National Health Surveillance Agency (ANVISA)

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

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

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

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

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

International Alignment

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

Please note: Brazil is party to the Nagoya Protocol on Access and Benefit-sharing (BRA-63), which may have implications for studies of investigational products developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see BRA-81.

Contact Information

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

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

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

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

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

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

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

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

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

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

Tanzania Medicines and Medical Devices Authority

As per the TMMDAct and TZA-4, the TMDA is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Tanzania. The TMDA grants permission for clinical trials to be conducted in the country in accordance with the TMMDAct and the CT-Regs.

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

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

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

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

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

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

The PV-Regs established the Pharmacovigilance Technical Committee, under the National Pharmacovigilance Centre of TMDA, to provide recommendations to the Director General on pharmacovigilance-related safety issues, including causality assessment of adverse drug reactions and adverse events. In addition, as stated in TZA-37, there is a TMDA Clinical Trials Technical Committee (CTTC), pursuant to the TMMDAct, that provides independent technical advice to the Director General. Members of the CTTC provide technical advice to assure that clinical trials are designed, conducted, analyzed, and reported in accordance with TMDA and the International Council for Harmonisation (ICH)’s guidelines. Members of the CTTC are required to be prudent, transparent, independent, and committed to their professional ethics while discussing all matters pertaining to clinical trials. The CTTC, which meets a minimum of once quarterly, is composed of experts with knowledge and experience in at least the following fields: clinical trials, medical research, clinical pharmacology, clinical epidemiology, medicine, dental surgery, pharmacy, medical statistics, public health, toxicology, microbiology, pathology, and regulatory affairs.

Tanzania Commission for Science and Technology

Per the COSTECH-Act, COSTECH is the principal advisory government entity on all matters relating to scientific research and technology development. The G-ResearchClearance states that COSTECH is under the Ministry of Education, Science and Technology. As delineated in the COSTECH-Act, COSTECH’s functions are to:

• Formulate policy on the development of science and technology and recommend its implementation by the government
• Monitor and coordinate activities relating to scientific research and technology development
• Acquire, store, and disseminate scientific and technology information
• Advise the government on priorities in scientific research, allocation, and utilization of research funds, research policies and programs, national scientific standards, and science and technology policy
• Promote research in science and technology, mobilize funds, popularize science and technology, and facilitate the full and advantageous application of research results

As indicated in TZA-21, COSTECH performs the following services:

• Advising the government on research and technology
• Funding for the advancement of science and technology
• Granting research permits
• Facilitating knowledge dissemination and sharing of science, technology, and innovation, including through digital connectivity
• Registering technology transfer agreements
• Profiling researchers, innovators, and information
• Fostering regional and international cooperation
• Facilitating the commercialization of research results and innovations to support economic development

See TZA-22 and TZA-25 for more information on COSTECH’s mission and organization.

Per the G-ResearchClearance and TZA-47, the COSTECH must review, approve, and issue permits for all research in Tanzania, for both foreign and local researchers. The G-ResearchClearance specifies that COSTECH, through its National Research Clearance Committee (NRCC), receives and reviews research proposals for their scientific merit, safety, and ethics. Upon approval, NRCC issues research permits that allow the permit holder to conduct research in the country, and by doing so, the approved research proposal is duly registered in the country’s research database.

Other Relevant Agencies

The DNA-Act and the GCLA-Act establish the Government Chemist Laboratory Authority (GCLA), under the MOH, as the regulator that is responsible for overseeing, regulating, and administering human DNA. Its functions include initiating and conducting research on human DNA and cooperating with designated laboratories and other institutions. GCLA has the power to grant or revoke research permits for human DNA research. See the DNA-Regs for more information.

As indicated in TZA-20, the Prime Minister's Office, Regional Administration and Local Government (PMO-RALG) must provide permission to conduct research in a local area. Per TZA-52, PMO-RALG is empowered to improve community wellbeing. It coordinates, empowers, and oversees regional and local government authorities and affiliated institutions through providing policies, directives, and guidelines for improved service delivery.

International Alignment

Per TZA-9 and TZA-27, Tanzania adopts the ICH's guidelines for clinical trials (TZA-28), where applicable. Regarding good clinical practice, TZA-9 indicates that Tanzania has adopted the ICH Guideline for Good Clinical Practice E6(R2) (TZA-13). See TZA-9 for relevant adopted guidelines.

