National Health Surveillance Agency (ANVISA)

As delineated in ResNo945 and ResNo705 (amending 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 ResNo705 (amending 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 ResNo705 and ResNo800 (amending 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 ResNo705 (amending 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 ResNo705 (amending ResNo585) for detailed information on GGMED, COPEC, and ANVISA’s organizational structure and administrative units.

Other Considerations

Per BRA-65, Brazil is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ResNo945 indicates that Brazil has formally adopted the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025).

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 Electronic Contact Form (BRA-68) may be used to submit technical questions.

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

National Institute of Health (INS)

As per Decree021-2017, Res006-2023, and the G-CTInspec, Peru’s National Institute of Health (Instituto Nacional de Salud (INS)) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections. The INS, through the Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))), grants permission for clinical trials to be conducted in Peru in accordance with Decree021-2017, Res184-2023, Decree028-2023 (which amends Decree021-2017), Res006-2023, the INS-CTManual, and Res252-2022 (which amends the INS-CTManual).

As indicated in Law27657 and Decree001-2003, the INS, a decentralized public executive agency within the Ministry of Health of Peru (Ministerio de Salud del Perú (MINSA)), was granted authority to approve clinical trials by the MINSA in 2003. Decree021-2017, Res006-2023, and the INS-CTManual explain that the DIIS carries out the INS’s mandate to authorize and supervise the conduct of clinical trials in the country to ensure the quality and integrity of the data or other elements related to the trial; to protect the rights and well-being of research subjects; to ensure the safety of the investigational products used in the trials; and to establish procedures within the framework of Decree021-2017, Res184-2023, Decree028-2023, the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (PER-53), and other applicable national and international standards and regulations. Additionally, per Res006-2023, PER-20, and PER-55, the DIIS is also responsible for regulating, promoting, developing, and disseminating research, innovation, and technology transfer; proposing policies related to regulating and standardizing clinical trials; providing technical assistance for clinical trial development; and issuing binding technical opinions and answering queries related to the promotion, management, and dissemination of health research and innovation as well as clinical trials (see PER-55 for additional DIIS responsibilities).

Res006-2023 and PER-56 further explain that the Clinical Trials Subdirectorate (Subdirección de Ensayos Clínicos) (formerly known as the Executive Office of Investigation (Oficina Ejecutiva de Investigación (OEI))), operates under the DIIS, and is responsible for formulating policies, strategies, and regulations as well as authorizing and supervising clinical trials. According to Decree001-2003, the DIIS, through the Clinical Trials Subdirectorate, also implements the INS’s objectives to promote, develop, disseminate, and manage scientific and technological research; establish administrative and technical procedures related to biomedical research; propose health research and technology transfer policies and guidelines; and provide health services to the Peruvian population. For information on DIIS’s role in clinical trial inspections, see Title XI of Decree021-2017 and the G-CTInspec. According to PER-74 and PER-68, the DIIS through its Health Research Subdirectorate (Subdirección de Investigación en Salud) is responsible for organizing and maintaining the Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2), the national registration system for clinical trials, institutional ethics committees (ECs) (los Comités Institucional de Ética en Investigación (CIEIs)), research sites, and contract research organizations (CROs). Refer to the Scope of Assessment, Submission Process, and Initiation, Agreements & Registration sections for additional information on PER-89.

National Authority for Pharmaceutical Products, Medical Devices and Medical Products (ANM)

As described in Decree016-2011, as a decentralized body of MINSA, the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM))’s fundamental objective is to ensure the Peruvian population has access to safe, effective, and quality medicines that are used rationally. Pursuant to Decree021-2017 and Decree016-2011, the ANM is responsible for issuing binding technical opinions on the safety and quality of investigational products (IPs) according to the stage and type of research; evaluating research protocols for bioequivalence studies to demonstrate interchangeability as part of the requirement for health registration in the country; authorizing, exclusively for research purposes, the import or manufacture of IPs and complementary products; and authorizing the use of an IP under post-study access conditions. Per Decree016-2011, the ANM also authorizes the importation, manufacture, and use of pharmaceutical products or medical devices without granting a sanitary registration for use in emergency or declared emergency situations. The ANM’s other responsibilities center on regulating, developing, promoting, monitoring, supervising, and evaluating the Peruvian Pharmacovigilance and Technovigilance System (Sistema Peruano de Farmacovigilancia y Tecnovigilancia). (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)).

Please note: Peru is party to the Nagoya Protocol on Access and Benefit-sharing (PER-11), 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 PER-57.

Contact Information

National Institute of Health (INS)

According to PER-63, the INS contact information is as follows:

Instituto Nacional de Salud
Sede Central
Jirón Cápac Yupanqui 1400 - Lima - Lima - Jesus Maria - Perú
Phone: (01) 748 1111
Email: comunicaciones@ins.gob.pe

According to PER-13, the INS’ DIIS contact information is as follows:

Instituto Nacional de Salud
Dirección de Investigación e Innovación en Salud 
Sede Chorrillos
Av. Defensores del Morro 2268 (Ex Huaylas) - Chorrillos
Lima 9
Perú

According to PER-58, the INS and DIIS phone numbers and email addresses are as follows:

DIIS Phone: 511 748 1111 (Ext. 2191)
DIIS Email: consultaensayos@ins.gob.pe

INS General Phone: (511) 748 1111
INS Email: webmaster@ins.gob.pe

National Authority for Pharmaceutical Products, Medical Devices and Medical Products (ANM)

PER-109 indicates the ANM’s contact information is as follows:

DIGEMID
Av. Parque de las Leyendas 240
San Miguel
Perú

Phone: 1-631-4300 Extension: 6700, 6705, and 6501
Email: atenciontramite@minsa.gob.pe

Overview

As set forth in ResNo945 and ResNo705 (amending 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 the specific standards of the National Research Ethics Authority.

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

Clinical Trial Review Process

As described in ResNo705 (amending 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, except in cases of 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. See the Timeline of Review section for ANVISA’s petition review timelines. See also BRA-40 for information on ANVISA drug registration requirements.

Pursuant to ResNo945, substantial modifications to the investigational product (IP) refer to changes that potentially have an impact on the quality or safety of the experimental drug, active comparator, or placebo. Per ResNo945 and the G-DDCMManual, substantial IP modifications and substantial protocol amendments 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 normative act regarding IP modifications considered to be substantial and non-substantial. See also the G-DDCMAmdmts for clarifying information on substantial and non-substantial protocol modifications. Refer to the Submission Process and Submission Content sections for IP modification submission process and documentation requirements.

Regarding substantial amendments to the clinical trial protocol, ResNo945 explains that an amendment should be considered substantial when it meets at least one (1) of the following criteria:

• Changes to the clinical trial protocol 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 data produced in the clinical trial

Per ResNo945 and the G-DDCMManual, substantial protocol amendments must also be linked as secondary petitions 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. ANVISA will issue a supplementary normative 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 the approval of DDCM, DEEC, and secondary petitions filed with ANVISA prior to the publication of ResNo945 that are 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 discussed below in this section.

Pursuant to ResNo945, the DDCM or any linked clinical trial or related secondary petitions may at, any time, be cancelled or suspended when ANVISA:

• Deems that the approval conditions have not been met, or if there are reports of safety, quality, or efficacy that significantly affect the trial participants or affect the reliability or robustness of the data obtained in the clinical trial
• Participants are being exposed to significant and unreasonable risks
• The sponsor violates the rules described in ResNo945 or fails to comply with the GCP principles and good manufacturing practice (GMP) requirements of the IP

In order to comply with these provisions, per ResNo945, ANVISA will notify the sponsor about the suspension or cancellation of DDCM or clinical trial and will open an administrative and/or investigative process, in accordance with current legislation, when applicable.

Inspection

In accordance with LawNo14.874, ANVISA is authorized to carry out good clinical practice (GCP) inspections of clinical research centers, sponsors, and contract research organizations (CROs) (clinical research representative organization (CRPO) in Brazil). ResNo945 further specifies that ANVISA may carry out GCP inspections of clinical trial centers, sponsors, CROs, laboratories, and other institutions involved in the development of the IP to verify the degree of adherence to current Brazilian legislation and compliance with GCP, in addition to ensuring the rights and duties that concern the scientific community and Brazil. In addition to specific GCP inspection standards issued by ANVISA, GCP inspections will follow the harmonized guidelines of the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates which Brazil has formally adopted. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025). 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 requires all clinical trial inspections to be conducted in accordance with BRA-28. GuideNo35-2020 and GuideNo36-2020 further explain that GCP inspections of sponsors and CRO representatives and in clinical trial centers may be carried out before, during, or after a clinical trial has been conducted and will be classified as either a routine inspection or complaint/suspected irregularity, per RegNo122. In addition, per GuideNo35-2020 and GuideNo36-2020, the inspections will involve at least two (2) ANVISA inspectors, one (1) of whom will be the lead inspector and the focal point for communication with either the clinical trial center or the sponsor/CRO(s). The inspections for both entities will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.

Priority Submissions

In addition to the previously stated DDCM requirements, ResNo204 establishes a priority category to register, amend previously registered, or request prior approval for drug submissions. ResNo204 states that the priority submission may be submitted as a DDCM or a DEEC. A priority DDCM submission is required to meet one (1) or more of the following criteria: new drug trial in any phase to be carried out in Brazil, the drug is part of the Ministry of Health (MOH)’s National Immunization Program, or the product is determined to be of strategic public health interest and included under the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53). A priority DEEC submission is required to comply with the following: the drug will be used for neglected, emerging, or reemerging diseases, health emergencies, or serious debilitating conditions for which there is no alternative; the trial will be conducted exclusively with the pediatric population; or the drug will be used in a Phase I trial only to be manufactured in Brazil. The sponsor should specify at the time of submission that the new or amended protocol is a priority category request. If not confirmed prior to the technical review phase, the request for approval may be denied. ANVISA is required to first issue a written opinion letter within 45 calendar days from the first business day following protocol submission, a final opinion in 120 days for new drug registration requests, and a final opinion 60 days for post-registration petitions. See the Timeline of Review section for detailed timeline information. Refer to ResNo204, ResNo811 (which partially amends ResNo204), and BRA-14 for detailed information on priority submission requirements. See also BRA-82 for additional information on priority submissions.

