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

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.

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).

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

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.

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.

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 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.

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.

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

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.

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.

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.

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.

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.

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.

Quality Assurance/Quality Control

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

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

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

Monitoring Requirements

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

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

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

Premature Study Termination/Suspension

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

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

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

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

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

Electronic Data Processing System

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

Records Management

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

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

Responsible Parties

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

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

Data Protection

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

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

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Children/Adolescents

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

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

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

Obtaining Consent

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

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

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

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

Re-Consent

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

Language Requirements

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

Documenting Consent

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

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

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

Waiver of Consent

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

Based on ResNo466 and OMREC, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

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

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

Pursuant to BRA-141, under the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos), the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) states that, in multicenter studies, the ICF must include, at a minimum, the following:

• Contact information for the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) of the coordinating center responsible for the ethical protocol review
• Contact details for the EC (CEP) and/or the local institutional contact channel at the participating center
• Contact information for the person(s) responsible for the research at the participating center

See BRA-141 for additional INAEP guidance on single EC (CEP) reviews.

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

Overview

In accordance with LawNo14.874 and ResNo466, Brazil’s ethical standards promote respect for all human beings and safeguard the rights and dignity of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.)

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. See also CLNo039 for CONEP guidance on accessing and using a participant’s medical records for research purposes while ensuring compliance with privacy and confidentiality standards. The guideline also states that all participants should be treated with dignity, respect for their autonomy, and ensure protection for vulnerable populations. See also BRA-29 for additional information on participant rights during the informed consent process.

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

The Right to Participate, Abstain, or Withdraw

As set forth in the LawNo14.874, ResNo466, and OMREC, the participant or legal representative/guardian, should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

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

The Right to Privacy and Confidentiality

As per the ResNo466 and OMREC, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. LawNo14.874 also states that the research must respect the participant’s privacy and the rules of confidentiality of their data, thereby ensuring the preservation of the confidentiality of their identity.

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

LawNo14.874 and ResNo466 clearly state that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

As delineated in LawNo14.874, the inclusion of a participant in research in an emergency situation and without their prior consent will follow the provisions of the approved protocol. The research participant or the legal representative/guardian must be notified at the first possible opportunity and the decision regarding their continued participation in the research must be collected.

OMREC and ResNo251 further state that the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner about participation in the study.

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

Overview

As set forth in LawNo14.874, in all Brazilian clinical trials, research participants from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Vulnerability is defined as a condition in which a person or group of people has reduced capacity to make decisions and to oppose resistance in the research situation as a result of individual, psychological, economic, cultural, social, or political factors. ResNo466 similarly defines vulnerability as the state of individuals or groups who, for any reason or motive, have their capacity for self-determination reduced or impeded, or are in any way prevented from resisting, especially with regard to providing free and informed consent.

DecreeNo12.651 further specifies that research involving human beings who belong to special groups may require differentiated ethical, methodological, or analytical treatment at all stages of the research process, as to be established in regulations issued by the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)). Special groups, due to their vulnerability or unique ways of life, are considered to be human communities whose dignity requires differentiated protection, and include the following: children and adolescents, pregnant and breastfeeding women, indigenous peoples, quilombola communities and other traditional populations, persons deprived of liberty; and people with disabilities that impair their capacity to consent. The participation of special groups in research will depend on the adoption of specific protection measures, taking into account the particular conditions of vulnerability of each group.

Pursuant to LawNo14.874, the inclusion of participants in vulnerable research situations, even if circumstantially, is subject to the following conditions being met:

• An informed consent form (ICF) signed by a legal representative, or one judicially appointed
• The research is essential for the population represented by the participant in a vulnerable situation, and it is not possible to obtain data of comparable validity through the participation of adults capable of giving their consent or through the use of other research methods
• The research participant should be provided with information, when possible and to the extent of their ability to understand, respecting their decision to participate, expressed through an ICF, whenever they are able to evaluate and decide on the information received
• The responsible investigator and the legal representative/guardian of the incapacitated person will co-sign a communication to the Public Prosecutor's Office, informing the schedule for the incapacitated person's participation in the research

LawNo14.874 and ResNo466, state that the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must pay special attention to protecting participants who are from vulnerable populations. LawNo14.874 also notes that EC (CEP) members may invite external experts and representatives of vulnerable groups to give their opinion on specific issues related to research projects, but these individuals will not have the right to vote. Additionally, per ResNo466, vulnerable individuals or groups should not be included when the desired information can be obtained through participants with full autonomy, unless the research can benefit the health of the vulnerable population represented.

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. Refer to BRA-28 for consent guidelines applicable to vulnerable populations.

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (CEPs) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. See also CLNo039 for CONEP guidance on accessing and using a participant’s medical records for research purposes while ensuring compliance with privacy and confidentiality standards. The guideline also states that all participants should be treated with dignity, respect for their autonomy, and ensure protection for vulnerable populations.

Indigenous Peoples

LawNo14.874 requires that the Public Prosecutor's Office be notified, as applicable, of the participation of a member of an indigenous group in research.

ResNo466 further explains that, in cases of restriction of freedom or clarification necessary for adequate consent, such as communities whose group culture recognizes the authority of the leader or collective over the individual, obtaining authorization for research must respect this particularity, without prejudice to individual consent, when possible and desirable. When Brazilian legislation provides for the competence of government agencies, such as the National Foundation for Indigenous Peoples (Fundação Nacional dos Povos Indígenas (FUNAI)), in the case of indigenous communities, under the guardianship of such communities, such agencies must authorize the research in advance.

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

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

As per ResNo466 and OMREC, when the research participant is a child, the child’s parent/legal guardian must sign the informed consent form. However, per OMREC, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand. The child’s opinion must be considered, even though the child may not be deemed competent to give consent. ResNo466 further notes that in cases where clarification is necessary for research with child and adolescent participants, investigators must provide a clear justification for their choice, specified in the protocol and approved by the EC (CEP), and by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), when applicable. In these cases, the stages of clarification and free and informed consent must be followed, through the legal representatives/guardians of those invited to participate in the research, to preserve their right to information to the extent of their capacity.