Contact Information

Tanzania Medicines and Medical Devices Authority

Tanzania Commission for Science and Technology

According to TZA-46, COSTECH’s contact information is as follows (Note: Information below will not necessarily be found in both sources, which provide overlapping and unique elements):

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

Telephone: +255 738746509
Research Permit Phone: +255 0738746511
Email: dg@costech.or.tz 
Research Permit Email: rclearance@costech.or.tz

Overview

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

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

Clinical Trial Review Process

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

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

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

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

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

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

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

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

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

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

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

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

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

Inspection

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

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

Priority Submissions

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

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

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

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

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

Optimized Analysis Procedure Submissions

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

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

Reliance Reviews

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

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

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

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

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

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

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

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

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

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

Risk and Complexity Based Reviews

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

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

Overview

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

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

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

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

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

The DNA-Regs states that a person intending to conduct human DNA research must first obtain COSTECH authorization before seeking a Government Chemist Laboratory Authority (GCLA) permit for human DNA research. See TZA-20 for the clinical trial application and registration workflow, and see the DNA-Act, the GCLA-Act, and the DNA-Regs for more information on human DNA research permits.

Clinical Trial Review Process

Tanzania Medicines and Medical Devices Authority

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

Per the G-AppConductCT, the TMDA reviews clinical trial applications and amendments to assess the quality of the products and determine that the use of the IP for the purposes of the clinical trial does not endanger the health of participants or other persons, the clinical trial is not contrary to the best interests of a participant, and the objectives of the clinical trial may be achieved. Evaluation of applications is conducted on a first-in, first-out basis unless the IP meets the fast-track criteria. The application assessment must involve the TMDA and external evaluators. If the TMDA requests additional information from the applicant, the evaluation process will stop until the TMDA receives a written response to the query. The response should be submitted within six (6) months after being issued a query letter. All queries issued in the same letter must be submitted together in one (1) transaction. Non-compliance with these requirements in content and format will lead to rejection of the clinical trial. Evaluation of applications will be completed within 60 working days of receiving the application. A new clinical trial application may be fast tracked and assessed within 30 working days of its submission if the applicant has requested this and paid twice the prescribed clinical trials application fees. If authorization is not granted, an appeal may be submitted to the TMDA within 60 days of the TMDA’s decision. If no appeal is submitted by the applicant within this period or, if after consideration of any comments submitted, the TMDA is still not satisfied, it must reject the application. In an appeal, the applicant must give grounds for review for each reason given for the rejection of a clinical trial. The grounds for the appeal request must be based on the information that was submitted in the application. Any additional or new information that was not submitted earlier will only be considered upon submission of a new application. The TMDA may review, reject, or vary its own decision.

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

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

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

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

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

Tanzania Commission for Science and Technology

As for COSTECH review, the G-ResearchClearance indicates that once COSTECH receives a new application, the Secretariat must do the following:

• Acknowledge receipt of the submitted application
• Internally screen the application for completeness, and if any document is missing, return the application to the applicant
• Submit to internal and external reviewers for evaluation if any application does not require EC clearance
• EC-cleared applications do not need to be reviewed by internal and external reviewers
• Send all applications to COSTECH management
• Submit applications to the National Research Clearance Committee (NRCC) for discussion and final verdict
• Record the decision of the NRCC on each application
• Inform the applicant of the NRCC decision, including minor and major comments which must be addressed through the online application system (TZA-48)

TZA-47 indicates that COSTECH’s processing time normally takes up to 14 working days after receipt of a complete application and payment. Delays may occur if additional clarification or documentation is required. The G-ResearchClearance states that COSTECH’s NRCC must reach a decision through a consensus of members forming a quorum at their meeting. The decision may be approval without amendments; approval subject to minor amendments such as recasting title, additional literature review, etc.; approval subject to consultation to stakeholders (e.g., government ministries or institutions); approval subject to major amendments, which holds if the proposal has scientific flaws (no justification, unclear objectives, poor/unclear methodology such as unjustified sample size/sampling frame and methods, unclear outputs and outcomes); or permit denial where the proposal compromises national security, fails to address ethical requirements, or implies possible detrimental effects to national and international policies. In such cases, the NRCC must include in its written notification to the applicant a statement of reasons for its decision and an opportunity to respond in person or in writing. If the applicant is still not satisfied with the NRCC’s decision, the arbitration mechanism must involve the principal investigator (PI) presenting an appeal to COSTECH. Researchers whose projects have been approved by the NRCC should access the research permit through the online application system (TZA-48). Non-Tanzanian applicants must pay a research permit fee using the control number generated by the system within 90 days, and failure to do so means the applicant must re-apply as a new application.

