the sponsor has completed the process of submitting a DDCM request (“petition” in Portuguese), 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)) fees. 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)

BRA-59 explains that once the fee is paid, a reference (transaction) number is generated that will be required for the subsequent submission of the associated checklist documents. The processing of this request can take up to two (2) days, which is the time given to the banking network to clear the payment. Refer to BRA-59 for additional instructions. 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 Request Form. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

Per the G-DDCMManual, all of the other documentation associated with the original DDCM including the secondary petitions and the DEEC(s) should be submitted electronically via BRA-56. ResNo204 and BRA-14 further note that DEECs may be submitted as priority requests to ANVISA to register, amend previously registered, or request prior consent for drug submissions. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections. The G-DDCMManual also specifies that for the electronic submission of secondary petitions and DEECs, the sponsor should append at least one (1) PDF file for each item contained in the petition checklist to enable text searching. It is possible to attach up to five (5) files of 750 kb each. BRA-8 also provides an example of an electronic submission in Annex 1.

Refer to the Submission Content section for detailed DDCM petitions content requirements and substantial protocol modification documentation requirements.

See also BRA-19 and BRA-90 for guidance on scheduling 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., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted.

Ethics Review Submission

Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the PI must also obtain approval from the EC (CEP). 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 EC review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil 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 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.

In addition, per OSNo001, 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.

Overview

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

Regulatory Submission

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

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

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

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

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

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

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

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

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

Ethics Review Submission

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

Regulatory Authority Requirements

As delineated in ResNo9 and the G-DDCMManual, to complete the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), the sponsor, the designated contract research organization (CRO), or the sponsor-investigator is required to submit the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s DDCM Petition Request Form (BRA-21) along with the following documentation (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Health Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResNo857 (fee required by individuals and companies engaged in clinical research)
• Drug development plan (known as experimental drug dossier) (See the G-BioIProdManual for instructions on completing a biological products dossier and the G-SynthDrugProdManual for completing a synthetic/semi-synthetic products dossier)
• Certified copy of the clinical agreement (contract or statement) that has been written, dated, and signed by the sponsor or the CRO
• Clinical research protocol
• Investigator’s Brochure (IB)
• Summary of the investigational product (IP)’s safety aspects based on previous research in humans
• Information on any discontinued development or withdrawal of IP
• IP dossier
• Specific dossier for each clinical trial to be conducted in Brazil
• Proof of clinical trial registration 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) (Note: the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.) Per ResNo449, which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25). Note that per ResNo205, the ResNo9 requirement to include the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval in the initial DDCM or in any protocol amendment submission has been revoked.

Substantial Protocol Modifications

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA using the DDCM Petition Request Form (BRA-21), as stated in ResNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial submission of the DDCM. Per BRA-8, if the modification has occurred following ANVISA’s issuance of the authorizing document known as the Special Notice (Comunicado Especial (CE)), ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version.

While the sponsor is required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, they are only required to submit substantial protocol amendments via a secondary petition whereas non-substantial DDCM protocol amendments should be submitted as part of the annual clinical trial report. Non-substantial amendments that do not impact the protocol should be presented to ANVISA as part of the drug development safety update report. See ResNo9 and the G-DDCMManual for detailed ANVISA application submission requirements, BRA-22 for the clinical trial submission form, and BRA-13 for updated ANVISA application forms. See also BRA-95 for instructions on providing expiration date information for imported IPs to be used during the trial and which the sponsor must include in its submission in BRA-22.

In order to fulfill the DDCM and the substantial quality modification requirements delineated in ServBltnNo104, the sponsor or the legal representative (also known as CRO in some sources) must provide all of the documentation required in ResNo9 and the following:

• An official document issued by at least one (1) of the regulatory authorities from one (1) International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) member country to prove the clinical trial or the substantial quality modification is authorized to be carried out
• A declaration of compliance with the ServBltnNo104 Form Attachment criteria regarding the IP to be administered in the trial to be conducted in Brazil: that it is identical to the one (1) administered in the ICH authorized country; is registered in at least one (1) ICH member country; contains the same substantial quality changes as the IP, active comparator, or placebo, if applicable, as those approved in at least one (1) ICH member country; complies with ICH manufacturing guidelines, where applicable, to the clinical development phase

Per ServBltnNo104, in the absence of the previously described official document, a justification must be presented showing that the conduct of the clinical trial or the substantial quality modification has been authorized.

In addition, ServBltnNo104 states that the previously listed documentation must be presented using the subject code of “11634 – ENSAIOS CLÍNICOS – Análise Simplificada de Dossiê de Qualidade” (11634 – CLINICAL TRIALS – Simplified Analysis of the Quality Dossier) to be linked to the DDCM petition or the substantial quality modification of interest, while the petition is in the queue waiting for ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC))’s technical analysis to begin. The status of the petition code will remain as the subject code of simplified analysis if all of the documentation requirements are met. In the event of non-compliance with the ServBltnNo104 criteria, COPEC will proceed with the non-simplified analysis per ResNo9. These provisions may be applied to DDCM and substantial quality modification petitions submitted prior to the publication of ServBltnNo104, upon request using the subject code of “11634 – ENSAIOS CLÍNICOS – Análise Simplificada de Dossiê de Qualidade” (11634 – CLINICAL TRIALS – Simplified Analysis of the Quality Dossier), as long as the relevant petition is still in the queue waiting for the technical analysis to begin. The ServBltnNo104 provisions do not presuppose prioritizing the analysis of these petitions. Furthermore, ANVISA may at any time analyze all of the documents required in items VII, art. 38 and item III, art. 43 of ResNo9 based on the risk analysis related to the IP. See ServBltnNo104 for detailed information.

Ethics Committee Requirements

As per OMREC and OSNo001, the CONEP requires sponsors to submit the following documentation online via BRA-34 (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 (BRA-20)
• 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)
• 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 to agree to comply with BRA-20; 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 the PANDRH-GCPs, 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 the PANDRH-GCPs, 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 G-CTAPHEmerg, SAHPRA states that during a public health emergency, new and experimental treatments may become necessary and clinical trials are essential to provide the evidence to develop appropriate policies for patient treatments. Under these circumstances, there may be limited information available. However, applications need to contain a certain minimum of information to enable a meaningful evaluation and regulatory decisions. To address this, SAHPRA provides an information grading system in the G-CTAPHEmerg wherein required information is labelled. Applicants must attempt to provide the information listed below and justify when this is not available. The required information is graded as follows:

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

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

Ethics Committee Requirements

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

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

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

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

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

Clinical Protocol

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

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

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

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

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

Overview

ResNo205 repealed the ResNo9 requirement that research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval must be submitted as part of the clinical trial application to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Therefore, as explained in BRA-2 and BRA-1, the regulatory and ethics reviews may be conducted in parallel.