In addition, per CLNo11, the CONEP has established guidelines related to the process of obtaining consent from research participants under 18 years of age. The process of consent to participate is essential and should be addressed to those who exercise parental responsibility or guardianship, without prejudice to listening to the participant under 18 years of age.

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

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

Assent Requirements

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

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

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

As delineated in LawNo14.874 and ResNo466, research with pregnant women will be preceded by similar research with women outside the gestational period, except when the pregnancy or the unborn child is the fundamental object of the research. Additionally, per LawNo14.874, this research will only be permitted when the foreseeable risk to the health of the pregnant woman or the unborn child is minimal.

ResNo466 also specifies that any Brazilian clinical studies involving women of childbearing age or who are pregnant, require additional safeguards to ensure that the participants are fully aware of the risks and that the research assesses the risks and benefits as well as any potential impact on fertility, pregnancy, the embryo or fetus, labor, lactation, and the newborn. Further, the investigator(s) should also ensure that female participants have the right to participate in the research without the use of compulsory contraceptives, if they have expressly indicated that they are free from the risk of pregnancy and sexual practices, or they are sexually active in a non-reproductive way.

ResNo466 states that freedom of consent must be guaranteed to those research participants, including prisoners, who are fully competent but are exposed to specific constraints or have restricted autonomy. These participants must have the freedom to decide whether to participate without any fear of reprisal.

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

According to ResNo466, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must approve the participation of research participants who are mentally or physically incapable of giving consent, and sufficient justification must be provided for involving this population in a study. In cases where clarification is necessary to obtain adequate consent from participants with mental disorders or diminished decision-making capacity, investigators must provide a clear justification for their choice, specified in the protocol and approved by the EC (CEP), and by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), when applicable. In these cases, the stages of clarification and free and informed consent must be followed, through the legal representatives/guardians of those invited to participate in the research, to preserve their right to information to the extent of their capacity.

Per CLNo11, CONEP has also established guidelines related to the essential process of obtaining consent from research participants with a "lack of autonomy," permanent or temporary, to consent.

CLNo11 further states researchers must ensure assent is obtained in the form of an invitation without any pressure or coercion, and written in simple, easy-to-understand language to ensure adequate comprehension of the research. See CLNo11 for additional information.

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

As per LawNo14.874, ResNo945, the G-BiolProdManual, and the G-SynthDrugProdManual, an investigational product (IP) is defined as an experimental drug, placebo, active comparator, or any other product to be used in a clinical trial. (Note: Experimental drugs are a subset of IPs, however, the sources and the profile use the two (2) terms interchangeably. In addition, IPs are also referred to as investigational medicinal products (IMPs) in Brazil, and the two (2) terms are used interchangeably.)

Pursuant to ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has also 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 detailed IP guidelines and definitions.

Manufacturing

As stated in LawNo14.874 and ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the manufacture of investigational products (IPs) in Brazil. ANVISA approves the manufacture of an IP as part of its review and approval of the clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)).

ResNo945 and the G-DDCMManual explain that IPs and the placebo used in clinical trials must be manufactured in accordance with good manufacturing practice (GMP), as established in ResNo658. Accordingly, the sponsor must provide ANVISA with a declaration that the IP and the placebo to be used in completed or ongoing clinical trials were manufactured in compliance with GMP and that the IP and placebo to be used in clinical trials in Brazil will also comply with GMP. (See also RegNo136, which provides complementary GMP for IPs to be followed in addition to ResNo658.) ResNo945 further specifies that, if available, a GMP Certificate or equivalent document for the IP must be submitted with the DDCM, or, if applicable, with a petition for substantial IP modification. See also G-ResNo945-FAQs for additional guidance on GMP certification requirements.

ResNo982 further explains that ANVISA has adopted a risk-based approach to granting and renewing GMP certificates, which may include reliance on inspections conducted by recognized Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) for GMP certification purposes. ANVISA may also carry out GMP inspections related to the IP to verify the information and data presented in the DDCM and to determine whether the IP is sufficiently safe to be administered to the clinical trial participants. For the optimized analysis procedure based on regulatory reliance (Reliance), the manufacturing process for the active pharmaceutical ingredient (API) and the IP approved by the AREE must comply with applicable International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines for the relevant phase of clinical development. See the Scope of Assessment section for information on optimized analysis procedure submissions. See the Submission Process and Submission Content sections for DDCM and substantial IP modification submission requirements.

In addition, ResNo1001 establishes the criteria and procedures for priority classification of petitions for prior approval for clinical trials, and GMP certification for medicines and APIs. See the Scope of Assessment section for additional information on priority classification criteria and requirements and the Timeline of Review section for related review timelines.

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

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

Import

Per LawNo14.874, ResNo945, and the G-DDCMManual, ANVISA authorizes the import of IPs. Information on the IPs to be imported for use in a clinical trial must be included in the Import Document (DI). As explained in ResNo945 and the G-DDCMManual, ANVISA issues one (1) DI for each DDCM, listing all the clinical trials to be conducted in Brazil and the related IPs authorized for import.

Per ResNo945 and the G-DDCMManual, ANVISA issues the DI within 30 business days of the filing date of the DEEC petition, before publication of the approval or rejection of the DDCM and DEEC petitions in the Official Gazette of the Union (Diário Oficial da União (DOU)). Importing IPs before publication in the DOU is at the sponsor’s discretion and responsibility of the sponsor. However, per the G-DDCMManual, this early issuance of the DI applies only to DDCM and DEEC petitions submitted together and does not apply to DEEC petitions submitted after DDCM approval. The G-ResNo945-FAQs further explains, ANVISA will issue an updated DI following substantial IP modifications. See G-ResNo945-FAQs for additional guidance on DI updates following substantial IP modifications.