Per the G-ResearchClearance, permits are valid for one (1) year, and can be renewed; the PIs who fail to submit satisfactory progress reports may be liable to termination. Where a researcher fails to conduct research within a given duration, the research permit will automatically expire and will not be transferrable. The ongoing research must be reviewed to ensure continued adherence to the study proposal approved in the previous permit and to see if any material changes have occurred in the research. The renewal application is also an opportunity for the NRCC to determine whether there are any important findings already that might influence policy or practice or cause the research to be terminated altogether. The application for renewal/extension should be done 60 days before the expiration of the current permit. Once COSTECH receives a renewal application, the Secretariat must acknowledge receipt of the submitted application; conduct internal screening to ensure that all the required documents have been submitted, and if any document is missing, request them from the applicant; send all applications to the COSTECH management; submit to the NRCC for discussion and final decision; record the decision of the NRCC on each application; and inform the applicant of the NRCC decision.

Further, the G-ResearchClearance describes COSTECH’s procedure for expedited review or fast track review and approval of applications outside of the normal schedule of the NRCC meeting. The expedited review process will take a maximum of 15 working days from submission of application by applicant to the final decision and issuance of the research permit. The procedure is applicable to the new applications already approved by an EC, renewals/extensions, and amendment applications.

Per the G-ResearchClearance, COSTECH monitors and supervises clinical trials with progress reports, site visits, and access to the data and research premises of the permitted research projects. Where necessary, COSTECH will coordinate joint supervision with the research institute in specific thematic areas. COSTECH reserves the right to suspend, terminate, or revoke a research permit in the event of gross misconduct, violation of the provisions of the G-ResearchClearance, or when deemed necessary. Such suspension, termination, or revocation will only take place after thorough investigation of allegations on non-compliance.

See TZA-47 for additional information about research permits and COSTECH’s other research and education initiatives.

National Health Surveillance Agency (ANVISA)

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

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

Payment Instructions

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

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

Tanzania Medicines and Medical Devices Authority

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

• $3,000 USD for submitting a clinical trial application
• Double the cost of registration and analysis fee for fast-track clinical trial applications
• $500 USD for amendments for major changes in clinical trials
• $300 USD for amendments for minor changes in clinical trials

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

Payment Instructions

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

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

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

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

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

The Pay-Overseas reiterates that overseas customers must make all payments via GEPG. Before making any payment, TMDA customers should receive the special payment identification number (Control Number) indicated on a Proforma Invoice issued by the TMDA, as per the TMMDAFees. The TMDA’s external customers who pay for services from abroad must fill out the relevant payment form (swift form), especially item/section No. 70, by ensuring that no other information is entered in this section except the payment identification number (Control Number). However, the payer should select “OUR” in the charge mode section 71A. Any payment made without a Control Number will not be reflected in any invoice. Further, payments of more than one (1) Control Number(s) cannot be combined. Note that deposited money in the TMDA’s account cannot be refunded.

Tanzania Commission for Science and Technology

As delineated in the G-ResearchClearance, the Tanzania Commission for Science and Technology (COSTECH) charges a $50 USD research application fee for new and renewal/amendment applications for both Tanzanian and non-Tanzanian applicants. However, the application fee may be reviewed and, where necessary, changed periodically without notice. The principal investigator (PI) should pay the nonrefundable research application fee, which is paid per project. The fees for expedited review of research projects are as follows:

• Tanzanian researchers, new applications: 700,000 Tanzanian Shillings
• Tanzanian researchers, renewal and amendment applications: 300,000 Tanzanian Shillings
• Non-Tanzanian researchers, new applications: 800 USD
• Non-Tanzanian researchers, renewal and amendment applications: 500 USD
• Tanzanian students, new applications: 300,000 Tanzanian Shillings
• Tanzanian students, renewal and amendment applications: 100,000 Tanzanian Shillings

In addition, the G-ResearchClearance states that before a permit is issued, COSTECH requires foreign researchers to pay a research permit fee of $300 USD, which applies to both normal and expedited review pathways.