New Drugs for Rare Diseases Submissions

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

In addition, per ResNo763, which modifies ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, and if the sponsor deems it necessary, then ANVISA will hold the meeting within 60 days following this request. Refer to ResNo205 and ResNo811 (which partially amends ResNo205) for additional submission documentation requirements.

Optimized Analysis Procedure Reviews

As delineated in ResNo945 and ResNo741, ANVISA has adopted a technical evaluation mechanism known as the “optimized analysis procedure” which uses the technical analysis or supporting documentation issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) as a sole or complementary reference, for its decisions. AREEs have regulatory practices aligned with those of ANVISA and are therefore considered to be in a practice of regulatory trust (referred to as Reliance). ANVISA designates a specific list of approved AREEs for each type of authorization request (see below for the AREE lists based on request type).

ResNo741 provides general criteria for the admissibility of the AREE regulatory documentation, which includes reports, opinions, or technical/legal documents, used to issue an opinion. Among other requirements, in order for ANVISA to adopt the optimized analysis procedure, the health surveillance process covered in the AREE’s documentation must meet all the requirements, criteria, and specifications established by ANVISA for the corresponding health surveillance process. ResNo945 also explains that the documents required for the instruction of each type of petition or process submitted, may be partially or fully exempted from technical analysis using 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 based on Reliance.

Drug & Biological Product Registration/Post-Registration

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

Pursuant to RegNo289, ANVISA has designated the following foreign agencies as AREEs to review registration and post-registration authorization requests of medicines, vaccines, biological products and their active substances:

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

Refer to RegNo289 for detailed requirements on submitting a request for ANVISA authorization via the optimized analysis procedure. See ResNo741 for additional information on the optimized analysis procedure and AREE related requirements. See also the Manufacturing & Import section for AREE manufacturing and inspection criteria and procedures and Good Manufacturing Practices Certification via the optimized analysis procedure as delineated in RegNo292.

DDCMs, DEECs, Substantial IP Modifications & Substantial Protocol Amendments by Reliance

As per ResNo945, RegNo338, and BRA-122, the optimized analysis procedure based on Reliance is also applicable to primary DDCM and DEEC petitions, and secondary petitions for substantial modifications to the IP and substantial amendments to the clinical trial protocol. 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:

• EMA and its member countries
• Health Canada
• Swissmedic
• MHRA
• 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 and RegNo345 (amending RegNo338) following its evaluation, 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 does not comply with the criteria for applying the optimized analysis procedure by Reliance, 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 by 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 ResNo204 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 details.

DDCM & IP Substantial Modifications by Risk Assessment

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 process may be partially or fully exempted from technical analysis, through the optimized analysis procedure, according to the 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, and/or the active comparator is identical to the registered drug, ANVISA’s evaluation of the documents present in the IMPD or DPI may also be analyzed by the optimized procedure by 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.

Overview

In accordance with the provisions delineated in Decree021-2017, the INS-CTManual, and Res252-2022 (which amends the INS-CTManual), Peru’s National Institute of Health (Instituto Nacional de Salud (INS)) is responsible for reviewing and approving clinical trial applications using registered or unregistered investigational drug products. As per Decree021-2017, the scope of the INS’s assessment includes Phases I through IV clinical trials for pharmaceuticals including medicines, herbal medicines and other complementary products, dietetic products and sweeteners, biological products, and compounded (galenic) products. As specified in Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, Res252-2022, and PER-61, the INS’s review and approval of a clinical trial application is dependent upon obtaining proof of approval from an accredited ethics committee (EC). Therefore, the INS and EC reviews may not be conducted in parallel.

Per the INS-CTManual and Res252-2022, EC approval of the research protocol and the informed consent form (ICF) must be submitted as part of the clinical trial application dossier in order for the INS to conduct its review. PER-83 further specifies that the sponsor or the contract research organization (CRO) must provide a copy of the research protocol and ICF that is stamped and signed by the EC in its entirety as evidence that the approved version is being presented. Refer to the INS-CTManual and Res252-2022 for additional submission information. Per Res0423-2019, the application for clinical trial authorization and corresponding instructions are in PER-24 and PER-10, respectively.

In addition, per Decree021-2017, the sponsor must also ensure authorization by the research institution where the clinical trial will be carried out.

Decree021-2017 states that the investigational product (IP) must meet at least one (1) of the following conditions to be authorized for use in clinical trials in Peru:

• Must be approved for use in humans by drug regulatory authorities of countries with high health surveillance

• Is produced in Peru, is used in preclinical research, and complies with Ministry of Health of Peru (Ministerio de Salud del Perú (MINSA))’s political and/or research priorities

• Will serve to establish pharmaceutical therapeutic equivalence

• Is considered a priority for the country’s public health or is within the scope of MINSA policies and/or research priorities
• At the request of the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)), requires a clinical trial to support its efficacy and safety for the health registry

Per Decree016-2011, the following are considered to be countries with high health surveillance: France, Holland, United Kingdom, United States, Canada, Japan, Switzerland, Germany, Spain, Australia, Denmark, Italy, Norway, Belgium, and Sweden.

Clinical Trial Review Process

In accordance with Decree021-2017, Res184-2023, Decree028-2023 (which amends Decree021-2017), the INS-CTManual, and Res252-2022, the INS’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))), is responsible for conducting the review and approval of clinical trial applications. As per Decree021-2017 and Res252-2022, the INS also requests that the ANM assess the safety and quality of the IP to be used in a clinical trial and issue a binding technical opinion as part of the INS’s application review and approval process. Following a review of the research protocol, the ANM technical opinion, and other required documentation included in the application package, the INS will approve the clinical trial. (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)).

Decree021-2017, the INS-CTManual, and Res252-2022 also note that the Clinical Trials Subdirectorate will be able to convene a technical commission of experts when controversial situations arise during the authorization process.

In addition, per Decree021-2017, the INS-CTManual, and Res252-2022, if the clinical trial is related to an IP for the prevention, diagnosis, or treatment of tuberculosis or HIV/AIDS infection, the specific technical opinion of the MINSA’s General Directorate of Strategic Interventions in Public Health (Dirección General de Intervenciones Estratégicas en Salud Pública (DGIESP)) will be requested to ensure the study does not interfere with its strategic interventions regarding these diseases.

Decree021-2017 and the INS-CTManual state that the INS’s DIIS grants clinical trial authorization for the total period of time scheduled for its completion as indicated in the PER-89 registration form submission. Further, per Decree021-2017, once the INS has completed the authorization process, the agency will post the approval status of a clinical trial via PER-89. The following application requirements, which align with the World Health Organization’s Trial Registration Data Set (PER-86), will also be provided in the approval status record: study title, sponsor and investigators, IP, condition under study, study design, and number of participants. See PER-111 for additional information on REPEC’s trial data record requirements. Refer to the INS-CTManual and Res252-2022 for details on the DIIS application review process, and PER-6 for a flowchart delineating the clinical trial authorization process.

See the Submission Process, Submission Content, and Timeline of Review sections for detailed submission and review requirements.

Per Decree021-2017, any modifications of the conditions under which a clinical trial was authorized, and amendments to the research protocol and/or informed consent, require prior authorization from the INS’s DIIS. The following are grounds for modification of clinical trial authorization conditions:

• Expansion of the number of research sites
• Expansion or modification of the list of supplies to be imported
• Change of sponsor or CRO
• Change of principal investigator (PI)
• Extension of time for conducting the clinical trial
• Closure of a research site for a clinical trial
• Suspension of clinical trial
• Cancellation of clinical trial

Decree028-2023 and Res184-2023 further modify Decree021-2017 to distinguish between amendments and minor changes to the protocol and/or ICF. The updated definition of amendment specifies that an amendment refers to a substantial change(s) that modifies the original version of the protocol and/or ICF and requires INS and EC reauthorization. A minor change(s) is defined as one proposed by the sponsor that complies with Decree028-2023 and the DIIS issued standards delineated in Res184-2023, and the responsibility for executing the protocol remains with the sponsor. Per Decree028-2023, a minor change(s) only requires the approval of the INS registered and accredited EC that originally approved the current version, and the sponsor must communicate the change(s) in writing to the INS’s DIIS prior to its implementation.

Res184-2023 states that changes or modifications must meet certain criteria to be considered minor changes. For changes that are not considered minor, it is necessary to initiate the corresponding amendment procedure delineated in Decree021-2017. Moreover, any new safety information derived from the Investigator’s Brochure is not considered a minor change. See the Scope of Review section and Res184-2023 for detailed descriptions of minor changes to the protocol and/or ICF that do not require DIIS approval.

See also the Submission Process section for additional information on trial extension documentation and review requirements.

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 (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). As per ResNo857 and BRA-47, once the sponsor has completed the process of submitting a 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).

National Institute of Health (INS)

Per Decree021-2017, the sponsor or the contract research organization (CRO) is responsible for paying a fee, as applicable, to the National Institute of Health (Instituto Nacional de Salud (INS)) to submit a clinical trial application for authorization. Additionally, per Decree021-2017, INS payment is required to modify the trial as follows: to increase the number of research sites participating in a study; to change the sponsor or the CRO under contract; to change the principal investigator; to request a time extension for the trial; to request authorization to change the trial name; or to request authorization to amend a report. Per Res0423-2019, the forms required to modify the trial may be obtained from PER-26, PER-27, PER-28, PER-43, and PER-31.