Additionally, as described in ResNo945 and the G-DDCMManual, if a sponsor intends to import IP(s) prior to DDCM approval, the DDCM documentation must be submitted with a declaration of commitment stating that the IP(s) will only be distributed to research centers after the DDCM and DEEC have been approved and ANVISA’s authorization has been published in the DOU. If ANVISA rejects the DDCM, the corresponding DEEC, and the prior authorization for IP import, the sponsor must submit, within 60 business days from the DOU publication, a petition amending the DDCM process to inform ANVISA of the destination or destruction of the IP(s), including their respective quantities consistent with what was previously imported. ResNo945 further states that changing the import purpose of goods and products requires ANVISA authorization. Any change to the IP information contained in the DI may only be made upon request to ANVISA’s clinical research technical area. The use of IPs imported under a DI before publication of the DDCM and DEEC approvals in the DOU constitutes a health violation subject to the penalties provided in LawNo6.437, other applicable health regulations, without prejudice to applicable civil and criminal sanctions.

For DDCM, DEEC, and clinical protocol amendment submissions involving imported IPs, BRA-95 provides instructions on completing the expiration date (or shelf life) information for imported IPs in the Clinical Trial Submission Form (FAEC) (BRA-22). Per BRA-123, BRA-22 must be completed electronically in ANVISA’s Solicita Electronic Petition Request System (BRA-56). See BRA-95 for detailed information on stability requirements and instructions on completing BRA-22. The updated BRA-22 also requires sponsors to identify the clinical trial risk category in accordance with RegNo338. See RegNo338 for the risk category criteria. See also Scope of Assessment and Submission Process sections for information on the optimized analysis procedure. See also G-ResNo945-FAQs for guidance on IP shelf-life petition modification requirements.

As stated in ResNo977, Brazil is transitioning to a new import framework in which the inspection of imported products subject to ANVISA control, including drugs, is carried out through the Single Import Declaration (Declaração Única de Importação (DUIMP)) within the Integrated Foreign Trade System (SISCOMEX)’s Single Foreign Trade Portal (BRA-80). While the DUIMP-based framework is being progressively implemented, the import license (Licença de Importação (LI)-based process remains in use. During the phased implementation, import authorizations are granted by ANVISA through an LI via the Licenses, Permissions, Certificates and Other Documents (Licença, Permissão, Certificado e Outros Documentos (LPCO)) module in BRA-80. Import procedures will continue to be governed by ResNo81 and ResNo172. See the G-DUIMP for detailed instructions on submitting a DUIMP via SISCOMEX (BRA-80). See also BRA-144 for useful background information on DUIMP.

Pursuant to ResNo945, imported IPs under investigation for exclusive use in clinical trials are subject to the registration of licenses, permits, certificates, and other documents specified in SISCOMEX (BRA-80); are subject to ANVISA inspection; and must comply with ResNo81, its updates, or any other regulation that may replace it.

ResNo81 and ResNo172 delineate procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. ResNo172 specifies that the import of goods and products intended for research involving human beings that have been approved by ANVISA will be analyzed within 48 hours after arriving in Brazil and after compliance with relevant legal requirements. Additionally, imports intended for clinical trials whose objective is to register or alter product registration will be analyzed within five (5) days after protocol approval and compliance with legal requirements. Refer to ResNo81 and ResNo172 for detailed import procedures.

As described in ResNo977, ResNo74, and BRA-108, the import petition must be submitted electronically via SISCOMEX (BRA-80), either through the DUIMP-based process with LPCO, or where still applicable, through the LI-based process with LPCO. Detailed operational procedures for DUIMP-based submissions are described in the G-DUIMP. For import petitions submitted under the LI-based process, per the G-LPCOImprtPetition, the first step in initiating ANVISA’s import protocol process is to apply for an LI via BRA-80. As indicated in BRA-108, the electronic petition must include the documentation specified in ResNo81 and other relevant legislation. Under ResNo81, the required documentation includes:

• Copy of the Special Communication (Comunicação Especial (CE)), Specific Special Communication (Comunicado Especial Específico (CEE)), and Document for importation of product(s) under investigation linked to the DDCM
• Bill of lading
• Commercial invoice
• In cases of imports carried out by those other than the DDCM holder, a document delegating import responsibilities

Note: Per G-ResNo945-FAQs, the CE has been replaced by the DI in ResNo945.

BRA-108 also indicates that in the case of documents already in electronic form, they should be attached as individual files for each LI request in BRA-80. The documents must be attached, preferably, in the order indicated in the checklist of the procedure specified in ResNo81. Refer to BRA-108 for detailed documentation presentation requirements. See also ResNo81 for detailed import documentation requirements.

Per the G-LPCOImprtPetition, once the LI is registered, the user also must make a request in the LPCO module in SISCOMEX (BRA-80). The G-LPCOImprtPetition explains how the LPCO registration will eventually be integrated with the LI registration, however, at this time, it is necessary for the user to link the LI with the LPCO in order to initiate the import petition protocol in ANVISA’s Solicita Electronic Petition Request System (BRA-56). Refer to the G-LPCOImprtPetition for detailed instructions on registering the LI and the LPCO in BRA-80. See also BRA-106 for additional information on using BRA-80 and obtaining an LI, and See also BRA-109, for additional background on linking imported medicinal products and controlled substances to BRA-80.

As described in BRA-47 and the G-LPCOImprtPetition, users are required to complete the company registration process prior to submitting an import petition via BRA-56. BRA-47 provides step-by-step instructions on company registration along with the information provided in BRA-105. BRA-107 also provides additional information on registering a company with the National Registry of Legal Entities (Cadastro Nacional de Pessoas Jurídicas (CNPJ)).