Regulatory Authority Approval

As specified in ResNo9, upon receipt of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), ANVISA has 90 calendar days to evaluate the application. If the agency fails to issue a response within 90 days of receipt, clinical development can begin as long as all of the ethical approvals have been obtained. ResNo9 further notes that ANVISA will conduct a technical review within 180 days following receipt of DDCMs that fall into at least one (1) of the following categories: national development, biological product clinical development including vaccines, and Phase I or II clinical development studies. For DDCMs in one (1) of these categories, ANVISA’s technical area only evaluates the clinical study technical reports.

Timeline information for ANVISA’s simplified analysis of DDCMs that meet the criteria for ServBltnNo104 is not available. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.) See also BRA-60 for details on the median analysis timelines for ANVISA to complete its technical review of prioritized and ordinary petitions.

Priority Submissions

As delineated in ResNo204, ANVISA is required to issue a final decision on applications for registration and post-registration of drugs classified as a priority within 120 days for new drug registration requests and in 60 days for post-registration petitions. The deadlines will be counted from the date of submission, and any requests for clarification or additional technical requirements will result in suspending the counting of deadlines until the requests have been met. See also BRA-40 for additional information on ANVISA drug registration requirements.

In addition, per ResNo204, ANVISA must first issue a written opinion letter within 45 calendar days from the first working day following protocol submission for priority petitions in the following categories:

• Prior consent petitions in the clinical development dossier process
• Prior consent petitions in the drug research process
• Secondary petitions referring to the prioritized primary process

Refer to ResNo204 and ResNo811 (which partially amends ResNo204) for detailed information on Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) submissions.

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, with an issuance of a notification of requirement or a manifestation 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 also ResNo811 (which partially amends ResNo205), BRA-8, and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.

Ethics Committee Approval

As set forth in LawNo14.874, which comes into force on August 27, 2024, a research ethics review carried out by the EC (CEP), with the issuance of the opinion, may not exceed 30 business days from the date of acceptance of all research documents, and the EC (CEP) must accept or deny these documents within 10 business days from the date of submission. Additionally, before issuing the opinion, the EC (CEP) may request additional information or documents from the researcher or research sponsor or make adjustments to the research documentation, for up to 20 business days. See the Scope of Review section for details on the EC (CEP) review processes.

The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

As delineated in OSNo001 and BRA-91, the institutional 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 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 CEP to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation.

CLNo040 further explains that new investigational brochure (IB) versions to be uploaded to the CEP/CONEP System via Plataforma Brasil (BRA-34) are often limited to updates pertaining to the investigational product’s efficacy and safety data and research team instructions. Updates should not alter research that has already been approved and must be processed as notifications in BRA-34. However, CLNo040 specifies that if the IB changes result in modifications to the detailed protocol and/or the informed consent form (ICF), it is necessary to submit a protocol amendment. In this case, the EC (CEP) will analyze the IB together with the other documents pertaining to the amendment, and, if necessary, the required amendments and/or clarifications will be requested. If the 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.

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

Overview

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

Regulatory Authority Approval

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

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

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

Ethics Committee Approval

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

Overview

In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, a clinical trial can only commence after the sponsor, the designated contract research organization (CRO), or the sponsor-investigator receives clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside Brazil require an additional review and approval by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. Please refer to Scope of Review and Oversight of Ethics Committees sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. No waiting period is required following the sponsor’s receipt of these approvals.

In addition, per ResNo9, 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). The trials should be conducted in compliance with the PANDRH-GCPs, ResNo466, and ResNo9. Clinical trials must also be conducted in a laboratory complying with the Organisation for Economic Co-operation and Development (OECD)’s Principles on Good Laboratory Practice (GLP) (BRA-15) as mandated by Brazil’s National Institute of Metrology, Quality and Technology (INMETRO). Refer to BRA-15 and BRA-48 for additional information on GLP requirements.

ResNo9 further states that the sponsor should register the clinical trial start and end dates within 30 calendar days of each date by submitting a secondary petition to the corresponding DDCM (see BRA-21 for the DDCM Petition Request Form).

Clinical Trial Agreement

As delineated in the PANDRH-GCPs, the sponsor or the CRO must sign an agreement or contract with the participating institution(s) and the investigator. In addition, if a sponsor decides to engage a CRO to conduct the trial, a letter of agreement should also be submitted to ANVISA as specified in the PANDRH-GCPs and ResNo9.

Clinical Trial Registration

As delineated in ResNo9, 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. Per ResNo449 which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25).

In addition, per BRA-32, ANVISA has developed a clinical trials search tool to obtain detailed information about scientific/academic research or clinical trials authorized by the agency to support the registration of medicines since 2015. The Clinical Trials (Ensaios Clínicos) tool may be accessed via ANVISA’s Consultation System webpage (BRA-44). BRA-44 provides public information about the status of each clinical trial, the trial location, and the researchers responsible for conducting the trial. See BRA-32 for additional instructions on searching BRA-44.

Overview

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

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

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

Clinical Trial Agreement

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

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

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

Clinical Trial Registration

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

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

Governance

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

Safety Reporting Definitions

In accordance with the PANDRH-GCPs, ResNo9, the AESafetyManual, 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 adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
• Adverse Drug Reaction or Adverse Reaction (ADR) – All harmful unintended responses to a medicinal product related to any dose
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any unfavorable occurrence that at any dose results in death, is life-threatening, requires or extends patient hospitalization, results in persistent or significant disability or permanent damage, or is a birth defect or congenital anomaly; significant medical occurrence, which based on appropriate medical judgment, may harm the participant and/or require medical or surgical intervention to prevent any of the other occurrences mentioned
• Unexpected Adverse Drug Reaction – One whose nature or severity is inconsistent with the applicable product information (i.e., the investigator’s brochure for an unapproved investigational product (IP), or package insert/summary of the characteristics of an approved product)

Safety Reporting Requirements

Investigator Responsibilities

As specified in ResNo9 and the AESafetyManual, the investigator must inform the sponsor within 24 hours of all SAEs/SADRs occurring during the study. The PANDRH-GCPs also states that the immediate reports should be followed promptly by detailed, written reports in which the participants are identified by unique code numbers. AEs/ADRs identified in the protocol as critical to safety evaluations should also be reported to the sponsor. Per the AESafetyManual, the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the research ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)) with any additional requested information (e.g., autopsy reports and terminal medical reports).