According to PER-77, the INS is revising the clinical trial application fees but in the meantime is charging the fees outlined in PER-97 and PER-112, which state that the processing fee for a clinical trial authorization is 1,775.00 Peruvian Soles. An email may be sent to consultaensayos@ins.gob.pe for any additional fee-related questions.

Pursuant to Res655-2019, which amends Decree021-2017, in the case of multicenter clinical trials, the sponsor or the CRO must submit a clinical trial application along with proof of payment information for the processing fee rather than requiring each of the participating research sites in Peru to submit their payment separately, as originally required.

Payment Instructions

As indicated in PER-112, the clinical trial application fee can be paid as follows:

• Via transfer to the beneficiary account number (Código de Cuenta Interbancario (CCI)): INS 018-00000000028241304 Banco de la Nación
• CURRENT ACCOUNT. 0000-282413 in the name of the INS of the Banco de la Nación
• In person in the form of cash or by cashier's check

For any additional questions, send an email to Ms. Ana Rojas of the Economics Office of the National Institute of Health at arojas@ins.gob.pe.

See PER-71 for payment receipt requirements to request authorization of a clinical trial via the Virtual Submission Platform (Mesa de Partes Virtual (MPV)) (PER-106). See PER-72 for a list of trial procedures and associated payment receipt requirements, if applicable. Refer to the Submission Process section for additional information on application submission requirements.

Overview

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos). The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) which must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

CEP/CONEP System

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 National Health Council (Conselho Nacional de Saúde (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 participants 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 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)

National Research Ethics Authority

LawNo14.874 specifies that the EC (CEP) should be composed of a collegiate, interdisciplinary team in the medical, scientific, and non-scientific areas, to ensure that the members 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)).

National Research Ethics Commission (CONEP)

As per OMREC, the EC (CEP) is required to be composed of a minimum of seven (7) members having proven expertise in research. ResNo706, in turn, states the EC (CEP) must be composed of at least nine (9) members with at least two (2) 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 is 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 Research Ethics Authority

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

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

As described in LawNo14.874, the deliberation on the ethical adequacy of the research will take place in a previously scheduled meeting, which must have a minimum quorum, as defined in the EC’s (CEP's) internal regulations. Only active EC (CEP) members are permitted to issue opinions and deliberate on the ethical adequacy of submitted research. EC (CEP) members may invite external experts and representatives of vulnerable groups to give their opinion on specific issues related to research projects, but they will not have the right to vote. Once duly accredited or certified, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP.

In addition, LawNo14.874 explains that depending on the degree of risk involved in the research, the role of the research ethics review body will be exercised by one (1) of the following:

• An EC (CEP) accredited or certified by the National Research Ethics Authority, in the case of low or moderate risk research
• An EC (CEP) accredited by the National Research Ethics Authority, in the case of high-risk research

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. Once duly accredited or certified, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP. The EC (CEP) 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. 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’s (CEP)’s activities are subject to inspection and monitoring by the National Research Ethics Authority. Failure by the EC (CEP) to comply with the provisions of LawNo14.874 will result in its de-accreditation by the National Research Ethics Authority, in accordance with regulations.

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

National Research Ethics Commission (CONEP)

As set forth in OMREC, 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’s (CEP’s) SOPs. As per ResNo706, the term of office of EC (CEP) members is valid for four (4) years, with the possibility of reappointment, at the discretion of the CEP. At the end of the term of office, an EC (CEP) member may remain in this role up to 90 days, until a replacement or reappointment takes place.

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

Overview

As set forth in Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, and Res252-2022 (which amends the INS-CTManual), and PER-71, Peru requires clinical trial approval from an institutional ethics committee (EC) (El Comité Institucional de Ética en Investigación (CIEI)) that is accredited by the National Institute of Health (Instituto Nacional de Salud (INS))’s National Registry of Accredited Institutional Ethics Committees (PER-61). There are no stated requirements regarding which EC the sponsor should choose to conduct the clinical protocol review. In addition, as noted in Decree021-2017, those research institutions that do not have their own EC may select an INS-accredited EC, preferably located in the same region.

Ethics Committees for Human Subjects Health Research Other than Clinical Trials

Res233-2020, which regulates human subjects research other than clinical trials of drugs or devices, states that health institutions or entities may establish one (1) or more ECs in order to fulfill their requirements to conduct health research with human beings. Per Res233-2020, ECs that conduct health research with humans are established by statute, resolution, or other document that establishes, as a minimum, among others, the committee’s mission, its members, and their respective positions. An EC may be constituted within a public, private, or mixed health institution that provides health services and is registered with the National Registry of Institutions that Provide Health Services (Registro Nacional de Instituciones Prestadoras de Servicios de Salud (RENIPRESS)). An EC may also be an entity within the Ministry of Health of Peru (Ministerio de Salud del Perú (MINSA)), one (1) of the Peruvian universities, or a non-profit legal organization. If the entities or institutions do not have an EC, they may select another INS-registered EC to evaluate their investigations. This arrangement may occur following a written agreement between the authorities of the entities or institutions involved and the respective EC. See the Oversight of Ethics Committees section for information on registering a health service provider institution in RENIPRESS.

Institutional Research Ethics Committee of the National Institute of Health (CIEI-INS)

As described in PER-94, Peru’s Institutional Research Ethics Committee of the National Institute of Health (El Comité Institucional de Ética en Investigación del Instituto Nacional de Salud (CIEI-INS)) is an advisory committee that aims to protect the rights, life, health, privacy, dignity, and well-being of research participant(s) while adhering to the ethical principles accepted by national and international regulations, and the agreements signed by Peru on research ethics. According to PER-77, the CIEI-INS is not accredited to approve clinical trials. It approves research with human participants conducted with the involvement of the INS except for clinical trials with drugs or devices. (See PER-102 for a list of accredited ECs.)

Ethics Committee Composition

As delineated in Decree021-2017, institutional ECs must be multidisciplinary, with the participation of civil society, and be composed of at least five (5) regular members, who must ensure independence in their decision-making process.

Decree021-2017 lists the following membership requirements:

• Persons with scientific expertise in the health field, including those with expertise in behavioral or social sciences
• Persons with expertise in ethical matters
• Persons with expertise in legal matters
• Community representatives, whose primary function is to share their views on the communities where research participants are likely to come
• At least one (1) full member must be from the community and not belong to the health field, or to the research institution

In addition, Decree021-2017 specifies that all members must have at least one (1) certificate of basic training in research ethics and one (1) of its members must have training in bioethics. Per Decree021-2017, the EC may consider the assistance of expert consultants on different topics, and the committee must also make the list of all members publicly accessible.

Ethics Committees for Human Subjects Health Research Other than Clinical Trials

As indicated in Res233-2020, ECs are multidisciplinary, reflecting the country’s social and cultural diversity, and must be comprised of at least five (5) members.

Res233-2020 lists the following membership requirements:

• Persons with knowledge in research methodology and knowledge in the health field as well as in behavioral or social sciences
• Persons with knowledge of legal and ethical matters
• Community representatives; people outside the entities and institutions that comprise the ECs should also be included

In addition, Res233-2020 states that researchers must possess the relevant qualifications to carry out the investigation proposal, including basic training in ethics of research with human beings with the corresponding diplomas, certifications, titles, among others. Res233-2020 further indicates that the authorities, managers, or the main persons in charge of the entities and institutions that constitute the ECs cannot be members or preside over the members; the list of all members must be publicly accessible.

Terms of Reference, Review Procedures, and Meeting Schedule

Pursuant to Decree021-2017, for their operations, ECs must have stated rules and prepare a procedures manual that is approved by the research institution. Per Decree021-2017, the manual must provide rules and procedures for the following:

• Composition and requirements that must be met by its members
• Minimum EC infrastructure requirements (e.g., specific areas that allow for work performance under conditions that guarantee confidentiality; adequate computer equipment; and administrative personnel to allow an EC to function properly)
• Meeting frequency
• Specific quorum requirements
• Administrative requirements for the presentation of files
• Monitoring authorized research protocols
• Preparing and approving meeting minutes
• Filing related documentation
• Obtaining specialist(s) advice on diseases or methodologies outside the EC’s expertise
• Ensuring alternate committee members have been selected
• Replacing a member with a conflict of interest
• Renewal procedures

See Title IV, Chapter 7 of Decree021-2017 for detailed EC requirements.

Decree021-2017 and PER-21 further note that minimum infrastructure requirements for the operation of institutional ECs must include ensuring specific work environments that permit their work to be conducted under conditions that guarantee confidentiality, and computer equipment with sufficient capacity to handle all the information generated by the EC.

Ethics Committees Human Subjects Health Research Other than Clinical Trials

As delineated in Res233-2020, ECs must have regulations and a procedures manual approved by the entity or institution that created them, specifying procedures, internal regulations, and other operational requirements.

Res233-2020 specifies that the procedures manual must include the following:

• Conditions and terms for the appointment of members
• Committee structure
• Member responsibilities
• Submitting research projects for review
• Assessing the types of review
• Classifying adopted decisions and processes to communicate these decisions
• Developing the mechanism for determining whether a research project requires ethical review or should be exempt
• Procedures for monitoring and surveillance of investigations, from the moment approved until terminated (including presenting amendments, deviations, adverse events, etc.)
• Specifying required procedures and criteria for submitting expedited reviews
• Reviewing projects based on ethical criteria (i.e., scientific validity and social value of the research, favorable benefit/risk balance ratio, equitable research participant selection, adequate informed consent process, respect for people, community participation and commitment)
• Independent deliberation by members (i.e., EC members, researchers, sponsors, or other agents related to the research project under review should not be present)
• Adopting research projects by consensus or by vote, and always with the participation of at least one (1) community representative and/or a member external to the entity or institution that constituted the EC
• Requesting external assistance from independent consultants when necessary, taking into account the specialty or complexity of research under review

See Chapter 7 of Res233-2020 for detailed EC requirements.