Per ResNo945, imported IPs subject to special control as referenced in OrdNo344 (Lists A1, A2, A3, B1, B2, C3, D1, E, and F), must comply with ResNo81 and ResNo659. OrdNo344 defines the substances included in these lists as follows: "A1" and "A2" (permitted narcotics), "A3”, "B1", and "B2" (permitted psychotropics), "C3" (immunosuppressants), "D1" (permitted precursors), "E" (plants that can originate narcotic and/or psychotropic substances), and "F" (substances for prohibited use in Brazil). See BRA-57 for details on ANVISA’s protocol for authorization requests to import medicines and substances subject to special control.

Additionally, the G-ImprtMeds provides information on ANVISA’s Import Authorization Office for Medication (PAFME)) submission requirements for imported IPs subject to special control (e.g., medicines, including advanced therapy products and human cells and tissues for therapeutic purposes). According to the G-ImprtMeds, although these IPs are subject to PAFME approval, imported IPs intended exclusively for clinical trials as well as those being used for expanded access, compassionate use, and post-trial IP programs are exempt from ANVISA’s operating authorization (AE) requirements, provided that the company holds an ANVISA import authorization required for the exemption request and for carrying out one of these activities. See the G-ImprtMeds for details.

Advanced Therapy Products

Per ResNo506, advanced therapy products refer to medicines for human use that are based on genes, tissues, or cells. As delineated in LawNo14.874, for clinical trial purposes, the export and import of experimental advanced therapy products must be authorized by ANVISA and by regulatory bodies, under specific regulations. Per G-LPCOImprtPetition, applicants may initiate an import petition via ANVISA’s Solicita Electronic Petition Request System (BRA-56) to request an import license for advanced therapy products. The process involves obtaining an LI via the steps discussed earlier in this section followed by making a request through the LPCO module of BRA-80, and linking the LI to the LPCO registration. The user will then be able to initiate an import petition. See G-LPCOImprtPetition for additional information on registering an LI and LPCO for advanced therapy products via BRA-80, and then initiating an import petition via BRA-56. Refer to ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products.

Per ResNo172, ANVISA will analyze and release imported goods and products intended for use in research involving human beings within 48 hours after arrival in Brazil, provided that the legal requirements are met and that the purpose of the research is not to register or change the product registration. As specified in ResNo81 and ResNo172, the investigator and institution must submit the imported products through one (1) of the following methods: BRA-80 or Express Shipping. As indicated earlier in this section, the import petition must be submitted electronically and should comply with the documentation submission requirements discussed above and include the information provided in ResNo74 and BRA-108. While each import option has different documentation requirements, they all require the submission of an electronic petition for import, a commercial invoice, a signed statement of responsibility (see ResNo81 (Chapter XXVII) and ResNo172 (Annex I)), research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) approval. See ResNo172 and ResNo81 for additional information on the required items based on the import method used. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

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

Investigator's Brochure

In accordance with ResNo945 and the G-DDCMManual, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must provide coverage for the following areas (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Physical, chemical, and pharmaceutical properties
• Pharmaceutical aspects
• Pharmacokinetics and metabolism
• Toxicological effects in any animal species tested under a single dose study, a repeated dose study, or a special study
• Results of clinical pharmacokinetic studies
• Information regarding safety, pharmacodynamics, efficacy, adverse events data, and dose responses obtained from prior clinical trials in humans
• For phase 1 clinical trials involving the use of a drug for the first time in humans (First-in-human, FIH), attach reports of toxicity and detailed pharmacokinetic and pharmacodynamic studies, as a complement to the IB as soon as they are available
• Reference Safety Information

Additionally, per ResNo945 and the G-DDCMManual, the sponsor must submit an updated IB to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) in cases where clinical trials aim to support a new therapeutic indication, an expansion of use to a new population, a new dosage regimen, new associations, or any post-registration change that requires clinical data. The updated IB should be submitted with the changes highlighted (track-changes format), or a specific IB, by means of a secondary petition to the clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) using the subject code of “10821 - ENSAIOS CLÍNICOS - Notificação de Atualização de Brochura do Investigador” (10821 - CLINICAL TRIALS - Notification of Update of Investigator's Brochure), per the G-DDCMManual. See ResNo945, the G-DDCMManual, and the G-ResNo945-FAQs for additional guidance on IB requirements.

In addition, per ResNo945, 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 detailed IB requirements.

Quality Management

Pursuant to ResNo945 and the G-DDCMManual, the sponsor is responsible for submitting an Investigational Drug Development Plan (PDME) (BRA-128) to ANVISA as part of the DDCM. The PDME should contain the following:

• Active pharmaceutical ingredient (API) or active substance name, including IP category (e.g., synthetic, biological, specific, dynamized, medicinal gas, phytotherapeutic or radiopharmaceutical), therapeutic class, pharmaceutical form, concentration and route of administration
• Mechanism of action and indications to be studied
• General objectives and planned duration of clinical development
• A list, in tabular form, of the countries where clinical development has been submitted, including details of the regulatory and ethical approval status, and respective clarifications or justifications in cases of approval under reservation, disapproval, interruption, or cancellation of clinical development in any of the countries where it was submitted
• Scientific advisory opinion of any foreign regulatory authority, if any, on the clinical development
• In cases of linking new Specific Clinical Trial Dossiers (Dossiê Específico de Ensaio Clínico (DEECs)) to the DDCM, and exclusion of protocols cited in the PDME in which the corresponding DEECs were not submitted, the updated version of the PDME must be submitted, by means of a secondary petition to DDCM petition

Refer to the G-DDCMManual, the G-BiolProdManual, and G-ResNo945-FAQs for detailed PDME submission requirements.