Sponsor Responsibilities

The AESafetyManual states that the sponsor should classify all AEs/ADRs and SAEs/SADRs according to the World Health Organization’s Uppsala Monitoring Centre (WHO-UMC)’s standardized causality assessment system (BRA-31). The recommended criterion to categorize each event is as follows: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and Unassessable/Unclassifiable.

As per ResNo9 and the AESafetyManual, the sponsor should ensure all relevant information pertaining to fatal or life-threatening SAEs/SADRs occurring in Brazil is documented and electronically reported to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) no more than seven (7) days after first knowledge. ResNo9 also indicates that any additional information should be included in the assessment up to eight (8) calendar days from the notification date. Additionally, per ResNo9 and the AESafetyManual, all other unexpected SAEs/SADRs whose causality is possible, probable, or certain for the products under investigation should be reported to ANVISA within 15 calendar days from the date of first knowledge by the sponsor.

Per the AESafetyManual, AEs/ADRs and SAEs/SADRs do not need to be reported to ANVISA under the above timelines when they occur outside of Brazil or are defined in the protocol as a primary or secondary outcome. Additionally, SAEs/SADRs that are categorized as Unlikely, Conditional/Unclassified, or Unassessable/Unclassifiable do not need to be reported under the above timelines. Per ResNo9 and the AESafetyManual, for events occurring within Brazil, this information should be included in the annual drug development safety update report (DDSUR), which must be filed within a maximum of 60 calendar days of the yearly anniversary of the date that ANVISA approves the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). Per ResNo9, in the case of international trials, within 12 months of the study in all countries, the sponsor must submit a final report, which must include information on AEs/ADRs and SAEs/SADRs occurring in other countries.

ResNo9 requires the sponsor to notify investigators of AEs/ADRs and SAEs/SADRs for which the causality has been assessed as possible, probable, or certain. The sponsor must adopt procedures for updating the Investigator’s Brochure (IB) and reassess the risk and benefits to study participants. The PANDRH-GCPs states that the sponsor is also required to notify all concerned investigator(s), institution(s), and ANVISA of findings that could adversely affect participant safety, impact the conduct of the trial, or alter the EC (CEP)’s approval of the trial.

In addition, ResNo9 and the G-DDCMAmdmts state that in cases where the sponsor temporarily suspends a clinical trial or DDCM as an immediate safety measure, they must notify ANVISA within seven (7) consecutive days from the suspension date. Per ResNo9, the reasons for suspension, the scope, the interruption of treatment, and the suspension of participant recruitment must be clearly explained in the notification of temporary suspension. See also BRA-8 for additional information on ANVISA’s AE reporting requirements.

Per BRA-73, Brazil has implemented the ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (BRA-66) and the ICH Harmonised Tripartite Guideline: Development Safety Update Report (E2F) (BRA-72).

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

Ethics Committee Responsibilities

CLNo13 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.

Other Safety Reports

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-37, VigiMed (BRA-83) is ANVISA’s online system for citizens, health professionals, drug registration holders, and study sponsors to report unexpected SAEs related to drugs and vaccines. Upon registration with BRA-83, BRA-37 indicates that companies (sponsors) must submit SAE notifications exclusively via BRA-83. See also BRA-85 for additional information on VigiMed.

Per BRA-78 and BRA-37, sponsors must email notifications of unexpected SAEs to notivisa.pesquisa@anvisa.gov.br. BRA-78 indicates that the title of the email must state “EVENTO ADVERSO GRAVE INESPERADO [NOME DO MEDICAMENTO]” (Unexpected Serious Adverse Event [Name of the medication]). BRA-78 and BRA-37 specify that the email must include the ANVISA Serious Adverse Event Notification Spreadsheet (BRA-84) containing all of the information that was previously registered with ANVISA. BRA-37 states that ANVISA advises sponsors of clinical research with medicines and biological products that have not yet been registered in VigiMed (BRA-83) to also include the following information for the company’s registration in the system:

• Corporate name
• Sender identifier (the official name should be used, if possible, since it will be used to identify the company in VigiMed)
• CNPJ (National Registry of Legal Entities (Cadastro Nacional de Pessoas Jurídicas), which serves as tax identification
• Short name: company name abbreviation [the company name abbreviation will be used in the Notification Identification, following the structure: BR-Company Name-Notification Number (Data element C.1.1 Sender’s (case) Safety Report Unique Identifier, from the ICH E2B (R3) (Electronic Transmission of Individual Case Safety Reports) (BRA-88)
• Data of users to be registered in VigiMed: name and e-mail of two (2) notifiers, who will be registered to enter data from notifications of SAEs occurring in clinical trials

Safety Reporting Definitions

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

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

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

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

Sponsor Responsibilities

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

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

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

The G-SafetyRpt delineates the following reporting timeframes:

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

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

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

Form Completion & Delivery Requirements

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

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

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

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

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

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

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

Interim and Annual Progress Reports

As per ResNo9 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. ResNo9 indicates that the annual report should contain the following information for each clinical trial protocol, in tabulated form, exclusively from Brazilian centers:

• Trial title
• Protocol code
• Participant(s) status
• Number of participants recruited by center
• Number/description of deviations and protocol violations by center
• Description of all adverse events/adverse drug reactions occurring by center

The report should be filed within 60 calendar days from the annual anniversary date of the trial’s commencement in Brazil. BRA-8 further explains that currently ANVISA does not require a template to be used to complete the annual clinical trial protocol monitoring report since the information should be based on the ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports (E3) standardized report format (BRA-27). See BRA-23 for the annual/final report form that may be used.

The PANDRH-GCPs state that the investigator or institution must submit written summaries on the status of the trial to the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) in Brazil) annually, or more frequently, if requested by the EC (CEP).