Payment Instructions

Per the G-ResearchClearance, the PI should pay the nonrefundable application fee at the beginning of an application. The application will not be processed without proof of payment of the application fee. All non-Tanzanian research teams listed in the research project proposal and online application system should pay the research permit fee through the control number auto generated by the system. The control number will link to the following bank details; the control number must be used instead of the bank account number.

Account name: Tanzania Commission for Science and Technology
Bank Name: National Bank of Commerce Ltd
Branch: Samora Avenue, P.O. Box 9002, Dar es Salaam, Tanzania
Swift Number/Code: NLCBTZTX

For help with the payment, contact COSTECH at rclearance@costech.or.tz.

Overview

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

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

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

Ethics Committee Composition

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

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

Research Ethics Committees (CEPs)

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

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

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

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

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

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

As set forth in OMREC, under the CEP/CONEP System, each EC (CEP) must have written standard operating procedures (SOPs), including a process for conducting reviews. The SOPs should include information on EC (CEP) composition, meeting schedules, frequency of reviews, requirements for initial and ongoing evaluation of the research study, and requirements for notifying the investigator and the institution of results related to the study’s initial and ongoing evaluation. ResNo706 further specifies the EC (CEP) is responsible for the following:

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

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

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

Overview

As indicated in the G-AppConductCT, all clinical trials require national ethics committee (EC) approval for each trial site. Per the G-TMRCC and TZA-50, the national EC in Tanzania is the National Health Research Ethics Committee (NatHREC), which focuses on the ethical issues surrounding submitted research proposals. As delineated in the G-TMRCC, NatHREC-Charter, TZA-5, and TZA-18, NatHREC is a subcommittee of the Medical Research Coordination Committee (MRCC), which serves as the national health research coordinating body, and is responsible for supervising, controlling, coordinating, evaluating, and promoting health research in Tanzania or elsewhere on behalf of or for the benefit of Tanzania. The MRCC, which is part of the National Institute for Medical Research (NIMR), delegates the registration, review, approval, and monitoring of clinical research to the NatHREC. As mandated by the MedRsrchAct, NIMR is the central body responsible for oversight, and for the promotion and coordination of research in Tanzania. NIMR is under the Ministry of Health (MoH) and coordinates with the Tanzania Commission for Science and Technology (COSTECH). See the Oversight of Ethics Committees section for additional information about NIMR.

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

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

Per the G-AppConductCT, G-EthicsHR-TZA, the G-ResearchIntegrity, the G-RevPrtcl, TZA-18, TZA-5, and TZA-1, all health research involving foreign collaborators must get ethics approval from both the institutional EC and NatHREC. In addition, TZA-5 specifies that the following also require review by both NatHREC and the zonal or institutional EC: all clinical trials; research dealing with vulnerable, special, or marginalized groups; and sensitive topics or indigenous communities. Protocols that do not involve foreign collaborators and non-clinical trials of investigational products (IP) can be reviewed and given ethics clearance at the zonal or institutional level. NatHREC may request zonal or institutional EC reviewers to assist in review or joint review of protocols when needed. The NatHREC-Charter indicates that institutional and zonal ECs complement NatHREC’s function of issuing institutional ethics clearance certificates and monitoring the approved research at their institutions. TZA-18 states that if there is no institutional EC available, the approval must be obtained from NatHREC.