ResNo945 also specifies that an Investigational Medicinal Product Dossier (IMPD) or Investigational Product Dossier (DPI) must be submitted to ANVISA as part of the clinical trial application (primary DDCM petition). The IMPD or DPI should include the following information on the IP:

• Description of the pharmaceutical form and composition
• Pharmacotechnical development
• Manufacturing process and in-process controls
• Quality control of excipients
• Quality control of the IP
• Standards/reference materials or chemicals
• Packaging material
• Results of stability studies
• Documentation relating to the control of transmissibility of Transmissible Spongiform Encephalopathies (TSE), in accordance with current health regulations or justifications for the exemption of this document

Per ResNo945, the sponsor should also include in the IMPD or DPI the manufacturing and process controls, quality control, and stability study results for the API or active substance; and the manufacturing process and analytical controls, packaging material, and stability study results of the placebo and modified comparator drug. See ResNo945 for additional information. In the event the IP is already registered in Brazil, the IMPD will be waived. However, in cases where there is a substantial change in the quality of the IP in relation to the registered drug, all documentation and information supporting the change(s) must be presented in the DDCM. ANIVSA requires the IMPD or DPI information to be presented following a logical structure that facilitates technical analysis, with the recommended format being Module 3 of the Common Technical Document (CTD) (BRA-133).

RegNo457 further establishes criteria for filing certain quality-related documents included in the IMPD or DPI for DDCM petitions and petitions for substantial IP modifications. The regulation addresses documentation for APIs with a Letter of Suitability of the Active Pharmaceutical Ingredient ((Carta de Adequabilidade do Dossiê de Insumo Farmacêutico Ativo) (CADIFA)) or pharmacopoeial monograph and establishes procedures for the continuous submission of API and IP stability study results and IP analytical method validation.

In addition to the initial PDME and IMPD submissions, the sponsor must submit to ANVISA any substantial IP modifications which may potentially have an impact on the quality or safety of the IP, active comparator, or placebo, as delineated in ResNo945 and the G-DDCMManual. These submissions must be linked as a secondary petition to the corresponding DDCM. Further, the optimized analysis procedure based on regulatory trust practices (Reliance) is also applicable to secondary petitions for substantial IP modifications. See BRA-127 for the Petition Form for Substantial Modification to the Product under investigation. For detailed information on substantial IP modifications, see the Scope of Assessment, Submission Process, and Submission Content sections.

ResNo945 and the G-DDCMManual further state that if a GMP certificate or equivalent document for the IP exists, it must be attached to the DDCM or to the petition for substantial IP modification, if applicable. See also G-ResNo945-FAQs for guidance on GMP certification requirements, BRA-28 for GMP guidelines for IPs, and RegNo136, which provides complementary GMP for IPs to be followed in addition to ResNo658. Refer to the Submission Process and Submission Content sections for DDCM submission instructions and documentation requirements.

In addition, per ResNo205, the DDCM submitted to ANVISA to conduct a clinical trial using IPs for rare diseases should also be accompanied by a request for GMP certification. See ResNo205 for detailed submission information.

International GMP Compliance

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

Furthermore, in accordance with ResNo741, RegNo292 establishes specific criteria and procedures for defining Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) for the purposes of the health inspection and Certification of Good Manufacturing Practices (Certificação de Boas Práticas de Fabricação (CBPF)) of APIs, cannabis products for medicinal purposes, medicines, and biological products. For purposes of health inspection and CBPF, AREEs must be regulatory authorities or international entities that are members of the PIC/S and the ICH (See Annex in RegNo292 for list of approved AREEs). See RegNo292 for detailed information on AREEs for the purposes of health inspections and GMP certificates. Also, see BRA-64 for additional information. ResNo945 also notes that the manufacturing process of the API and the IP approved by an AREE must comply with the guidelines and principles described in the current ICH guides, where applicable, according to the clinical development phase. See the Scope of Assessment section for additional information on AREE requirements.

Investigational product (IP) labeling in Brazil must comply with the requirements set forth in ResNo945, the G-DDCMManual, RegNo136, and the G-BiolProdManual. As described in the RegNo136 and the G-BiolProdManual, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Name, address, and telephone number of sponsor, contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or investigator (the main contact for information about the product, clinical trial, and emergencies)
• Presentation, pharmaceutical form, route of administration, quantity of dosage units, and the drug name/identifier and concentration/potency in the case of open studies
• Batch and/or product identification code
• Clinical trial reference code
• Clinical trial participant identification code, and where relevant, the visit number
• Investigator name, if not included in earlier contact information
• Instructions for use (reference may be made to an explanatory pamphlet or other document that guides the trial participants or person administering the IP
• Storage conditions
• Period of use (use limit date, expiration date, or retest date, as applicable), considering, at least, in the month/year format, and in a way that avoids any ambiguity
• Warning phrases in capital letters such as: “For clinical trial use only” or “EXCLUSIVE USE IN CLINICAL TRIALS”
• “KEEP OUT OF REACH OF CHILDREN”, except when the IP is for use in hospitals or in trials in which the product is not taken home by clinical trial participants

RegNo136 further explains that the labeling information must appear on the primary and secondary packaging, unless the IP is packaged as follows:

• Provided inside a primary package, together with the secondary package, and the secondary package contains the labeling data, or
• The primary packaging is a blister or small units, such as ampoules, on which the labeling information cannot be displayed, and requires the outer packaging to be provided with a label containing this information

Additionally, as described in RegNo136, when the primary IP packaging is always combined with the secondary packaging, the secondary packaging should contain the following:

• Name of the sponsor, CRO, or investigator
• Presentation, route of administration (may be excluded for oral solid dosage forms), dosage, and in the case of open trials, the name/identifier of the IP and strength/potency
• Batch and/or code number to identify the contents and packaging operation
• A trial reference code allowing identification of the trial, site, investigator, and sponsor if not given elsewhere
• The trial participant identification number/treatment number and where relevant, the visit number