Res233-2020 further notes that the entities and institutions that constitute the ECs must provide all of the economic, human, logistical, infrastructure, or the availability of other resources necessary for its operation.

Overview

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos). The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available.) See also BRA-117 for additional information.

National Research Ethics Authority

According to LawNo14.874, the primary scope of information reviewed by ECs (CEPs) relates to protecting the dignity, safety, and well-being of research participants throughout the conduct of a clinical trial. The ECs (CEPs) are responsible for acting independently and autonomously before and during the trial through their analysis, review, and ethical approval of research protocols and their amendments, as well as through their evaluation of the methods and materials used to obtain and document the free and informed consent of research participants.

As part of their ethical review and analysis, LawNo14.874 indicates that the ECs (CEPs) are also responsible for requesting the provision of additional information to research participants when deemed essential to protect their rights, safety, and well-being; ensuring the research project and other documents adequately address relevant ethical issues and satisfy applicable regulatory requirements, including those related to good clinical practice (GCP); and, ensuring adequate means are provided for obtaining consent from the research participant or the legal representative, among others. The ECs (CEPs) must also pay special attention to protecting the welfare of participants deemed to be vulnerable (See the Vulnerable Populations and Pregnant Women, Fetuses & Neonates sections for additional information about these populations).

As part of the National System of Ethics in Research with Human Beings, per LawNo14.874, the ECs (CEPs) are guided by the following principles:

• Protection of the dignity, safety, and well-being of the research participant
• Encouragement of technical and scientific development
• Independence, transparency, and publicity
• Equality in the application of criteria and procedures for analyzing research projects, according to the risk-benefit relationship inferred from their protocols
• Efficiency and agility in the analysis and issuing of opinions
• Multidisciplinary focus
• Social control, with the participation of research participant representative(s)
• Respect for GCP

National Research Ethics Commission (CONEP)

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 a clinical trial.

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

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

CONEP-Designated Protocol Reviews

Per ResNo580, the Ministry of Health (MOH)’s Secretary of Science, Technology and Strategic Inputs refers protocols to CONEP that are determined to be of strategic public health interest for the Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53). ResNo580 recognizes strategic research protocols as those studies that may contribute to public health, justice, reduction of social inequalities and technological dependencies, and those that address public health emergencies. Refer to the Oversight of Ethics Committees section for additional information on CONEP’s review requirements for this type of protocol. A working group was also created to support the MOH’s assessment of research involving human beings when carried out in the SUS sphere, per OrdNo552. The interagency working group includes National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), CONEP, and the National Health Council (Conselho Nacional de Saúde (CNS)), and is coordinated by an MOH representative.

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

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

EC analysis varies according to the type of research and modulation factors (i.e., consent process, confidentiality, and/or research methods), and requires the reviewer to verify the documentation the investigator submits in Plataforma Brasil (BRA-34). Per BRA-93, Plataforma Brasil is a national and unified database of human subjects research records that represents the entire CEP/CONEP System. The platform is also used to track research applications from submission to final approval by the EC (CEP), and when necessary, by CONEP. See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.

There are four (4) ways of processing protocols in the CEP/CONEP System: express, simplified, collegiate, and special collegiate; the modulation factors per Annex II of ResNo674 provides additional characteristics to further modify the protocol processing method to be used. See ResNo674 and BRA-4 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures. (Note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor Plataforma Brasil (BRA-34) for any developments.)

Role in Clinical Trial Approval Process

National Research Ethics Authority

As delineated in ResNo945, ANVISA and the EC (CEP) must approve a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) before a trial is permitted to commence. Research involving human beings must be subject to prior ethical analysis by ECs (CEPs) according to National Research Ethics Authority legislation and regulations. Clinical trial applications can be submitted in parallel, however, a drug clinical trial may only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

In addition, as indicated in ResNo945, the EC (CEP) must 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.

As stated in LawNo14.874, the EC (CEP) research ethics analysis process will be instructed with the information and documents established in specific regulations. All documents requested by the EC (CEP) must be provided for in an act of the MOH, in a regulation, or in the rules of the EC (CEP) itself and be relevant to the matter analyzed.

Per LawNo14.874, the EC (CEP) will issue an opinion following acceptance or denial of the all the submitted research documents. Before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor, or request that adjustments be made to the research documentation. The EC’s (CEP’s) review will be suspended during this time, and the investigator will be given time to meet the EC’s (CEP’s) demands. However, the EC (CEP) study analysis process may be canceled in case of non-compliance with the deadline. At the discretion of the EC (CEP), the investigator may participate in the collegiate meeting to provide clarifications about the research, but the investigator is prohibited from attending the meeting while the final decision is being made. Upon completion of its review, 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 decision contained in the EC’s (CEP's) opinion may be initially appealed to the EC (CEP) that issued the opinion and, subsequently, the opinion may be appealed one (1) final time to the National Research Ethics Authority. All those involved in conducting, monitoring, evaluating, or approving the research who have direct access to its records, to verify compliance with the procedures and applicable legislation and the validity or integrity of the data, must ensure the preservation of the confidentiality of the data and the anonymity of the research participant, in accordance with current legislation.

After the start of the research, per LawNo14.874, if there is a need for a change that interferes with the risk-benefit relationship or the approved documentation, the coordinating investigator will submit, in writing, an amendment to the research project, duly justified, for analysis and opinion by the EC (CEP) that analyzed the research. 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.

LawNo14.874 also notes that the ethical analysis of research involving more than one (1) research center in the country will be carried out by a single EC (CEP), preferably the one linked to the research coordinating center, which will issue the opinion and notify the ECs (CEPs) of the other participating centers of its decision. Additionally, 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 given priority in ethical analysis and will be subject to special analysis procedures, including deadlines. See the Timeline of Review section for detailed timeline information.

In addition, research conducted with human beings that does not comply with the provisions of LawNo14.874 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 CRO is affiliated, without prejudice to applicable civil and criminal sanctions. For the purposes of applying the disciplinary sanctions, the EC (CEP) or the National Research Ethics Authority 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.

National Research Ethics Commission (CONEP)

As per ResNo466 and OSNo001, ANVISA and the EC (CEP) (and CONEP, if applicable) must approve a clinical trial application before a trial is permitted to commence. Per OSNo001, the EC (CEP) must also review and approve any protocol amendments prior to those changes being 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 the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via BRA-34. CLNo24 and CLNo24-Note for CONEP’s general guidelines for investigators and ECs (CEPs) on conducting clinical trials.

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. In this case, the EC (CEP) will analyze the IB together with the other documents pertaining to the amendment, and, if necessary, the required amendments and/or clarifications will be requested.

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 to CONEP itself. From an analysis of the resources submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal, the processing of the appeal is terminated, the research protocol is archived, and no other appeal requests will be permitted. 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.

Foreign Research

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

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

Multicenter Research

Per ResNo346, for multicenter research protocols, the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. Per OSNo001, the principal investigator is also required to submit a list of the participating institutions and associated protocols, the coordinating center, and the EC (CEP) designated to monitor the study’s progress as part of the research protocol package sent to the EC (CEP) for review. ResNo346 further notes that CONEP will only evaluate the first protocol submitted and then send its final opinion to the original EC (CEP) and the other participating institutions. ResNo674 similarly explains that the initial analysis of the research protocol using the research classification procedure will occur at the EC (CEP) of the coordinating center or the accredited EC (CEP), when applicable, and will be subsequently forwarded for analysis by the EC (CEP) of the other co-participating centers and/or institutions, after approval.

See ResNo346 for additional multicenter protocol processing information.

Exemption from Review

Pursuant to Article 26 of ResNo674, CLNo12 provides further guidance on research that is exempt from ethical assessment by the CEP/CONEP system. Research that is exempt includes protocols that fall exclusively into the following categories: public opinion surveys with unidentifiable participants; research that uses publicly accessible information; research that uses public domain information; census research carried out by government agencies; research carried out exclusively with information or data already available in aggregate form, without the possibility of individual identification; research carried out exclusively with scientific texts to review the scientific literature; research that aims at the theoretical deepening of situations that emerge spontaneously and contingently in professional practice, as long as it does not reveal data that can identify the individuals; activity carried out with the sole purpose of education, teaching, extension or training, without the purpose of scientific research, of undergraduate students, technical course, or professionals in specialization; market research; scientific research carried out with cells, tissues, organs, and organisms of nonhuman origin, including their biological products, provided there is no interaction with research participants or imply the collection or use of human biological material to obtain them; and, activity whose purpose is to describe or analyze the productive or administrative process exclusively for organizational development purposes.

Overview

According to Decree021-2017 and the G-EC-CTRev, the primary scope of information assessed by institutional ethics committees (ECs) (Comités Institucional de Ética en Investigación (CIEIs)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. The EC scope also aligns with the principles delineated in the PeruConstitution and Decree011-2011, which assert that the defense of the human person and respect for their dignity are the supreme goal of society and the state.

As per Decree021-2017, Decree011-2011, and the G-EC-CTRev, ECs must also pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable. Per Decree021-2017, when a clinical trial is proposed for subordinate groups (e.g., students, health workers, employees, military members, police, prisoners, etc.), one (1) or more members of the population under study, or another person within this community capable of guarding the conditions and human rights that correspond to the group in question, should participate in the EC review. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these populations).