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

Ethics Committee Composition

National Health Research Ethics Committee

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

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

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

Institutional Ethics Committees

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

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

National Health Research Ethics Committee

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

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

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

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

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

Institutional Ethics Committees

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

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

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

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

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

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

Overview

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

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

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

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

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

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

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

Exemption from Review

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

Role in Clinical Trial Approval Process

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

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

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

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

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

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

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

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

Risk-Based Framework

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

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

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

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

High-Risk Research Protocols

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

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

Priority Review for SUS Strategic Research

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

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

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

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

Multicenter Research

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

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

CONEP Review Pathways

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

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

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

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

High-Risk Research Protocols

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

Priority Review for SUS Strategic Research

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

Multicenter Research

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

Foreign Research

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

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

Overview

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

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

Role in Clinical Trial Approval Process

National Health Research Ethics Committee

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

As described in TZA-18, the NatHREC’s delegated functions include reviewing, approving, and monitoring research in Tanzania. G-RevPrtcl and TZA-5 indicate that the NatHREC operates through the National Health Research Management Information System (NHRMIS) (TZA-32), formerly known as the Research Ethics Information Management System (REIMS). Per the G-RevPrtcl, the NatHREC Secretariat will validate submissions for completeness upon receipt in TZA-32. See TZA-1 for NatHREC’s ethics clearance checklist. The G-RevPrtcl recommends the following review sequence after the materials are checked for completeness: write comments in an MS Word document; read the PI’s cover letter, the institution’s commitment letter, and other supporting letters; review the abstract/summary; review the application form, protocol, and appendices; and synthesize and submit comments online through TZA-32. Per TZA-5, following successful validation of an application to TZA-32, the system generates a unique protocol number/identifier; this unique identifier must be used in reference to all communications to the PI or applicant regarding the application. Depending on the research area of the submitted protocols, at least two (2) primary reviewers must be assigned to review a new protocol by the NatHREC Secretariat. Comments from reviewers will reach the PI within two (2) days, depending on the type of study protocol. If the applicant fails to respond to the comments within 30 days, the NatHREC Secretariat must notify the PI of its intent to remove the protocol from TZA-32. Once the research protocol is removed from TZA-32, the PI must re-apply for ethical clearance and pay the application fee. For clinical trial applications, reviewers’ comments and the outcome of the NatHREC meeting must be forwarded to the PI within 30 days from the date of acceptance by the NatHREC. If the research protocol is cleared and the ethical clearance certificate is issued, the PI must receive it via mail at the institution’s postal address. Additionally, the PI may be able to download the soft copy of the ethical clearance certificate from TZA-32. A PI may appeal a decision in writing to the Medical Research Coordination Committee (MRCC) Chairperson within 30 days of receipt of the decision, stating the precise issues upon which the appeal is based. The MRCC will respond to PIs in writing within 30 days or upon scrutiny of the appeal. The MRCC Chairperson may invite the PI to appear in person to the MRCC within 30 days of receiving the written appeal.

Expedited Review

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

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

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

Reviews During Public Health Events

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

Approval Duration

Regarding duration of the NatHREC approval, per TZA-5, the NatHREC Secretariat determines how often the committee must re-evaluate the research study, appropriate to the degree of risk, but not less than once per year. Studies whose approval has expired must be suspended until an extension through a renewal process is approved. The PI must submit an electronic continuing review report through TZA-32 with a frequency as indicated in the terms and conditions of the ethics clearance certificate. The NatHREC Secretary must place the continuing review report on the next meeting’s agenda for review. The NatHREC may provide directives or guidance to the study following review that will be communicated to the PI. In addition, the committee may recommend that the research study is halted.

Protocol Amendments

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

Institutional Ethics Committees

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

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

Expedited Review

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

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

Accelerated Review

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

Continuing Review

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

Suspension or Termination

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

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

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

Multicenter Research

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

Exemption

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

National Health Research Ethics Committee

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

As per TZA-17, the fees are as follows:

• Tanzanian researchers, expedited review – 3,875,000 Tanzanian Shillings
• Tanzanian researchers, ordinary review – 2,625,000 Tanzanian Shillings
• Tanzanian researchers, amendment – 750,000 Tanzanian Shillings
• Tanzanian researchers, extension – 300,000 Tanzanian Shillings
• Tanzanian students, expedited review – 390,625 Tanzanian Shillings
• Tanzanian students, ordinary review – 390,625 Tanzanian Shillings
• Tanzanian students, amendment – 250,000 Tanzanian Shillings
• Tanzanian students, extension – 125,000 Tanzanian Shillings
• International researchers, expedited review – $5,125 USD
• International researchers, ordinary review – $2,625 USD
• International researchers, amendment – $750 USD
• International researchers, extension – $300 USD
• International students, expedited review – $548 USD
• International students, ordinary review – $548 USD
• International students, amendment – $375 USD
• International students, extension – $125 USD

See TZA-17 for appeal fees and late renewal penalties.

Payment Instructions

No information is currently available regarding payment instructions for the NatHREC.