Final Report

ResNo9 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. Per ResNo9 the final report should contain at least the following:

• Trial title
• Protocol code
• Breakdown of the number of participants recruited or removed from the trial
• Description of participants included in each statistical analysis and those who were excluded from the efficacy analysis
• Participant demographics and statistics
• Number/description of protocol deviations and violations
• All adverse events/laboratory abnormalities with causality assessment occurring in participants
• Results obtained in the measurement of outcomes for each participant
• Rationale for early termination in Brazil or elsewhere in the world, where applicable

Per G-CTReptsManual, the annual and final reports for each clinical protocol shall contain the minimum requirements set forth in Articles 68 and 69 of ResNo9, or they may be submitted using the ICH E3 format (BRA-27). See BRA-23 for the annual/final report form.

As specified in the PANDRH-GCPs, upon the trial’s completion, the investigator or the institution should also provide the sponsor with all required reports, present the EC (CEP) with a summary of the trial’s outcome, and supply any additional report(s) required by ANVISA.

Other Reporting Requirements

As stated in ResNo9 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. The secondary petition should be submitted to ANVISA using the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) Petition Request Form (BRA-21). 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-GCPs requires the investigator to submit written progress reports to the ethics committee (EC) annually and to the SAHPRA every six (6) months. ECs and the SAHPRA may request reports more frequently. The G-EthicsHR-ZAF states that ECs should request regular, at least annual, reports from principal investigators (PIs) on matters including: progress; current enrolment status; whether participant follow-up is still active or completed; record maintenance and security; evidence of compliance with the approved protocol and any conditions of approval; negative reports from monitors or good clinical practice (GCP) inspectors; all adverse events in the past 12 months; and all amendments made in the past 12 months.

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

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

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

Final Report

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

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

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

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

As per ResNo466, ResNo9, and the PANDRH-GCPs, a sponsor is defined as an individual, company, institution, or organization that supports research through the initiation, management, or financing of a clinical trial.

ResNo9 states that a sponsor can authorize a contract research organization (CRO) to carry out certain work and obligations regarding the trial. As delineated in ResNo9, any trial-related responsibilities to be transferred and assumed by a CRO should be specified in a written agreement or contract.

As delineated in ResNo9, 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. See also BRA-79 for additional information on sponsor and CRO requirements in Brazil.

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

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

Overview

As set forth in the PANDRH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial while taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by education, training, and experience to assume responsibility for the proper conduct of the trial. Investigator(s) should also provide evidence of all the qualifications specified by the applicable regulatory requirements through up-to-date curriculum vitae(s) (CVs) and/or other relevant documentation requested by the sponsor, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), and/or the regulatory authority(ies).

Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. See the Submission Content section for additional information on clinical trial application requirements. 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 PANDRH-GCPs and ResNo9, the sponsor may transfer any or all of the sponsor’s study related duties and functions to a contract research organization (CRO). 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. Other duties, functions, or responsibilities not specifically transferred shall be deemed as retained by the sponsor. However, as per ResNo9, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

Data Safety and Monitoring Board

According to ResNo9, an Independent Safety Monitoring Committee (ISMC) should be established to systematically evaluate aggregate adverse event/adverse drug reaction data.

Multicenter Studies

Per the PANDRH-GCPs, in the event of a multicenter clinical trial, the sponsor or the CRO should ensure that all investigators conduct the trial in strict compliance with the protocol as well as with the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s and the EC (CEP)’s requirements. The sponsor must also organize a coordinating committee or select coordinating investigators.

Overview

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

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

Capacity Building & Training

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

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

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

Management of Investigators

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

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

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

Foreign Sponsor Responsibilities

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

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

Data and Safety Monitoring Board

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

Multicenter Studies

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

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

Insurance

As set forth in the PANDRH-GCPs, the sponsor is responsible for providing insurance coverage for any unforeseen injury to research participants. Before the clinical trial begins, the sponsor should also provide insurance or indemnify the investigator and the institution against claims arising from malpractice or negligence.

In addition, according to BRA-1, in the event that National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) asks for additional information to assess insurance and indemnity coverage for injures related to the study, the sponsor must provide a Medical Assistance Letter. See BRA-79 for additional information on sponsor/contract research organization (CRO) insurance coverage requirements in Brazil.

Compensation

Injury or Death

As specified in the PANDRH-GCPs and ResNo466, the sponsor is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries or death. The sponsor must also ensure that participants who suffer any trial-related injuries are provided with free medical treatment for such injuries.

Trial Participation

As specified in ResNo466 and the G-ClinResSubjectRts, compensation to participants is only provided for transportation costs and meals for the participants or legal representative/guardian during the trial.

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

Post-Trial Access

According to ResNo563, 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. In addition, per ResNo466, 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 their participation in the trial and the end of the study.

Furthermore, ResNo311, which amends ResNo38, states that the sponsor/CRO should guarantee access to the post-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (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-Study Medicine Supply Programs (see Annex VI of ResNo38). See also BRA-79 for additional information on sponsor/CRO insurance coverage.

Insurance

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

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

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

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

Compensation

Injury or Death

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

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

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

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

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

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

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

Trial Participation

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

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

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

Post-Trial Access

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

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

Quality Assurance/Quality Control

As stated in ResNo9, the sponsor or the contract research organization (CRO) must ensure that quality assurance and quality control be implemented in all areas of the institution’s development of the investigational drug in accordance with the PANDRH-GCPs and the International Conference on Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28). The PANDRH-GCPs and BRA-28 specify that the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol, good clinical practices (GCP), and other applicable requirements.

Per the PANDRH-GCPs and BRA-28, the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

Additionally, the PANDRH-GCPs and BRA-28 state that the sponsor must also obtain the investigator(s) and the institution(s) agreement to:

• Conduct the trial in compliance with GCP, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP))
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor indicates they are no longer needed

Monitoring Requirements

As part of its QA system, the PANDRH-GCPs, and BRA-28, note that the sponsor or the CRO should ensure the trial is adequately monitored. The PANDRH-GCPs and BRA-28, also explain that if or when the sponsor performs audits as part of implementing QA, the following should be considered:

· The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and other applicable regulatory requirements.

· The sponsor should appoint auditors to review the clinical trial who are independent of the clinical trial/data collection system(s).

· The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also verify that the audit is conducted in accordance with their own SOPs, the auditor observations are documented, and data is available as needed for the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s review.