As delineated in RegNo136, if the primary container takes the form of blister packs or small units, such as ampoules, and cannot be displayed, the outer packaging should be provided bearing a label with this information. However, the primary container should bear the following information:

• Name of the sponsor, CRO, or investigator
• Route of administration (may be excluded for oral solid dosage forms), dosage, and, in the case of open trials, name/identifier and concentration/potency
• Batch and/or code number for identifying the content and packaging operation
• Clinical trial reference code for study, site, investigator, and sponsor identification, if not provided elsewhere
• Trial participant identification number/treatment number and where relevant, the visit number

In addition, per RegNo136, the labeling information must be in the language of the country where the clinical trial takes place, however, other languages may be included. By comparison, the G-BiolProdManual indicates that all of the text labeling must be written in Portuguese. RegNo136 and the G-BiolProdManual further note that symbols, pictograms, and warnings may also be included on both the primary and outer packaging. Also, the primary contact’s address and telephone number for IP or clinical trial information, and for emergency unblinding, need not appear on the label when the trial participant has been provided with a leaflet or card containing this information and has been instructed to keep this contact in their possession at all times. ResNo945 further states that the sponsor must ensure the IP, modified active comparator drug, or placebo be coded and labeled in a manner that protects blinding, if applicable, and characterizes them as products under clinical investigation.

As explained in RegNo136 and the G-BiolProdManual, additional information, warnings, or handling instructions may also be displayed. The additional label must indicate the new expiration date and repeat the batch number. The additional label may be superimposed over the old expiration date but may not be superimposed over the original batch number for quality control reasons. This operation may only be carried out at a duly authorized manufacturing site. If duly justified, the operation may be carried out in a location authorized by the sponsor, a pharmacist, or other authorized health professional. This operation may also be carried out at the research site under the supervision of the clinical trial center pharmacist, or another health professional, in accordance with national regulations, or when this is not possible, by the clinical trial monitor(s), who must be adequately trained. Furthermore, this operation must be carried out in accordance with good manufacturing practice (GMP) principles, standard and specific operating procedures, and under contract, if applicable, and must be verified by a second person. Additional labeling must be adequately documented in the test documentation and batch records.

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 and the G-ResNo945-FAQs for additional guidance on IP labeling requirements.

Supply, Storage, and Handling Requirements

As delineated in LawNo14.874, medicines should be packaged, stored, and disposed of in accordance with the applicable regulations. As specified in ResNo945 and the G-DDCMManual, the investigational products (IPs) must be stored in a protected area, under the sponsor’s control, and may only be distributed to the locations where they will be used following the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s approval of the clinical trial applications (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions published in the Official Gazette of the Union (Diário Oficial da União (DOU)). If a company is interested in importing IP(s) prior to DDCM approval, along with the DDCM documentation, the sponsor must submit a declaration of commitment to distribute to clinical trial centers and use IPs only after authorization from the corresponding DDCM and DEEC, when import is authorized prior to publication of the approval/rejection in the DOU. The sponsor is also responsible for acquiring a sufficient quantity of the IP and other supplies to be used in the clinical trial, and may only distribute them to the institutions informed in the approved Clinical Trial Submission Form (FAEC) (BRA-22) and authorized by the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)).

Additionally, per ResNo945, the sponsor is responsible for the final disposal of medicines and products that were not used in the clinical trial. ResNo945 and the G-DDCMManual further state that in the event ANVISA rejects the DDCM and corresponding DEEC, and the IP(s) were imported prior to approval, the sponsor must submit a petition to amend the DDCM process with a document informing ANVISA of the destination or destruction of the IP(s). This document must be submitted to ANVISA within a maximum period of 60 business days from the publication of the DDCM rejection and respective DEEC and must contain information on the destination given to the IPs, including their respective quantities compatible with what was previously imported.

In addition, per ResNo945, 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 IP supply, storage, and handling requirements. See also ResNo982 for ANVISA’s risk-based approach to granting and renewing Good Distribution and/or Storage Practice certificates, which may include reliance on inspections conducted by recognized Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)).

Record Requirements

Brazil does not have country specific IP record requirements. Refer to BRA-28 for IP record requirements.

As per OrdNo2201, ResNo504, ResNo441, and the G-BiolMatTransprt, a specimen is defined as any human biological material such as organs, tissues, cells, body fluids, excreta, and other fluids of human origin obtained from a single participant at a particular time. ResNo81 further defines cells and tissues as materials of human origin used for therapeutic purposes, including skin, musculoskeletal tissues, heart valves, hematopoietic progenitor cells, germ cells and tissues and pre-embryos, corneas, and other human cells and tissues. ResNo836 adds that these biological samples are intended to be used for laboratory or quality control tests.

Additionally, per ResNo504, human biological material is classified as Category A or B infectious biological material, or Category Risk Minimum. Category A includes materials where exposure can cause permanent disability or fatal disease to humans and animals. Category B includes those materials not listed in Category A such as samples suspected or known to contain infectious agents causing diseases in humans. Category Risk Minimum or “exempt human specimens” include biological materials from healthy individuals. Human biological materials must also be classified according to the World Health Organization (WHO)’s risk classification diagram (see the Appendix in ResNo504).

The G-BiolMatTransprt also states that these materials are not considered hazardous if they are unlikely to cause disease in humans or animals. However, they are considered infectious substances, therefore dangerous materials, if through exposure to them, these substances can spread diseases.

Import/Export

As set forth in ResNo81 and ResNo172, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the import of human biological materials for clinical research purposes.