Institutional Ethics Committees

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

Overview

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

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

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

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

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

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

National Research Ethics Authority (INAEP)

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

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

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

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

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

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

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

Registration, Auditing, and Accreditation

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

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

National Research Ethics Authority (INAEP)

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

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

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

Overview

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

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

Registration, Auditing, and Accreditation

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

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

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

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

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

See the G-ResearchIntegrity for guidance on the introduction and strengthening of research integrity mechanisms at institutions. When such mechanisms are well established, institutional ECs can advance to a stage of accreditation.

Overview

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

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

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

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

Regulatory Submission

Primary Petitions

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

ResNo945 provides the following additional DDCM submission requirements:

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

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

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

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

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

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

Secondary Petitions

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

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

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

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

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

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

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

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

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

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

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

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

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

Electronic Filing

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

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

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

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

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

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

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

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

Ethics Review Submission

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

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

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

Overview

According to the TMMDAct, the CT-Regs, and the G-AppConductCT, the Tanzania Medicines and Medical Devices Authority (TMDA) requires the sponsor, the designated contract research organization (CRO), or the investigator to obtain TMDA approval. Per TZA-5, the principal investigator (PI) is required to submit an application for ethical review of a research study to the national ethics committee (EC), the National Health Research Ethics Committee (NatHREC). All clinical trials must get ethics approval from both the institutional EC and the NatHREC. TZA-18 states that if there is no institutional EC available, the approval must be obtained from NatHREC. According to the G-AppConductCT and TZA-4, TMDA and NatHREC reviews may be conducted in parallel. However, the TMDA application must include a copy of the NatHREC's acknowledgement of receipt for the study protocol. In addition, the TMDA's approval will only be finalized once NatHREC approval is obtained.

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

See TZA-20 for a clinical trial application and registration workflow.

Regulatory Submission

Tanzania Medicines and Medical Devices Authority

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

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

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

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

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

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

Tanzania Commission for Science and Technology

Per the G-ResearchClearance, the PI should submit an application for a research permit or renewal of a permit. It must be submitted to the Director General of COSTECH through the online system (TZA-48) at least 60 days before the intended commencement of research in Tanzania; or, in the case of renewals, 60 days before the expiration of the 12-month permit. For support or clarification, TZA-47 states that applicants should contact COSTECH at rclearance@costech.or.tz or +255 0738 746511. See the G-ResearchClearance and TZA-47 for additional information about applying for a research permit through COSTECH’s National Research Clearance Committee (NRCC).

Ethics Review Submission

National Health Research Ethics Committee

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

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

Institutional Ethics Committees

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

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

Regulatory Authority Requirements

Clinical Drug Development Dossier (DDCM)

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

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

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

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

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

Specific Clinical Trial Dossier (DEEC)

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

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

Substantial IP Modifications

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

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

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

Substantial Protocol Amendments

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

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

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

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

Optimized Analysis Procedure (Reliance) Submissions

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

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

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

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

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

Ethics Committee Requirements

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

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

Clinical Protocol

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

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

For complete protocol requirements, refer to OMREC and OSNo001.

Regulatory Authority Requirements

Tanzania Medicines and Medical Devices Authority

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

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

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

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

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

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

Tanzania Commission for Science and Technology

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

• A full research proposal, including a summary, abstract, introduction, research objectives, problem statement, hypotheses or questions framework, methodologies, and timeframe
• CV of the PI
• Sponsor’s cover letter
• For foreign applicants, scientific and ethics committee approval from an institution in the PI’s country of residence
• Introduction or support letter from foreign applicant’s host institution
• Research ethical clearance from subject matter authorities in Tanzania
• Clearance from the TMDA
• A supporting letter from a Tanzanian affiliate institution
• A Tanzanian applicant should provide details of their national ID and passport
• A foreign applicant should submit a copy of their passport details page and a current passport size photo with a blue background
• A scanned copy of a receipt as proof of payment of the non-refundable research application fee to COSTECH (See Regulatory Fees section for details)
• All Co-PIs and members of the project (they should have registered on the online system (TZA-48) so that the PI can include them during the application)

Per the G-ResearchClearance, to renew a research permit, the PI should send a request to COSTECH with the annual progress report and a supporting letter of recommendation from the affiliated institution.

Ethics Committee Requirements

National Health Research Ethics Committee

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

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

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

Institutional Ethics Committees

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

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

Clinical Protocol

The G-AppConductCT indicates that the protocol should state the background, rationale, and objectives of the trial, and describe its design, methodology and organization, including statistical considerations, and the conditions under which it is to be performed and managed.