No specific timeframe is provided for the audit process. Refer to the PANDRH-GCPs and BRA-28 for detailed audit requirements.

In addition, per ResNo449, which amends ResNo9, ANVISA is allowed to use remote GCP inspection mechanisms for temporary and emergency use in lieu of in-person inspections. Remote inspections are carried out by means of videoconferencing and data transmission technologies for GCP verification. Remote inspections replace the need for in-person inspectors in the establishment. Establishments under inspection may be inspected remotely at any time by ANVISA.

RegNo122 provides further guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with the GCPs delineated in ResNo9, the PANDRH-GCPs, and the BRA-28. Per BRA-30, ANVISA’s administrative unit, the Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)), requires all clinical trial inspections to be conducted in accordance with BRA-28.

In the event of a routine inspection, RegNo122 states that ANVISA 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 shall 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.

ANVISA has also published GuideNo35-2020 and GuideNo36-2020 to provide guidance on the procedures for conducting GCP inspections in clinical trial centers, and provide guidance for sponsors and CROs respectively for clinical trials involving medicines and biological products. Both guides describe ANVISA’s compliance with the GCP inspection requirements set forth in RegNo122 with the goal of guiding those involved in the inspection procedures to ensure a unified standard and the safety of all involved parties.

GuideNo35-2020 and GuideNo36-2020 explain that GCP inspections of sponsors and CRO representatives and in clinical trial centers may be carried out before, during, or after a clinical trial has been conducted and will be classified as either a routine inspection or complaint/suspected irregularity, per RegNo122. In addition, per GuideNo35-2020 and GuideNo36-2020, the inspections will involve at least two (2) ANVISA inspectors, one (1) of whom will be the lead inspector and the focal point for communication with either the clinical trial center or the sponsor/CRO(s). The inspections for both entities 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.

See ResNo620 for information on the Certification of Good Practices for conducting bioavailability/bioequivalence drug studies and requirements for which bioavailability/bioequivalence drug studies must be carried out in certified research centers.

Premature Study Termination/Suspension

As set forth in ResNo9, the sponsor may cancel or suspend a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) or a clinical trial, at any time, provided that the appropriate technical-scientific justifications are submitted to ANVISA along with a plan to monitor the research participants in clinical trial(s) that have already begun. Per ResNo9 and the G-DDCMManual, DDCM or clinical trial suspensions and cancellations must be submitted to ANVISA in the form of a secondary petition attached to the previously submitted DDCM or Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)). Refer to the Submission Content section for instructions on submitting a secondary petition to suspend or cancel a DDCM or clinical trial.

ResNo9 and the G-DDCMAmdmts state that the sponsor must notify ANVISA within a maximum period of 15 consecutive days following a decision to suspend or cancel a clinical trial or DDCM. In cases of the temporary suspension of a clinical trial or DDCM as an immediate safety measure, the sponsor must notify ANVISA within seven (7) consecutive days from the suspension date. Per ResNo9, the reasons for suspension, the scope, the interruption of treatment, and the suspension of participant recruitment must be clearly explained in the notification of temporary suspension. As per the G-DDCMAmdmts, in the case of a temporary suspension of a DDCM or a clinical trial protocol, the suspension can be reversed with the submission of a secondary petition to ANVISA. ResNo9 specifies that these requests must be accompanied by due justification so that the trial(s) can be restarted. The clinical trial(s) or DDCM may be reactivated only after approval is obtained by ANVISA. The timeline for ANVISA’s review of these cases is not delineated in ResNo9 or in the G-DDCMAmdmts.

Regarding DDCM cancellations, the G-DDCMAmdmts emphasizes that cancellations, under the terms of ResNo9, are definitive, with no possibility of further reactivation, and that once a DDCM is cancelled, no clinical trial related to it can be continued in the country. In the specific case of a voluntary request to cancel a DDCM, the sponsor must follow the requirements detailed in the AESafetyManual when submitting the follow-up plan and the risk minimization/mitigation measures to protect the participants of clinical trials already underway. A DDCM cancellation can occur even if it has not yet been evaluated. Similarly, clinical trial cancellations are also definitive under ResNo9, with no possibility of further reactivation. The cancellation only applies to clinical trial protocols that have already been initiated by the sponsor. If the protocol is provided for in the DDCM, but has not yet been started, the protocol must be deleted.

In addition, ResNo9 states that ANVISA may, at any time, cancel or suspend a DDCM or any related clinical trial if it believes that the approval conditions have not been met or if there are safety or efficacy reports that significantly affect either the trial participants or scientific validity. In this case, ANVISA will inform the sponsor of the reasons for this cancellation or suspension. Per ResNo9, the sponsor must immediately inform those involved in a clinical trial when it is prematurely cancelled or suspended for any reason. The PANDRH-GCPs and BRA-28 also explain that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). Additionally, per the PANDRH-GCPs and BRA-28, if the investigator terminates or suspends a trial without the sponsor’s prior agreement, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the EC, and should provide the sponsor and the EC a detailed written explanation of the termination or suspension.

Quality Assurance/Quality Control

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

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

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

Monitoring Requirements

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

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

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

Premature Study Termination/Suspension

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

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

Electronic Data Processing System

Per the PANDRH-GCPs, when using electronic trial data processing systems, the sponsor or the contract research organization (CRO) must ensure that the system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance, and that standard operating procedures (SOPs) are maintained when using these systems. Refer to the PANDRH-GCPs for detailed information on electronic trial data systems.

Records Management

As set forth in ResNo9, the sponsor or the CRO should maintain the clinical trial data on file in physical or digital format for a period of five (5) years after the last approval of a request for registration in Brazil. ResNo9 and the PANDRH-GCPs also state that 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, a marketing application receives the last approval, or there are no pending or contemplated marketing applications. Per the PANDRH-GCPs, the sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

Electronic Data Processing System

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

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

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

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

Records Management

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

Responsible Parties

For the purposes of data protection requirements, the LGPD delineates that the sponsor acts as the “controller” who is responsible for decisions regarding the processing of personal or sensitive personal research data. Within this context, the controller (sponsor) 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 and 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. See also BRA-116 for additional information.

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.

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.