ResNo81 and ResNo172 state that the import license will be carried out through the Integrated Foreign Trade System (SISCOMEX)’s Single Foreign Trade Portal (BRA-80) and express shipping. The following documentation is required to be submitted by the investigator and institution:

• Declaration from the importer with information on the Notice number (Special Notice (Comunicado Especial (CE)), Specific Special Notice (Comunicado Especial Específico (CEE)), Document for Import of Product(s) under investigation in the Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)), or Dossier of Medical Device Clinical Investigation (DICD) issued by ANVISA
• Bill of lading cargo
• Commercial invoice
• Research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) approval

See ResNo81 and ResNo172 for additional import documentation requirements. See the Manufacturing & Import section for details on how to submit an electronic import petition via ANVISA’s Solicita Electronic Petition Request System (BRA-56).

ResNo172 further states that ANVISA will analyze and release human biological samples intended for use in clinical research within 48 hours after arrival in Brazil, provided that the legal requirements are met. Refer to ResNo81 and ResNo172 for additional required items depending on the import method used.

Other requirements described in ResNo81 and ResNo172 include, but are not limited to, compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; a mandate that the investigator or institution provide a final destination for the materials in accordance with the legal provisions of environmental control; and in ResNo172, a prohibition on imports with accompanied and unaccompanied baggage.

As explained in ResNo504 and the G-BiolMatTransprt, procedures for the import and export of human biological material should be determined by the biological material type and the mode of transport. Regardless of the material type or mode of transport, transport operations must be recorded and standardized through regularly updated written instructions. All documents and records of activities relating to human biological material transport equipment should be readily available to the health authorities, upon request. Biological material must be packed in a form that will preserve its integrity and stability, and the packaging must be validated and approved by the supervisory technician. Per ResNo504, human biological material labeling should conform to the material type, risk classification, and specific requirements of the biological materials to be transported. Labels for imported materials must be legible, understandable, and in English and Portuguese.

In addition to complying with ResNo504 and the G-BiolMatTransprt, human biological material transport should be conducted in accordance with applicable legislation issued by the Ministry of Transport (Ministério dos Transportes), the Ministry of Ports and Airports (Ministério dos Portos e Aeroportos), the National Land Transportation Agency (Agência Nacional de Transportes Terrestres (ANTT)), the National Civil Aviation Agency (Agência Nacional de Aviação Civil (Anac)), and the National Waterway Transport Agency (Agência Nacional de Transportes Aquaviários (ANTAQ)).

Refer to ResNo504 and the G-BiolMatTransprt for detailed import and export transport requirements. See also ResNo836 for transport requirements applicable to human cells and advanced therapy products, and BRA-97 for preparing reports on biobanking for research purposes.

Material Transfer Agreement

As set forth in LawNo14.874, human biological material and its associated information may be formally transferred to investigators, in accordance with the provisions of LawNo14.874 and other current regulations, through the execution of a Biological Material Transfer Agreement (Termo de Transferência de Material Biológico (TTMB)) and the presentation of proof of approval of the research project by the relevant ethical and regulatory bodies. OrdNo2201 defines a TTMB as a document duly approved by a research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and CONEP (CEP/CONEP System) when requested by an investigator in a research project submission. The investigator uses the TTMB to receive stored human biological material with its associated information, and assumes responsibility for its safekeeping and use, for guaranteeing respect for the person and confidentiality, and for providing the biobank with the information obtained in their research.

LawNo14.874 further explains that the samples and components of the human biological material and associated information that have been transferred may not be passed on to third parties by the initial recipient institution, except when a new TTMB is signed between the original sending institution and the new recipient institution. The transfer of human biological material from the sending institution to the recipient must follow current health regulations, without prejudice to specific regulations for each type of biological material and the method of transport. The sending and storage of human biological material to a research center located outside the country is the responsibility of the sponsor and is subject to the following conditions:

• Compliance with national and international health legislation on the shipment and storage of biological material
• Guarantee of access and use of biological material and its data, for scientific purposes, to researchers and national institutions
• Compliance with national legislation, especially with regard to the prohibition of patenting and commercialization of biological material

OrdNo2201 also states that the transfer of stored human biological material is formalized through a specific term of transfer of responsibility between the legal representatives of the institutions involved. LawNo14.874 specifies that human biological material and its associated information used exclusively for a specific research purpose and stored in either a biorepository or a biobank, may be formally transferred to another biorepository or biobank in accordance with current regulations. In addition, OrdNo2201 specifies the sharing of stored human biological material and associated information between biobanks of partner institutions must follow the current regulations for the transportation, processing, and the use of human biological material applicable to the specimen. Additionally, the transfer of human biological material stored in a biobank to the biobank of another institution, depends on the approval of the ECs (CEPs) of the institutions involved.

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.

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

Under the SINEP framework, in accordance with LawNo14.874, studies involving biological material of human origin must avoid discrimination and stigmatization of any person, family, or group, regardless of the benefits achieved through the research. LawNo14.874 and DecreeNo12.651 also specify that biological material and research data must be used exclusively for the purpose provided for in the respective project, except when, in the informed consent form (ICF), express authorization is granted for their use in future research, exclusively for scientific purposes, and subject to the provisions of LawNo14.874 and INAEP-issued standards. (Note: ICF is also referred to as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.)

LawNo14.874 further indicates that the research participant has the following rights which must be included in the ICF:

• To be duly informed and enlightened, in a clear and objective manner, whenever deemed pertinent, about the object and the potential benefits and risks inherent in the disposal of their biological material
• To have their health and physical and mental integrity protected during the biological material collection procedures
• To withdraw consent for the storage and use of stored human biological material at any time, in writing and signed, without charge or loss, having the right to return the samples
• To have access, at any time, without charge or prejudice, to information on the purposes of storage, including the names of the technical and institutional managers, the potential risks and benefits, the guarantees of conservation quality and the integrity of their biological material
• To have access, at any time, without charge or prejudice, to information associated with their biological material and be informed and guided by researchers responsible for findings when the implications of this information could cause harm to their health, including genetic counseling when applicable
• To have the privacy and confidentiality of their personal information guaranteed
• To be promptly informed about the dissolution of the repository in which their biological material is stored
• To be promptly informed about the transfer, loss, alteration, or disposal of their biological material
• To designate legal representatives who may consent to the use and disposal of their biological material, and to have access to such materials and their associated information in the event of death or incapacitating condition
• To be informed, at the time of signing the ICF, about the possibility of providing or not providing consent for possible future uses of their data and biological material in research
• To be informed, at the time of signing the ICF, about the possibility of authorizing or not sending their data and biological material to a research center located outside the country

LawNo14.874 also notes that consent for the disposal of human biological material and its data, in life or post mortem, must be formalized by means of an ICF, and occur in a free, altruistic, and informed manner, in accordance with the LGPD.