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

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

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

Overview

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

Regulatory Authority Approval

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

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

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

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

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

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

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

Priority Submissions

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

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

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

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

Ethics Committee Approval

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

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

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

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

Overview

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

In addition, the DNA-Regs states that after the COSTECH approval, a human DNA research permit is required, if applicable, from the Government Chemist Laboratory Authority (GCLA). Further, TZA-20 shows that the Prime Minister's Office, Regional Administration and Local Government (PMO-RALG) must also provide permission to conduct research in a local area.

See TZA-20 for a clinical trial application and registration workflow.

Regulatory Authority Approval

Tanzania Medicines and Medical Devices Authority

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

As set forth in the TMMDAct, the CT-Regs, and the G-AppConductCT, the TMDA coordinates the clinical trial application process. Upon receipt of a clinical trial application, the TMDA initially screens the application for completeness. If complete, the TMDA officer acknowledges receipt of the application by returning a signed copy of the cover sheet to the applicant (see Annex 1 of the G-AppConductCT or First Schedule of the CT-Regs). Per the G-AppConductCT, the TMDA may request clarification, certificates, and/or samples through a query letter. Once a query has been raised and sent to the applicant, the evaluation process stops until the TMDA receives a written response to the query. The response should be submitted within six (6) months after the query letter was issued. In addition, TMDA reserves the right to request information or set conditions not specifically described in the G-AppConductCT to allow it to adequately assess the safety, efficacy, or quality of an investigational product (IP). If authorization is not granted, an appeal may be submitted to the TMDA within 60 days of the TMDA’s decision. If no appeal is submitted by the applicant within this period or, if after consideration of any comments submitted, the TMDA is still not satisfied, it must reject the application.

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

Tanzania Commission for Science and Technology

The G-ResearchClearance indicates that COSTECH will make its decision about research permits at the National Research Clearance Committee (NRCC) meetings which are scheduled every two (2) months. For expedited or fast-track review and approval of applications outside of the normal schedule of the NRCC meeting, the process will take a maximum of 15 working days from submission of application by applicant to the final decision and issuance of the research permit. However, per TZA-47, COSTECH’s processing time normally takes up to 14 working days after receipt of a complete application and payment. Delays may occur if additional clarification or documentation is required.

Ethics Committee Approval

National Health Research Ethics Committee

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

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

Institutional Ethics Committees

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

Overview

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

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

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

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

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

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

Clinical Trial Agreement

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

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

Clinical Trial Registration

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

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

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

Overview

In accordance with the TMMDAct, the CT-Regs, and the G-AppConductCT, a clinical trial can only commence after an applicant receives permission from the Tanzania Medicines and Medical Devices Authority (TMDA) and approval from the national ethics committee (EC), the National Institute for Medical Research (NIMR)’s National Health Research Ethics Committee (NatHREC). Per the G-ResearchClearance, following TMDA and NatHREC approvals, the applicant must also apply to the Tanzania Commission for Science and Technology (COSTECH) for review, registration, and to obtain a research permit prior to initiating a study. No waiting period is required following the applicant’s receipt of these approvals. However, the DNA-Regs states that after COSTECH approval, a human DNA research permit is required, if applicable, from the Government Chemist Laboratory Authority (GCLA). Further, TZA-20, shows that the Prime Minister's Office, Regional Administration and Local Government (PMO-RALG) must also provide permission to conduct research in a local area.

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

See TZA-20 for a clinical trial application and registration workflow.

Clinical Trial Agreement

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

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

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

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

Clinical Trial Registration

As per the CT-Regs and the G-AppConductCT, all clinical trials taking place in Tanzania must be registered with the Tanzania Clinical Trials Registry (TzCTR) which is accessed via the Regulatory Information Management System (RIMS) Customer Self Service Portal (TZA-34). An applicant must submit detailed clinical trial information to the TzCTR no later than 21 days after the first participant is enrolled in the trial. See the CT-Regs for complete registry submission requirements. The G-AppConductCT further stipulates that applicants have the option to register in any other publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization (WHO). The registration number should be made available to the TMDA.