Pursuant to the LGPD, the controller may implement a privacy governance program that, at a minimum:

• Demonstrates the controller’s commitment to adopt internal processes and policies that ensure comprehensive compliance with the rules and good practices regarding the protection of personal data
• Is applicable to the entire set of personal data that are under its control, regardless of the way it was collected
• Be adapted to the structure, scale, and volume of its operations, as well as to the sensitivity of the processed data
• Establish adequate policies and safeguards based on a systematic assessment of impacts and risks to privacy
• Has the objective of establishing a relationship of trust with the holder through transparent action and that ensures participation mechanisms exist for the holder
• Is integrated into its general governance structure and establishes and applies internal and external supervisory mechanisms
• Counts on incident response and remediation plans
• Is constantly updated based on information obtained from continuous monitoring and periodic evaluations

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.

Additionally, 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, 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.

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.

Data Protection

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

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

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

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

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

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

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

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

Consent for Processing Personal Data

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

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

Consent for Processing Personal Data of Minors

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

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

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

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 the PANDRH-GCPs, ResNo466, and the G-ClinResSubjectRts. Per OMREC and G-ClinResSubjectRts, the informed consent form (ICF) is also known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.

As per the PANDRH-GCPs, ResNo466, the G-ClinResSubjectRts, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by an research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and provided to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) with the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). 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.

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the investigator, or their designated representative, must provide detailed research study information to the participant or legal representative/guardian. As delineated in ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, OMREC, and the G-ClinProtocols-FAQs, the ICF content should be presented in a clearly organized format using practical and non-technical language commensurate with the participant’s level of understanding. Per the PANDRH-GCPs and the G-ClinResSubjectRts, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. The PANDRH-GCPs further explains that 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, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. ResNo466 and the G-ClinResSubjectRts further note 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 the PANDRH-GCPs, the G-ClinResSubjectRts, and the G-ClinProtocols-FAQs, the information should be in both written and oral form, and the participant and the legal representative/guardian should also be given adequate time to consider whether to participate. See also BRA-29 for additional information on informed consent.

Re-Consent

According to the PANDRH-GCPs and CLNo17, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by the EC (CEP) and submitted to ANVISA before such changes are implemented. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and 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.

Language Requirements

As earlier stated, the PANDRH-GCPs and the G-ClinResSubjectRts require the ICF to be presented orally and in writing at a level that the participant is able to understand. Per the PANDRH-GCPs, the investigator should provide the ICF in the participant’s own language when they do not speak the language currently spoken in the country. 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

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. In addition, the PANDRH-GCPs explains that if the participant or legal representative/guardian is illiterate, an impartial witness should be present throughout the 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.

Before participating in the study, per the PANDRH-GCPs, OMREC, and the G-ClinResSubjectRts, 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 available on consent waivers for research participants. See the Consent for Specimen section information on waivers pertaining 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-GCPs, and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (ZAF-27).

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

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

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

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

Re-Consent

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

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

Language Requirements

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

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

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

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

Documenting Consent

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

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

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

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

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

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

Waiver of Consent

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

Based on the PANDRH-GCPs, 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 all sources, which provide overlapping and unique elements):

• The study purpose, the procedures, and duration of the trial
• The participant’s responsibilities
• Experimental aspects of the study
• The approximate number of participants in the study
• Any expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Any expected benefits to the participant; if no benefit is expected, the participant should be informed of this point
• Treatments available to participants, how they are administered, and the probability of receiving every treatment
• Compensation and/or treatment available for the participant in the case of trial-related injury
• The disclosure of specific appropriate alternative procedures or therapies available to the participant
• The probability for random assignment to each treatment
• Any expenses the participant needs to pay to participate in the trial
• Confidentiality of records identifying the participant will be maintained, and permission given to monitors, auditors, the ethics committee(s), and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to access the participant’s medical records to verify the procedures or trial data without violating the participant’s confidentiality, insofar as the applicable laws and regulations permit
• That participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
• Contact information for the sponsor and investigator in the event of participant problems or trial-related injuries
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• The consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
• That the participant or legal representative/guardian will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant’s willingness to continue

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

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

• The study involves research and an explanation of its nature and purpose, including that it conforms to the protocol
• The procedures to be followed and their purpose and nature
• Why the potential participant has been approached, their responsibilities, and the research-related activities and procedures that the participant is being asked to consent to
• Who the researchers are, the nature of their expertise, and their responsibilities
• The aspects of the clinical trial that are experimental
• Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant; information should include the probability and magnitude of the foreseeable risks of harm
• The measures to be taken to minimize risk of harm
• Any benefits to the participant or to others that may reasonably be expected from the research both during and after the research; if no benefit is expected, the participant should also be made aware of this
• A disclosure of appropriate alternative procedures or treatments, and their potential benefits and risks
• The probability for random assignment to each treatment
• Participation is voluntary, the participant may withdraw at any time without explanation or prejudice, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
• Compensation and/or medical treatment available to the participant in the event of a trial-related injury
• The planned incentives, if any, to attract the participant and the planned reimbursements, if any, for time, inconvenience, and expenses
• The extent to which confidentiality of records identifying the participant will be maintained, the possibility of record access by the sponsor, the ethics committee (EC), or the South African Health Products Regulatory Authority (SAHPRA)
• How the personal information of participants, including confidentiality of data collected during the research, will be protected
• Who will have access to participants' information, biological samples and associated data, including whether samples will be shared with other researchers
• That participants may request that corrections to their information be made or that their information or samples be deleted or destroyed; in cases where withdrawal of samples and information is not possible, the potential limitations and consequences of not withdrawing samples and data from research should be explained
• Instances where a legal obligation to disclose information may arise
• Statement that participants may contact the EC at the contact details provided if they have questions or complaints about their rights and welfare
• The sponsor’s identity
• Potential conflicts of interest of the principal investigator (PI)
• The consequences of a participant's decision to withdraw from the study
• Information about approval from a registered EC and SAHPRA
• Information about the EC monitoring the clinical trial
• The approximate number of participants in the research study, locally and globally
• The expected duration of participation
• Whether feedback about the study will be provided and, if so, how it will be provided
• Whether biological samples will be used for commercial benefit
• Where relevant, whether incidental findings will be shared with participants
• An explanation of whom to contact in the event of research-related injury
• A statement that participants may contact the researcher at the contact details provided if they have questions about the research project
• Foreseeable circumstances under which the investigator(s) may remove the participant without consent
• The research may be terminated early in particular circumstances
• The participant or legal representative/guardian will be notified if significant new findings developed during the study which may affect the participant's willingness to continue
• Information on post-trial or continued access (PTA/CA)
• Whether data and/or samples can be used after the person’s death, especially if it is possible that the person may die during the study
• Description of a measure to probe understanding and comprehension of the information is planned (e.g., a teach-back method), and how it proposes to do so especially for very vulnerable potential participants.