Decree021-2017 and the G-EC-CTRev also state that the National Institute of Health (Instituto Nacional de Salud (INS))-registered and accredited ECs are responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must act in the interests of the potential research participants and the communities involved by 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.

Res686-2020, in turn, states that in the ethical review of clinical studies of vaccines in humans, ECs must comply with the ethical criteria delineated in Res233-2020. Additionally, in all deliberations, ECs must ensure the following ethical criteria are present: social value and scientific validity of the research; favorable benefit/risk balance and risk minimization; fair selection of research subjects; informed consent process; respect for people; and community participation and commitment. Therefore, per Res686-2020, an EC decision regarding the approval or disapproval of a vaccine clinical study protocol must have a solid and justified ethical basis in the Council for International Organizations of Medical Sciences (CIOMS) criteria (PER-78).

Ethics Committees for Human Subjects Health Research Other than Clinical Trials

Res233-2020, which regulates human subjects research other than clinical trials of drugs or devices, similarly states that the focus of ECs that conduct human health research is to ensure the protection of the rights, safety, and well-being of the research participants. In addition, the INS must ensure the governance of all health research involving human beings is conducted ethically; the scientific validity and social value of the research is considered by the research studies; the equitable selection of research participants; the adequacy of the informed consent process; respect for the participants; and the participation and commitment of the communities. Res233-2020 further specifies that human studies include, but are not limited to, epidemiological research, genetic research, social science research, research on medical records, and research on stored samples, among others.

Per Res233-2020, the ECs are also responsible for conducting rigorous, timely, and competent ethical reviews of research projects based on the CIOMS' International Guidelines for Health-Related Research Involving Humans (PER-78). Furthermore, the ECs should monitor the progress of an approved research project until it has concluded.

Additionally, per Res233-2020, the research entities or institutions that constitute ECs conducting human health research must have policies of scientific integrity in accordance with international standards on the matter and the National Code of Scientific Integrity (PER-79), which includes appropriate investigation and sanction procedures.

Role in Clinical Trial Approval Process

As per Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, Res252-2022 (which amends the INS-CTManual), and the G-EC-CTRev, an INS-accredited EC must provide written confirmation of review and approval of the clinical trial protocol and the informed consent form (ICF) prior to the sponsor or the contract research organization (CRO) submitting the clinical trial application to the INS. Therefore, the INS and EC reviews may not be conducted in parallel.

According to Decree021-2017, each institutional EC determines its own review and approval timeline and continuing review requirements based on its internal regulations and standard operating procedures.

Per Decree028-2023 (which amends Decree021-2017), a minor change(s) to the protocol and/or ICF only requires the approval of the INS registered and accredited EC that originally approved the current version, and the sponsor must communicate the change(s) in writing to the INS’s DIIS prior to its implementation. Decree028-2023 and Res184-2023 (which amends Decree021-2017) also note that a minor change does not generate a new version of the protocol or ICF; however, if a subsequent amendment is made to the protocol, it must also contain the minor change(s) made. (See Timeline of Review section for timeline information on submitting minor changes to the INS’s DIIS.)

Res184-2023 specifically lists the following as minor changes to the protocol and/or ICF:

• Typographical error corrections - A material unintentional error in a word, term, or expression that results from the writing, transcription, or translation of a specific expression that does not alter the meaning, objective, or intent of the word, term, or expression.
• Modification of the conditions of clinical trial authorization or amendments - Updates made to the approved protocol and/or ICF, as a result of procedures for clinical trial modifications or amendments, linked to the change of protocol title, and/or name of the principal investigator, sponsor, and/or CRO; and/or study completion date, provided that the change is previously authorized by Director's Resolution or Official Letter issued by the INS's DIIS, as a result of the corresponding administrative procedure.
• Clarifications and/or modifications of an administrative or operational aspect - Changes made to the approved protocol and/or ICF for strictly administrative or operational reasons. In addition, a clarification refers to a clarification of the protocol and/or ICF information or content which does not alter the meaning, objective, or intention of the document.

See Res184-2023 for detailed descriptions of minor changes to the protocol and/or ICF.

Per Decree021-2017, ECs must also conduct regular monitoring, with a frequency based on the degree of risk to participants, but no less than once a year. Further, they must suspend or cancel the trial when participants are exposed to uncontrolled risk and inform the research institution, the sponsor and/or the CRO, and the INS’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) of the suspension or cancellation.

(See the Submission Process and Timeline of Review sections for detailed submission process and timeline details.)

National Research Ethics Authority

No information is currently available regarding research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) fees.

National Research Ethics Commission (CONEP)

According to ResNo466, OMREC, and ResNo706, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit 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.

Fees are determined by each accredited institutional ethics committee.

Overview

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos). The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

National Research Ethics Authority

Per LawNo14.874, the National Research Ethics Authority, an interdisciplinary and independent collegiate body that is part of the MOH, is responsible for the following:

• Issuing regulatory standards on ethics research
• Evaluating the effectiveness of the National System of Ethics in Research with Human Beings
• Accrediting and certifying the ECs (CEPs) so that they are able to perform the function of ethical analysis in research, according to the degree of risk involved
• Monitoring, supporting, and supervising the ECs (CEPs) in relation to the analysis of research protocols and compliance with the pertinent standards
• Promoting and supporting the training of EC (CEP) members, with special emphasis on ethical and methodological aspects
• Acting as an appeals court for decisions made by ECs (CEPs)

National Research Ethics Commission (CONEP)

As per ResNo466, OSNo001, and ResNo446, CONEP is the central statutory body responsible for the registration, audit, and accreditation of ECs (CEPs). CONEP was created by the MOH to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. CONEP reports to the CNS, the advisory body to the MOH.

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

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

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

Registration, Auditing, and Accreditation

National Research Ethics Authority

As stated in LawNo14.874, the National Research Ethics Authority is responsible for accrediting and certifying the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) so that they are able to perform ethical research reviews according to the degree of risk involved.

National Research Ethics Commission (CONEP)

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

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

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

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

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

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

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

See CNSResNo506 for additional documentation requirements.

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

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

High-Risk Research Protocols

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

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

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

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

Suspension and Cancellation of Accreditation

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

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

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

Overview

As set forth in Decree021-2017, the INS-CTManual, and PER-61, the National Institute of Health (Instituto Nacional de Salud (INS))’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) is responsible for registering and accrediting institutional ethics committees (ECs) (Comités Institucional de Ética en Investigación (CIEIs)) listed in the INS’s Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2) to review and approve clinical trials. The DIIS must evaluate and verify EC compliance with the registration and accreditation standards established in the INS-CTManual. Per Decree021-2017, the INS-CTManual, PER-71, and PER-61, Peru requires clinical trial approval from an EC that is accredited by the INS’s National Registry of Accredited Institutional Ethics Committees (PER-61). (See PER-102 for a list of accredited ECs.)

Ethics Committees for Human Subjects Health Research Other than Clinical Trials

As delineated in Res233-2020, the INS is also responsible for providing advice, guidance, and technical assistance to all ECs and their entities or institutions that review health research with human beings; organizing training and education activities for EC members and researchers; promoting integration and cooperation networks among participating ECs; promoting relations between the ECs and different entities linked to the research ethics field; providing access to international resources to strengthen research ethics; establishing flexible review procedures and mechanisms appropriate for an expedited and rigorous ethical review of human health research in disaster situations and disease outbreaks; and assigning the INS’s DIIS to disseminate information and supervising ECs at the national level per the ethical research guidelines delineated in Res233-2020.

Registration, Auditing, and Accreditation

Per Decree021-2017, each research institution may establish an EC and register it with the INS via PER-89. (Refer to PER-102 for instructions on registering in the REPEC system.)

Per Decree021-2017, Res233-2020, the INS-CTManual, and the G-ECRegProcs, INS-registered ECs are only required to obtain accreditation if they are conducting a review of a clinical trial protocol involving pharmaceutical products. In addition to completing the accreditation/renewal application form (see PER-85 for FOR-OGITT-025), the applicant should complete the affidavit form (see PER-21 for FOR-OGITT-026) to demonstrate compliance with the accreditation standards delineated in the INS-CTManual. Both forms must be electronically submitted via PER-89. See PER-81 for instructional videos on registering on the REPEC platform.

PER-61 explains that once the registration form is electronically submitted, the user will receive a temporary EC registration number. Both the affidavit form and the registration forms should be printed and signed, and then attached along with the other accreditation documents required to be sent to the DIIS via the Document Processing Office located in the INS headquarters (refer to PER-61 and PER-98 for detailed requirements and instructions).

Decree021-2017 and the INS-CTManual state that accreditation is temporary and must be renewed every three (3) years. Per Decree021-2017, Res655-2019 (which amends Decree021-2017), and the INS-CTManual, the following accreditation requirements must be completed:

• EC accreditation application sent to INS (PER-85), per Res0423-2019
• Copy of the resolution/decision issued by the highest authority of the research institution authorizing EC operation
• Copy of institutionally approved EC regulations and its Manual of Procedures submitted in electronic form (editable PDF)
• Affidavit of compliance with INS-CTManual accreditation standards (PER-21), per Res0423-2019
• Curriculum vitaes signed by each EC member submitted in electronic form (editable PDF)

Per the INS-CTManual, it is recommended that applications for EC accreditation renewals be submitted 30 calendar days before the end of term. Additionally, the INS-CTManual provides detailed information on the inspections that the INS-accredited ECs may be subject to before, during, and after EC registration.

Refer to the INS-CTManual and PER-61 for detailed submission instructions, and PER-85, PER-21, PER-22, and PER-35 for the EC accreditation application and EC affidavit of compliance forms.