Safety Reporting Definitions

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

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

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

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

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

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

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

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

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

Sponsor Responsibilities

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

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

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

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

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

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

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

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

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

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

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

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

Other Safety Reports

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

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

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

Form Completion & Delivery Requirements

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

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

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

Safety Reporting Definitions

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

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

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

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

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

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

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

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

Safety Reporting Requirements

Investigator Responsibilities

As stated in the G-ReptSafetyData and the G-AppConductCT, the investigator is responsible for documenting and reporting all AEs/ADRs, SAEs/SADRs, and SUSARs to the sponsor using the case report form (CRF)/reporting form and the SAE/SADR Reporting Form approved in the protocol, or CIOMS Form I (TZA-7). See section 3 of the G-ReptSafetyData for key data elements to include on the form. TZA-5 requires the principal investigator (PI) to ensure that the protocol includes all required elements for safety monitoring, including assessment and reporting of any anticipated or unanticipated AEs and SAEs. Ethics committees (ECs) (both the National Health Research Ethics Committee (NatHREC) and institutional ECs) must review and address AEs, SAEs, and/or SUSARs. Investigators must be familiar with the regulations, policies, and procedures concerning reporting and continuing review requirements, as well as timelines for submission of notifications and reports.

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

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

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

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

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

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

Sponsor Responsibilities

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

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

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

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

Form Completion & Delivery Requirements

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

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

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

Interim and Annual Progress Reports

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

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

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

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

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

Final Report

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

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

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

Other Reporting Requirements

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

Interim and Annual Progress Reports

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

Per the G-EthicsHR-TZA, researchers must submit progress reports to the ethics committee (EC) at regular intervals as stipulated by the EC. The G-ResearchClearance further states that researchers must submit progress reports biannually (after every six (6) months) and annually to the Tanzania Commission for Science and Technology (COSTECH).

In addition, per the G-EthicsHR-TZA, the investigator must ensure appropriate and timely feedback on the research process including progress reports. Periodic progress reports enable the EC to determine whether the research study is progressing according to the approved protocol. Furthermore, the G-ResearchClearance indicates that the PI is required to submit annual progress reports (as part of the annual permit-renewal process) that include the title of the study, COSTECH registration reference number, study site, brief background and objective of the study, progress in the reporting period, any problems encountered, output of the project during the reporting period, implementation plan for the next period, and data collection tools.

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

Final Report

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

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

The G-ResearchClearance requires the PI to submit a soft and hard copy of the final report to COSTECH. The report should be accompanied with any relevant publications, electronic raw data (which is also shared with local collaborating institutions), commitment letter for feedback to the data source community when research is completed, and dissemination of research findings to the beneficiaries. The final report should include:

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

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

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

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

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

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

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

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

Overview

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

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

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

Foreign Sponsor Responsibilities

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

Data Safety and Monitoring Board

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

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

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

Multicenter Studies

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

Overview

The Tanzanian government complies with the requirements delineated in the G-AppConductCT. Investigators and sponsors are urged to read the International Council for Harmonisation's guidelines for conducting clinical trials alongside the G-AppConductCT. Clinical trials must be carried out under conditions which ensure adequate safety for the participants. The site selected should be appropriate to the stage of development of the product and the potential risks involved. The trial site must have adequate facilities, including laboratories, equipment and sufficient medical, paramedical, and clerical staff to support the trial and to deal with all reasonable foreseeable emergencies. Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s).

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

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

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

Per the G-AppConductCT, all laboratory assays must be validated, and principles of Good Laboratory Practice (GLP) should be observed.

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

Foreign Sponsor Responsibilities

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

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

Data and Safety Monitoring Board

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

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

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

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

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

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

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

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

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

Multicenter Studies

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

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

Insurance

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

Compensation

Injury or Death

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

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

Trial Participation

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

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

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

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

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

Post-Trial Access

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

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

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

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

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

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

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

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

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

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

Insurance

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

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

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

• Cover the conduct of the relevant clinical trial in Tanzania

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

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

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

Compensation

Injury or Death

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

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

As per the G-CTInsurance-TZA, the amount of compensation paid should be appropriate to the nature, severity, and persistence of the injury. Compensation should be abated, or in certain circumstances excluded, in light of the following factors (which will depend on the risk level the participant can reasonably be expected to accept):

• The seriousness of the disease being treated

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

Trial Participation

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

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

Post-Trial Access

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

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

Quality Assurance/Quality Control

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

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

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

Monitoring Requirements

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