CEP/CONEP System (Pre-SINEP Framework)

Under the CEP/CONEP system, in accordance with OrdNo2201, ResNo441, ResNo466, and ResNo340, prior to collecting, storing, or using a research participant’s human biological material, consent must be obtained from the participant or legal representative/guardian in writing.

As delineated in OrdNo2201, ResNo441, and ResNo340, investigator(s) must also obtain EC (CEP) approval, and where applicable, CONEP approval of a new research project involving human biological materials. Per ResNo340, if it is not possible to obtain the participant’s consent, a formal justification shall be presented to the EC (CEP) for evaluation.

In addition, per ResNo441 and ResNo340, investigators should explain the possibility of using the participant’s stored genetic materials in a new research project in the ICF. In this case, the participant will be contacted for further authorization or their waiver. If it is impossible to obtain either one (1) of these documents, this fact shall be justified to the EC (CEP). The investigator(s) is also required to explain to the participant that the material will only be used upon approval of a new project by the EC (CEP) and when necessary, CONEP. OrdNo2201 further states that when it is not possible to contact the research participant, the EC (CEP) must authorize the use of the biological material stored in a biobank.

As described in ResNo340, the G-ClinProtocols-FAQs, and CLNo041, the ICF for genetic research projects must communicate the following information to the participant:

• A clear explanation of the exams and tests that will be performed to identify genes, and clarification of the genetic materials to be studied and their possible correlation with the participant’s health
• A guarantee of secrecy, privacy, and when necessary, anonymity
• The provision of free genetic advice, planning, and clinical surveillance by responsible people
• The type and degree of access to results by the participant, with the option to acknowledge this information or not
• In the case of genetic material storage, the ICF should explain the possibility of the materials being used in a new research project and that the participant will be contacted for further authorization
• Measures to be taken to protect participant data, exam, and test results, including limiting clinical report access to the involved investigators
• Measures to be taken to protect the participant from any collective discrimination and/or stigmatization
• The need for a separate ICF to be completed by each family member in the case of a family investigation. An explicit statement of the need for new consent for each study, or an explicit waiver of consent for each new study

CLNo041 further notes that for human genetics research, CONEP requires investigator(s) to be able to describe the genes studied in a grouped manner according to functionality or effect (e.g., genes related to the onset of cancer, inflammation, cell death, or response to treatment). In the case of studies involving large-scale genetic studies (e.g., complete genome or exoma sequencing), the ICF shall contain an explanation of the procedure to be performed in a language the participant can understand.

See also BRA-29 for additional information on participant rights to their genetic data.

Biobanks

As delineated in LawNo14.874, human biological material stored in a biobank or biorepository belongs to the research participant, provided that its custody is under institutional responsibility. The management of stored human biological material will be the responsibility of the institution to which it is linked, in the case of storage in a biobank; or the investigator coordinating the research, in the case of storage in a biorepository. At the end of the validity of the research project, the human biological material may remain stored, if in compliance with current and relevant legislation and ethical and regulatory standards; be transferred to another biorepository or biobank; or, be discarded. DecreeNo12.651 further notes that biobanks and biorepositories will be regulated by standards to be issued by INAEP and other competent regulatory authorities.

ResNo441 and the G-ClinProtocols-FAQs, in turn, state that the ICF for the collection, deposit, storage, and use of human biological materials in biobanks must include the following:

• A reference to the data types that may be obtained from the participant’s stored biological material for future research
• An express guarantee of the participant’s right to access the biological material information including who to contact, knowledge of the results obtained and implications of findings when the biological material is used, and the provision of genetic counseling, when applicable
• An explicit statement of the participant’s wishes regarding the cession of rights to the stored material to successors, or others appointed by him, in case of death or disabling condition
• A statement informing the participant that the biological information provided, collected, and obtained from the current research may be used in future research
• A reference to the participant’s authorization to dispose of the remainder of the material and the situations in which it is possible

As delineated in OrdNo2201 and ResNo441, the participant or legal representative/guardian may withdraw consent at any time for care and use of biological material stored in a biorepository or biobank without any negative consequences. The G-ClinProtocols-FAQs further indicates that the participant or legal representative/guardian may also withdraw consent specifically for genetic data stored in a storage bank without any negative impact. The withdrawal is valid from the date that the decision is communicated. The withdrawal must also be formalized in a document signed by the participant or legal representative/guardian. In addition, the transfer of human biological material to be stored at a biorepository or a biobank, or another institution, must be communicated to the participant. If it is not possible to communicate with the participant or legal representative/guardian, a justification must be submitted to the CEP/CONEP System, per ResNo441. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., including protocols on the constitution and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically; and CLNo26 for information on submitting research protocols involving human bodies and/or anatomical parts, and; CLNo23 for instructions on standardizing consent and electronic assent for research participants and biobanks.

Please refer to OrdNo2201, ResNo441, and the G-ClinProtocols-FAQs, for detailed requirements and issues associated with storing human biological materials in a biorepository or a biobank. See also ResNo836 for informed consent requirements pertaining to human cell collection and other procedures conducted by cell processing centers.

(See the Required Elements and Participant Rights sections for additional information on informed consent).