Ethics Committees for Human Subjects Health Research Other than Clinical Trials

Res233-2020, which regulates human subjects research other than clinical trials of drugs or devices, requires ECs to be registered with the INS via the National Registry of Research Ethics Committees (Registro Nacional de Comités de Ética en Investigación), per the G-ECRegProcs. The G-ECRegProcs establishes standardized procedures for the INS’s DIIS to conduct EC registration evaluation in compliance with Res233-2020. As specified in the G-ECRegProcs, the DIIS’s Clinical Trials Subdirectorate (Subdirección de Ensayos Clínicos) (formerly known as the Executive Office of Investigation (Oficina Ejecutiva de Investigación (OEI)) is responsible for receiving, evaluating, and responding to EC registration requests. Depending on the implementation period, registration can be immediate, in which registration occurs at the time of the request, or progressive, in which implementation is carried out over a maximum period of two (2) years after initial EC registration. During the implementation of progressive requirements, the DIIS can provide advice and guidance to the EC upon request.

Per the G-ECRegProcs, in the case of immediate registration approval, once the registration application file is initially reviewed for completeness, it is forwarded to the application evaluator who verifies whether the file minimally complies with all the immediate requirements within 30 days. If the registration file meets the immediate requirements and the information provided complies with the INS-CTManual and the G-ECRegProcs provisions, the evaluator prepares a favorable response report and a draft record of registration, addressed to the Clinical Trials Subdirectorate. Once the favorable response report has been received, the Clinical Trials Subdirectorate evaluates and endorses it, sending the report and draft record of registration to the DIIS. The DIIS issues the EC certificate of registration and incorporates registration into the National Registry of Research Ethics Committees (Registro Nacional de Comités de Ética en Investigación) database. In addition, per the G-ECRegProcs, an EC registration may be suspended if the EC has not completed implementation of the progressive registration requirements within the two-year term. Refer to G-ECRegProcs for additional information on the DIIS’s registration review and approval process.

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 approval for a clinical trial application (Clinical Drug Development Dossier (Dossier 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).

According to LawNo14.874 and ResNo945, research involving human beings must be subject to 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 drug clinical trial may only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

According to National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) regulations and guidelines as delineated in ResNo466 and OSNo001, the principal investigator (PI) must obtain approval from the EC (CEP). Applications with coordination or sponsorship originating outside of Brazil require additional EC (CEP) review by CONEP unless the co-sponsor is the Brazilian Government.

Note: Regulatory requirements for both the National Research Ethics Authority and CONEP will be included in the profile until the CONEP system has fully transitioned to the new national system enacted by LawNo14.874.

Regulatory Submission

Primary Petitions

As per ResNo945, the 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 the 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 defined as a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) in the DDCM. DEECs must be filed in the form of individual processes for each clinical trial and linked to the respective DDCM. Per the G-DDCMManual, DEECs must be submitted as primary petitions and, therefore, will have a case number, with specific subjects for each clinical trial that is to be carried out in Brazil and that have not yet been submitted to ANVISA. Also, only DEECs from clinical trials to be carried out in Brazil should be submitted. ResNo945 further indicates that the sponsor, CRO, or sponsor-investigator may link new DEECs to the submitted DDCM at any time following the initial submission.

ResNo945 provides the following additional DDCM submission requirements:

• The person responsible for submitting the DDCM to ANVISA must be the same for all subsequent petition submissions related to it
• Submissions by the CRO may only be made when 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
• In cases where a sponsoring investigator wishes to conduct a clinical trial with a drug that already has an approved DDCM, the sponsoring investigator, with the initial DDCM owner’s permission, may use the information previously sent, without having to resubmit all the documentation. When an authorization from the initial DDCM owner is not provided, the sponsoring investigator must submit to ANVISA all the required information through updated and indexed literature that supports the proposed development rationale

In addition, per ResNo903, when a sponsor or CRO transfers responsibility for submitting a DDCM petition and the linked specific clinical trial processes for an 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 respective specific processes. When a secondary petition is related to a DDCM, it must be filed together with the Petition Consent Form (BRA-21). Some 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 DEECs must be linked to the respective clinical trial processes. Some 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.

A stated in ResNo945 and the G-DDCMManual, for substantial protocol modifications of the investigational product (IP), the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM. ResNo945 also indicates that 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 report (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 for DDCM modifications. See also BRA-127 for the Substantial Modification of the Investigational Product form. Refer to the Submission Content section for substantial IP modification 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.

ResNo204 and BRA-14 further note that DEECs may be submitted as priority requests to ANVISA to register, amend previously registered, or request prior consent for drug submissions. However, as described in the G-DDCMManual, in cases where the DDCM or DEEC has been prioritized, under the terms of ResNo204, ResNo205, and ResNo811 (which partially amends ResNo205), prioritization does not automatically extend to secondary petitions. The company must request the prioritization of analysis at the time of petitioning each secondary petition, if applicable. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections.

See ResNo742, ResNo931 and ResNo942 (amending ResNo742), BRA-6, and BRA-7 for requirements associated with submitting DEECs linked to DDCMs for comparative bioavailability/bioequivalence studies and comparative pharmacokinetic studies with biosimilar products.

In addition, for the purposes of regulatory submission, the G-SUSARs indicates that Drug Development Safety Reports (DSURs) must be submitted as secondary electronic petitions linked to the DDCM process. The subject of petition 10825 – CLINICAL TRIALS – Safety Update Report of the Development of the Investigational Drug should be used.

As delineated in ResNo945, RegNo338, the G-DDCMManual, and BRA-122, the sponsor may also submit a request for technical analysis by the optimized procedure based on regulatory trust practices (Reliance) or by risk or complexity criteria of the clinical trial or the IP at any time, by means of a secondary petition, before ANVISA begins its technical evaluation of the corresponding DDCM petition. 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 Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) recognized by ANVISA. The AREE approved documents must also be the same versions as those presented to ANVISA.

The G-DDCMManual further explains that the optimization procedure concerns the documentation that may be exempted from technical analysis when the criteria for each of the specific situations are met. However, all documents required for the instruction of each type of petition or process must be submitted.

In accordance with ResNo945 and RegNo338, the G-DDCMManual and BRA-122 indicate that the applicant must file a secondary petition to request the optimized analysis procedure by Reliance using one (1) of the subject codes listed below:

• 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

BRA-122 also explains that only a single subject code (12102) is used to submit a request to ANVISA to apply the optimized analysis procedure by Reliance for the DEEC. Additionally, per the G-DDCMManual and BRA-122, the petitioning system does not allow a secondary petition to be linked to another secondary petition. Since requests for the application of the optimized analysis procedure must be made through secondary petitions, and petitions for substantial IP modifications and clinical protocol amendments are also secondary petitions, requests referring to these petitions must be linked to the DDCM and DEEC by subject codes 11634 and 12103, respectively. Therefore, in the case of a DDCM petition and linked DEECs, for both petitions to be analyzed according to the optimized procedure, a company must make the request in parallel and individually for each of the petitions (codes 12102 and 12104), including for each related secondary petition, if applicable. 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 based on 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).”
• 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)) should be submitted electronically. ResNo947 also notes that documents to be filed with ANVISA must be submitted exclusively electronically 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, and BRA-58 explain that when the DDCM has been submitted, the sponsor is then required to electronically file all the documents corresponding to the initial DDCM petition’s subject code checklist. As described in BRA-75, the sponsor must electronically attach all the documents required in the related DDCM checklist (accessed online via BRA-56) that corresponds to one (1) of the following related subject codes: 10748, 10749, 10750, 10751, 10752, 10753, 10754, and 10755. ResNo945 also specifies that the documentation presented must allow for textual searches, copying, and contain bookmarks and hyperlinks that facilitate navigation. Refer to BRA-47 and BRA-59 for instructions for submitting the DDCM checklist documents via BRA-56. Additionally, per the G-DDCMManual, for DEEC petition electronic submissions, one (1) file needs to be attached for each item contained on the corresponding checklist. DEECs can be submitted to ANVISA using one (1) of the following subject codes: 10482, 10479, 10476, 10773, 10483, 10478, 10477, 10774. See the G-DDCMManual and BRA-47 for additional DEEC petition submission instructions. See also ResNo947 for 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)) fees. ResNo857 explains that petitions subject to TFVS will only be eligible for filing after confirmation of full corresponding payment. Once the full TFVS payment is confirmed, the electronic petitions will be automatically filed. (See the Regulatory Fees section for detailed information on the payment process.)

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

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

BRA-59 explains that once the fee is paid, a reference (transaction) number is generated that will be required for the subsequent submission of the associated checklist documents. The processing of this request can take up to two (2) days, which is the time given to the banking network to clear the payment. Refer to BRA-59 for additional instructions. See also BRA-47 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition 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 investigator’s brochure) 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.

See also BRA-19 and BRA-90 for guidance on scheduling pre-submission meetings with ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted.

In addition, per ResNo763, which modifies ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, if the sponsor deems necessary, and ANVISA should hold the meeting within 60 days following this request. Refer to ResNo205 and ResNo811 (which partially amends ResNo205) for additional submission documentation requirements.

Ethics Review Submission

National Research Ethics Authority

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, including any amendments.

National Research Ethics Commission (CONEP)

Per ResNo466 and OSNo001, the PI must obtain approval from the EC (CEP). The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional EC (CEP) 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.