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

Overview

In accordance with ResNo466, the PANDRH-GCPs, and OMREC, Brazil’s ethical standards promote respect for all human beings and safeguard the rights of research participants, including rights to their autonomy, culture, beliefs, and values. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.)

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and research ethics committees (ECs) (Comitês de Ética em Pesquisas (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 information on participant rights during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, the participant or legal representative/guardian, should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per the ResNo466, the PANDRH-GCPs, and OMREC, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The PANDRH-GCPs also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identities and records of research participants.

The Right of Inquiry/Appeal

The PANDRH-GCPs, OMREC, and the G-ClinResSubjectRts explain that the research participant or legal representative/guardian, should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of their rights.

The Right to Safety and Welfare

ResNo466 and PANDRH-GCPs clearly state that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

Overview

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

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

The Right to Privacy and Confidentiality

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

As per the PANDRH-GCPs, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If the prior consent of the participant or legal representative/guardian cannot be obtained, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must provide documented approval in order to protect the participant’s rights, safety, and well-being, pursuant to the applicable regulations. The participant or legal representative/guardian should provide consent as soon as possible. OMREC and ResNo251 similarly state that the EC (CEP) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner about participation in the study.

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

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

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

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

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

Overview

As per the PANDRH-GCPs and the G-ClinResSubjectRts, in all Brazilian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The PANDRH-GCPs, ResNo466, and the G-ClinResSubjectRts characterize vulnerable populations as those who are relatively (or absolutely) incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes. These participants may include those with incurable diseases, people in convalescent homes, the unemployed or indigent, patients in emergency situations, ethnic minorities, homeless people, seasonal workers, refugees, minors, and those who cannot give their consent.

The G-ClinResSubjectRts further notes that in general, all individuals including healthy research participants should be seen as intrinsically vulnerable. These participants may currently be exposed to or are at risk of being exposed to an investigational product of unknown safety and efficacy, or one that is not fully understood, which could affect their overall health. In addition, other social, cultural, economic, psychological, or medical factors may adversely affect a participant’s ability to make rational and objective decisions that protect their own interests; however, this factor(s) may not be easily perceptible to the investigator.

The ResNo466 and PANDRH-GCPs specify that research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) must pay special attention to protecting participants who are from vulnerable populations. If the EC (CEP) regularly evaluates studies involving vulnerable populations, it should consider including members or consultants who know or have had experience working with the group in question. ResNo466 and the G-ClinResSubjectRts also state that vulnerable groups should not be included unless the research is necessary to promote the health of the population represented, and this research cannot instead be performed on legally competent participants.

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (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.

Indigenous Peoples

As delineated in ResNo304, special attention should be paid when conducting a study involving indigenous peoples in Brazil. Studies involving this population should comply with ethical requirements while also considering the unique qualities of each community. The benefits and advantages resulting from conducting a study with indigenous peoples must also meet the needs of individuals or groups targeted by the study or of related societies, and/or the country as a whole. Investigators should take into account the need to promote and maintain the well-being of participants while protecting and preserving their biological, cultural, individual, and collective health while also contributing to the development of the participants’ knowledge and abilities. Refer to ResNo304 for detailed information on research and protection requirements when conducting a study with this population.

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

Overview

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

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

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

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

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

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

Persons in Dependent Relationships or Hierarchical Situations

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

Persons Highly Dependent on Medical Care

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

Persons with Physical Disabilities

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

Elderly Persons

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

Research Involving Collectivities

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

LawNo8.069 (also known as the Statute of Children and Adolescents) states that a child is a person up to 12 years of age, and a teenager is one between 12 and 18 years of age.

As per PANDRH-GCPs, ResNo466, and OMREC, when the research participant is a child, the child’s parent/legal guardian must sign the informed consent form. However, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand.

As stated in the G-ClinResSubjectRts, children should only participate in clinical studies when their participation is necessary to promote the health of the population represented.

In addition, per CLNo11, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) has established guidelines related to the process of obtaining consent from research participants under 18 years of age. The process of consent to participate is essential and should be addressed to those who exercise parental responsibility or guardianship, without prejudice to listening to the participant under 18 years of age.

Per BRA-73, Brazil has also implemented the ICH Harmonised Guideline Addendum to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population E11 (R1) (BRA-74).

Assent Requirements

ResNo466 indicates that an assent form should be used to obtain informed consent from minors or those legally incapable of giving their own consent. The form should be prepared in a language that is accessible to minors or those legally incapable of giving their own consent. After the form is explained and the research study is clarified, the child participants should provide their consent to participate in the study, without the influence of their parent or legal guardian.

CLNo11 further states that researchers must ensure the assent is made in the form of an invitation without any degree of pressure or coercion, and written in simple, easy-to-understand language to ensure adequate comprehension of the research. The assent process must consider the understanding capacity of the participant under 18 years of age. Pursuant to LawNo8.069 which upholds the principle that the full protection of children and adolescents is the duty of everyone including public authorities and society in general, CLNo11 delineates that seven (7) years is the minimum age for the obligation to obtain the term or registration of consent. The guideline also recommends an assessment of each research participant’s needs, capabilities, and emotional maturity for the presentation of different terms or records of assent according to the age group (from childhood and adolescence), complexity of the research, and for analysis by the CEP/CONEP system. See CLNo11 for additional details.

See the Personal Data Protection section for requirements on processing personal data of children and adolescents.