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

Overview

In accordance with Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, and Res252-2022 (which amends the INS-CTManual), the sponsor or the contract research organization (CRO) is responsible for submitting a clinical trial application to the National Institute of Health (Instituto Nacional de Salud (INS)) to obtain approval to conduct a clinical trial in Peru. Per Decree021-2017, Res655-2019, the INS-CTManual, Res252-2022, and the G-EC-CTRev, the INS-accredited ethics committee (EC) must first approve the research protocol and informed consent form (ICF), and the sponsor or the CRO must submit this information as part of the application dossier in order for the INS to conduct its review. Therefore, the INS and EC reviews may not be conducted in parallel. Decree021-2017 also states that sponsors not based in Peru are required to appoint a legal representative in the country who coordinates all communication with the INS’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) for the trial’s duration, unless such responsibility is delegated to a CRO.

Regulatory Submission

REPEC Pre-Submission Registrations

As delineated in Decree021-2017, Res655-2019, Res252-2022, the INS-CTManual, PER-60, and PER-59, prior to submitting an application for clinical trial authorization, the sponsor and the CRO must register with the Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2). The INS-CTManual also notes that the sponsor registration application (PER-36) must be submitted in Spanish or accompanied by a proper translation if issued in a language other than Spanish. See the INS-CTManual, PER-60, and PER-59 for detailed sponsor and CRO registration instructions and PER-36 and PER-37 for the sponsor and the CRO registration forms. Refer to Res393-2021 for additional information on the updated sponsor registration form (PER-36). See also PER-81 for instructional videos on registering with PER-89.

Additionally, as specified in PER-89, the REPECv2 platform should be used to obtain information or request feedback on procedures and operations related to a newly submitted clinical trial, to track the status of the authorization process, to identify critical events that require immediate attention via an alert system (e.g., expiring or expired authorizations and necessary notifications per Decree021-2017), and to obtain updated information on clinical trials being conducted in Peru. Also, as explained in PER-114, DIIS has initiated the process of migrating information from the older platform (REPECv1) (PER-91) to PER-89 to receive and manage clinical trial information on a single platform, therefore all new requests for clinical trial procedures should be entered through PER-89. However, per PER-88, any requests for procedures related to an already active clinical trial must still be requested using the older REPEC platform via PER-91. PER-114 further notes that requests for clinical trials that are in progress and have been entered through REPECv1 will not be migrated to REPECv2 until the procedure is concluded.

Submissions

Pursuant to Res252-2022, all application related documents must be electronically submitted through the Virtual Submission Platform (Mesa de Partes Virtual (MPV)) (PER-106). According to PER-103, all notifications relating to procedures submitted via PER-106 will only be responded to in the PER-106 notification mailbox; notifications will not be communicated via email or other forms of communication.

Per PER-104, users must also be registered on PER-106 prior to submitting any application related documents. Registration is done through PER-106 or via the MPV link on the INS webpage. Although, as indicated in PER-106, non-citizens cannot register directly with PER-106, and require an in-country representative to provide proof of citizenship to register using either a national identity document or an immigration card. Refer to the G-MPVManual and the G-VirtSubPlatfrm for detailed user instructions and procedures, and PER-107, PER-110, and PER-105 for additional information on the MPV system.

As explained in Decree021-2017, the INS-CTManual, Res252-2022, and PER-71, once the sponsor or the CRO is registered in the REPEC and MPV systems, a request for clinical trial authorization must be submitted electronically via PER-89. (See PER-24 for the clinical trial application form and PER-10 for instructions on completing the form.) Per Res252-2022, the completed electronic request form should then be submitted via PER-106 along with the required documentation as set forth in Decree021-2017 and Res655-2019.

Decree021-2017 and Res655-2019 further indicate that the clinical trial application and accompanying material (including the updated Investigator’s Brochure (IB)) must be provided in Spanish. Any document not in Spanish must be submitted with a corresponding translation. Decree021-2017 also states that if the protocol title is written in English, a single title in Spanish must be assigned for all purposes. In addition, the research protocol and the ICF must also be in Spanish and in the original language, if different from Spanish, and include a copy of the approval by an INS-accredited EC. Per Decree021-2017, research and complementary investigational product (IP) media labeling must also be printed in indelible ink in Spanish or English. The INS-CTManual also notes that notification reports for IPs should contain a translated summary in English and Spanish.

For amended protocols or ICF submissions, Res655-2019 states that any changes should be electronically submitted (editable PDF) with track changes in Spanish and in the original language. The final protocol and ICF should include all of the incorporated amendments in an editable PDF file and comply with all of the previously discussed protocol submission requirements. See also Res655-2019, PER-32, PER-33, PER-34, and PER-35, for additional details on submitting protocol amendments and the related forms. See PER-105 and G-MPVManual for information on submitting documents electronically via PER-106 or via the MPV link on the INS webpage.

PER-92 indicates that for questions or problems with PER-89, contact:

Jenny Parillo, Engineer
Phone: (511) 748 0000 Extension: 2616 or 984108368 (Cell)
Email: jparillo@ins.gob.pe

(Note: Application submission instructions in earlier sources including Res655-2019, the INS-CTManual, and PER-71, do not reflect this new electronic submission option.)

For reference, the following are applications and forms that may be used to submit various procedures via PER-106:

• PER-24 for the clinical trial application for authorization
• PER-26 for the application to extend the number of research sites
• PER-28 for the application to change the principal investigator (PI)
• PER-29 for the application to change the sponsor/CRO
• PER-31 for the application to cancel a clinical trial
• PER-35 for the affidavit to be signed by the principal investigator (PI) and sponsor on the research site’s preparedness for the clinical trial
• PER-43 for the application to close a clinical trial research site
• PER-44 for the affidavit of compliance with minimum research site requirements
• PER-50 for the research team curriculum vitae form
• PER-85 for the EC accreditation/accreditation renewal form
• PER-87 for the form and requirements to request INS approval to supervise a clinical trial virtually

Refer to the INS-CTManual, Res252-2022, and PER-71 for additional submission information. See PER-6 for a flowchart delineating the clinical trial authorization process. See also the Submission Content section for detailed documentation requirements.

Ethics Review Submission

Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements.

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 (Dossier 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)
• Declaration of commitment to distribute to clinical trial centers and use investigational products (IPs) only after authorization from the corresponding DDCM and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)), when import is authorized prior to publication of the approval/rejection in the Official Gazette of the Union (Diário Oficial da União (DOU))
• 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 authorization from DDCM and corresponding initial and subsequent DEEC(s). This document should only be attached to the DDCM if the sponsor is interested in receiving the Import Document (DI) prior to the DDCM's analysis and approval. If the company has attached this to the DDCM, the DI will be issued for early importation both for the initial DEECs submitted together with the DDCM, and for the clinical trials submitted after the approval of the DDCM.

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 the linked specific clinical trial processes for an 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. 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)

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 (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025)
• Statistical analysis plan (PAE), at least in draft version, in the case of phase 3 clinical trials and adaptive clinical trials
• Opinion of any country/region's scientific advisory board, if any, on the clinical trial
• Pediatric investigation plan of any country/region, if any
• Sample investigational drug label
• Proof of registration of the clinical trial, in the same version of the clinical protocol submitted to ANVISA, in the registration database of 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.); and, if proof of registration is not available at the time of DEEC submission, it must be submitted together with the notification of commencement of the clinical trial.)

Substantial IP Modifications

Per ResNo945 and the G-DDCMManual, for substantial modifications of the IP, the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM. ResNo945 states that the petition for substantial IP modification must contain a copy of the previously approved IMPD or Investigational Product Dossier (DPI), containing the proposed modifications highlighted (track-changes format) and a table comparing the current situation with the proposed changes, the justifications for each change, and the assessment of the impacts of the modifications on clinical development. ResNo945 and the G-DDCMManual also indicate that if there is a GMP certificate or equivalent document for the IP, it must be attached to the petition for substantial IP modification. In addition, the Petition Form for Substantial Modification to the Product under investigation (BRA-127) and other information in accordance with each proposed modification must be attached to the petition. See the G-DDCMAmdmts for detailed submission instructions.

ResNo945 also indicates that 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 report (DSUR), whichever occurs first.

Substantial Protocol Amendments

As per ResNo945 and the G-DDCMManual, petitions for substantial amendments to clinical trial protocols must also be filed electronically as a secondary petition linked to the corresponding DEEC. ResNo945 further indicates that the petition must contain a 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, the justifications for each change and the assessment of the impacts on clinical development. In addition, clean and track changes versions of the updated Clinical Trial Submission Form (FAEC) (BRA-22) must be attached to the petition, along with the new clean version of the clinical protocol. See the G-DDCMAmdmts for detailed submission instructions for protocol amendments. See also BRA-125 for the Substantial Amendment to Clinical Trial Protocol form.

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 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.

Optimized Analysis Procedure (Reliance) Submissions

Pursuant to ResNo945, to comply with the documentation requirements for the optimized analysis procedure by Reliance, the sponsor must present official proof issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) regarding the clinical protocol approval or clinical protocol amendment, or, official proof of the DDCM or substantial IP modification of the IMPD or Investigational Product Dossier (DPI). In the absence of this official document, a declaration signed by the sponsor's legal and technical representatives 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. Among the documents required for the instruction of each type of petition, the optimized analysis procedure based on risk assessment may be applied to the documents listed below:

• IB, when dealing with the risk categories defined in the low-risk clinical trial categories for medicine used as registered in Brazil or by an AREE, without substantial modifications; and fixed-dose combinations with registered active pharmaceutical ingredients 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, when dealing with low-risk clinical trial categories and moderate risk clinical trial categories for new therapeutic indication, and/or target population, and/or dosage regimen

RegNo338 further indicates that ANVISA will review the following documents based on the optimized analysis procedure by Reliance:

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

See also BRA-124 for the Form for Declaration of Compliance with the Requirements for the Admissibility of the Optimized Analysis Procedure by Regulatory Trust (Reliance) to be completed by the sponsor’s legal representative or technical manager.

See also BRA-42 for additional information on ANVISA protocol filing requirements.