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

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

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

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

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

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

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

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

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

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

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

• The study objective(s) can also be achieved if conducted on an adult
• The research is unlikely to significantly improve scientific understanding of the minor’s condition, disease, or disorder to such an extent that it will result in significant benefit to the minor(s)
• The reasons for the consent to the research by the parent/legal guardian and, if applicable, the minor, are contrary to public policy
• The research poses a significant risk to the health of the minor
• The risk to the health or well-being of the minor is not significantly outweighed by the potential benefit

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

Assent Requirements

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

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

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

As per ResNo466, the PANDRH-GCPs, and the G-ClinResSubjectRts, any Brazilian clinical studies involving women of childbearing age or who are pregnant, require additional safeguards to ensure that the participants are fully aware of the risks and that the research assesses the risks and benefits as well as any potential impact on fertility, pregnancy, the embryo or fetus, labor, lactation, and the newborn. ResNo466 further states that research on pregnant women should be preceded by research on women outside the gestational period, except when pregnancy is the fundamental purpose of the study. The investigator(s) should also ensure that female participants have the right to participate in the research without the use of compulsory contraceptives—if they have expressly indicated that they are free from the risk of pregnancy and sexual practices, or they are sexually active in a non-reproductive way.

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

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

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

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

According to the PANDRH-GCPs, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. ResNo466 also states that freedom of consent must be guaranteed to those research participants who are fully competent but are exposed to specific constraints or have restricted autonomy. These participants must have the freedom to decide whether to participate without any fear of reprisal.

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

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

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

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

According to ResNo466 and the G-ClinResSubjectRts, the research ethics committee (Comitê de Ética em Pesquisa (CEP)) must approve the participation of research participants who are mentally or physically incapable of giving consent, and sufficient justification must be provided for involving this population in a study. As delineated in the PANDRH-GCPs, consent should only be provided once the participant is informed about the study, to the extent that the participant is able to understand it, and if able, the participant should sign and date the written informed consent in person. The participant’s legal representative/guardian must also be present during the informed consent process and sign and date the informed consent form.

Per CLNo11, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) has also established guidelines related to the process of obtaining consent from research participants people with a "lack of autonomy", permanent or temporary, to consent. The process of consent to participate is essential and should be addressed to those who "lack of autonomy", permanent or temporary, to consent.

CLNo11 further states researchers must ensure the assent is made in the form of an invitation without any pressure or coercion, and written in simple, easy-to-understand language to ensure adequate comprehension of the research. The assent process must consider the discernment of the research participant with a "lack of autonomy", whether permanent or temporary, to consent. See CLNo11 for additional information.

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

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

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

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

As delineated in the PANDRH-GCPs, an investigational product (IP) is defined as a dosage form of an active ingredient or placebo that is being tested or used as a reference in a clinical trial. ResNo9, the G-BioIProdManual, and the G-SynthDrugProdManual add that the IP may also be referred to as an experimental drug, comparator, or any other product to be used in a trial. According to BRA-8, the definition of an IP in ResNo9 differs from that of the PANDRH-GCPs because when ResNo9 was adopted, an IP was mainly thought of in relation to the imports required to carry out each clinical trial. For this reason, the definition of “product under investigation” encompasses all products to be used in a trial, including medicine comparators, equipment, and laboratory kits. In addition, the PANDRH-GCPs definition further states that an IP may include a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form, or when it is used to gain further information about an approved use. Note: The terms experimental drug and IP are used interchangeably throughout the profile.

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

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

Manufacturing

As stated in ResNo9, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the manufacture of investigational products (IPs) in Brazil. ANVISA approves the manufacture of an IP as part of its review and approval of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))).

ANVISA has also released ServBltnNo104 to expedite the evaluation of clinical drug research development in Brazil without compromising the quality of the technical analysis. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.) According to ServBltnNo104, the IP manufacturing process must meet the criteria and recommendations described in the current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s guidelines, as applicable, according to the phase of clinical development. In addition, the technical experts in ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) require DDCM petitions and substantial quality modifications to meet ServBltnNo104 criteria and be accompanied by the documentation required in ResNo9. COPEC will then analyze the following:

• The results of stability studies under accelerated and long-term conditions that support the proposed expiration date for the IP and, where applicable, for the modified placebo and comparator, when the storage recommendation is at room temperature (between 15 and 30 degrees Celsius)
• The sample IP label for DDCM petitions

In the event of non-compliance, COPEC will conduct a non-simplified analysis per ResNo9. ServBltnNo104 further explains that ANVISA may also at any time analyze all the documents required by ResNo9, related to the IP risk analysis. Refer to the Submission Content section for DDCM petitions and substantial quality modifications documentation requirements.

In addition, per BRA-55, ANVISA is a member of the Pharmaceutical Inspection Co-operation Scheme (PIC/S). Per BRA-100, as a PIC/S member, ANVISA meets internationally harmonized good manufacturing practice (GMP) inspection standards and quality systems of inspectorates in the field of medicinal products for human or veterinary use. Refer to BRA-55 for additional information.

Per BRA-73, Brazil has also implemented the ICH Harmonised Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Q7) (BRA-112).

Import

Per ResNo9 and the G-DDCMManual, ANVISA is responsible for authorizing the import of IPs. The sponsor may request approval to import/export IPs for study purposes at the same time that a DDCM is submitted to ANVISA, as indicated in ResNo9. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while their DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation in the case of non-manifestation of the DDCM. The sponsor is required to present one (1) of these ANVISA documents at the location where IPs for import/export are unloaded. (See Submission Process and Submission Content sections for additional application requirements). See also BRA-103 for detailed instructions on obtaining a drug import license authorization. See ANVISA’s Consultation System (BRA-44) to check on the status of a petition submission using the “Document Status” (Situação de Documentos) tool.

BRA-95 also provides instructions to sponsors or the legal representatives in Brazil on completing the expiration date information for imported IPs in the clinical trial submission form (BRA-22). The expiration date is frequently updated, and is, therefore, often linked to inconsistencies and requests for clarification of requirements by those responsible for importing drugs and products for clinical trials. See BRA-95 for detailed information on stability requirements and instructions on completing the form.

ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. Pursuant to ResNo74 and BRA-108, the import petition must be submitted electronically. Per the G-LPCOImprtPetition, the first step in initiating ANVISA’s import protocol process is applying for an import license (Licença de Importação (LI)) via the Integrated Foreign Trade System (SISCOMEX)’s Single Foreign Trade Portal (BRA-80). As indicated in BRA-108, the electronic petition must include the documentation specified in ResNo208 (amending ResNo81) and other relevant legislation. ResNo208 (amending ResNo81) explains that the following documentation must be included with the petition:

• Copy of the CE, CEE, and Document for Importation of Product(s) under Investigation from DDCM
• Knowledge of cargo on board
• Commercial invoice
• In cases of imports carried out by others than the DDCM holder, document of delegation of import responsibilities