Ethics Committee Requirements

National Research Ethics Authority

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 EC (CEP)/National Research Ethics Authority submission documentation requirements.

National Research Ethics Commission (CONEP)

As per OMREC and OSNo001, the CONEP requires sponsors to submit the following documentation online via BRA-34 (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

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

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

Clinical Protocol

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

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

For complete protocol requirements, refer to OMREC and OSNo001.

Regulatory Authority Requirements

As specified in Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, Res252-2022 (which amends the INS-CTManual), PER-71, and PER-83, a clinical trial application submission must include the following documents (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Application for clinical trial authorization and proof of payment (PER-24) (per Annex B in Res655-2019)
• Approval(s) issued by legal representative of institution(s) where research will be conducted (per Annex 1 in INS-CTManual and Annex 2 in Res252-2022)
• Copy of the approved research protocol and informed consent form (ICF) stamped and signed by the ethics committee (EC) in its entirety (per Annex 3 in INS-CTManual and Annex 3 in Res252-2022)
• Research protocol in Spanish, and in the original language if different from Spanish, submitted in electronic form as an editable PDF (per Annex B in Res655-2019)
• ICF in electronic form as an editable PDF (per Annex B in Res655-2019)
• Updated Investigator’s Brochure (IB) in Spanish, and in the original language if different from Spanish, submitted in electronic form as an editable PDF (per Annex B in Res655-2019)
• Affidavit stating no conflict of financial interest signed by the sponsor or the contract research organization (CRO) and the principal investigator (PI) (PER-34)
• Affidavit signed by the PI and sponsor on preparation of research institution for trial (PER-35)
• In the case of foreign sponsor: copy of proof of delegation of functions to the sponsor representative, duly authenticated by Peru’s Ministry of Foreign Affairs
• Affidavit on compensation for participants signed by the sponsor or the CRO and PI (covers budget and expenses for any trial-related injuries) (PER-51)
• Copy of current insurance policy purchased by the sponsor
• List of clinical trial supplies (PER-42)
• Information related to the investigational product (IP) quality (electronic form) (per Annex B in Res655-2019)
• Updated curriculum vitaes (CVs) of all research team members with attached copies (PER-50) (per Annex B in Res655-2019)
• Copy of documents demonstrating training in Good Clinical Practices and Research Ethics in human beings for the entire research team within the past three (3) years (PER-50) (per Annex B in Res655-2019)
• Detailed national budget total for trial form (PER-25)
• Copy of current record of authorized research institution(s) for clinical trials
• Payment receipt for research site registration; in the case of multicenter trials, proof of payment for processing fee (per Annex B in Res655-2019)

Refer to Decree021-2017, Res655-2019, the INS-CTManual, Res252-2022, and PER-71 for detailed submission information; PER-24 for the recently amended clinical trial application form per Res0423-2019; and PER-10 for detailed instructions on completing the form.

See also the Submission Process section for additional submission requirements, and PER-6 for a flowchart delineating the clinical trial authorization process.

Trial Extensions

Decree021-2017, Res655-2019, PER-72, PER-27, and PER-93 indicate that the sponsor or the CRO must submit the following documents for clinical trial application extensions: (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Application for extension of time to conduct the clinical trial, explaining the reasons for such request and stating the number and date of the proof of payment of processing fees (using FOR-OGITT-037 (PER-27)) per PER-72
• Copy of the document approving the time extension granted by the legal representative of the research institution(s) where the trial will be conducted
• Copy of the document containing the time extension approval by an National Institute of Health (Instituto Nacional de Salud (INS))-accredited EC

• Report justifying the reasons for submitting the request
• Current insurance policy

Ethics Committee Requirements

Specific institutional EC requirements are not provided in Peru’s regulatory sources. However, according to PER-77, ECs generally require PIs to submit the following documentation for ethics approval:

• Letter from the PI to the EC Chairman
• Basic Format Application
• Research protocol
• ICF
• PI and co-investigator(s) CV(s)
• Declaration of the PI and research site director/research institution head
• Declaration of financial details and potential conflicts of interest of the PI
• Sponsor’s insurance policy
• PI’s training in good clinical practices and human research ethics

Clinical Protocol

As delineated in Decree021-2017, the clinical protocol should contain the following elements:

• General information
• Protocol summary
• Background and justification (including IP description) (See Investigational Products topic for detailed coverage of this subject)
• Objectives, valuation criteria, or specific results and hypotheses
• Test design
• Participant selection/withdrawal
• Participant treatment
• Study evaluation and procedures
• Adverse events (See Safety Reporting section for additional information)
• Statistical considerations
• Data collection and monitoring
• Data management and record maintenance
• Ethical aspects
• Publications results
• Bibliography
• Appendices

For complete protocol requirements, refer to Annex 1 of Decree021-2017.

Overview

As stated in ResNo945, clinical trial applications can 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’s analysis of the primary petitions for clinical trials with human beings (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento de Medicamentos Clínicos (DDCMs))) must be completed within 90 business days. If no response is provided after regular receipt of the primary DDCM petition, clinical development may be initiated, provided that it contains the relevant ethical approvals. ResNo945 further specifies that upon receipt of the primary DDCM and the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions, ANVISA has 90 business days, counting from the date of issuance of the DEEC document, to evaluate the application. If the agency fails to issue a response within 90 days of receipt, the DDCM and respective DEEC will be released after the deadline, and clinical development can begin after the relevant ethical approvals have been obtained. The 90-day deadline also applies to primary petitions for new DEECs subsequently linked to the DDCM, and to secondary petitions for substantial modifications to the investigational product (IP) and substantial amendments to the clinical protocol. See Scope of Assessment section for detailed DDCM and DEEC submission requirements.

Additionally, per ResNo945, ANVISA’s analysis of the DDCM will only occur after the filing of at least one (1) DEEC, which must be carried out within 15 business days from the DDCM’s issue date. The absence of the DEEC, after the 15-day deadline, will result in the rejection of the DDCM without technical analysis, except in cases of clinical trials involving more than one (1) investigational product (IP), whose DEEC has already been linked to one of the DDCMs of these drugs.

LawNo14.874 and ResNo945 further explain that ANVISA may request, one (1) time only, by means of a technical requirement, additional clarifications and documents during the analysis of primary DDCM and DEEC petitions and secondary petitions for substantial IP modification or substantial clinical protocol amendment. ANVISA’s technical requirement will result in the suspension of the analysis deadlines, and its interruption is prohibited. ResNo945 also notes that the deadline for the sponsor’s compliance with this technical requirement is 30 business days, counting from the date of confirmation of receipt by ANVISA.

In addition, per BRA-122, petitions submitted to request an ANVISA evaluation using the optimized analysis procedure based on regulatory trust practices (Reliance) that have not been analyzed within ANVISA’s 90-day deadline, will be released due to the expiration of the term in accordance with ResNo945 and LawNo14.874. The petitions will have their status 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.

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

Priority Submissions

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

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

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

Refer to ResNo204 and ResNo811 (which partially amends ResNo204) for detailed information on DEEC submissions.

In addition, as set forth in ResNo205, for a clinical trial with medicines for rare diseases to be conducted in Brazil, ANVISA must evaluate a DDCM, DEEC, or substantial modification due to inclusion of a clinical trial protocol within 30 days after submission, 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 also ResNo811 (which partially amends ResNo205) and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.

Ethics Committee Approval

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings. The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the ECs (CEPs), which must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

National Research Ethics Authority

As set forth in LawNo14.874, the EC (CEP) must conduct a research ethics review and issue an opinion within 30 business days from the date of acceptance of all research documents. The EC (CEP) must accept or deny these documents within 10 business days from the date of submission. Additionally, before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor or make adjustments to the research documentation, for up to 20 business days. The investigator will have 10 working days, extendable for an additional 10 working days upon justification, to meet the demands requested by the EC (CEP), and the study analysis process may be canceled in case of non-compliance with the deadline.

LawNo14.874 further explains that the decision contained in the EC (CEP)’s opinion may be appealed, in the first instance, within 30 business days, to the EC (CEP) itself that issued the opinion, and in the second and final instance, within 30 business days, to the National Research Ethics Authority. The appeals provided will be decided by the National Research Ethics Authority 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, the EC (CEP) opinion regarding research of strategic interest to the Ministry of Health (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 research documents.

National Research Ethics Commission (CONEP)

As delineated in OSNo001 and BRA-91, the institutional EC (CEP) is required to issue an initial report in 30 days from the date the principal investigator (PI) submits an application for review. The CEP’s review of the protocol documentation for completeness should be accomplished within 10 days following submission. Per BRA-91, the review period must be counted from the date the project entered “Ethical Assessment” (i.e., after going through the validation of documents which takes around 10 days and when the Certificate of Presentation for Ethical Assessment (Certificado de Apresentação de Apreciação Ética) (CAAE)) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment. If these deadlines have expired, BRA-91 further suggests that the investigator responsible for the research project, contact the CEP to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation. 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 to CONEP itself. From an analysis of the resources submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal, the processing of the appeal is terminated, the research protocol is archived, and no other appeal requests will be permitted.

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

Overview

Based on Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, and Res252-2022 (which amends the INS-CTManual), the National Institute of Health (Instituto Nacional de Salud (INS))’s review and approval of an application to conduct a clinical trial is dependent upon obtaining ethics committee (EC) approval from an INS-accredited EC. Therefore, the INS and EC reviews may not be conducted in parallel.

Regulatory Authority Approval

As per Law27444 and Decree004-2019 (which amends Law27444), the INS is required to complete its review and approval of a clinical trial application in a maximum of 30 working days. Per Decree021-2017, this timeline includes the 30-day requirement for the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)) to issue a binding technical opinion on the safety and quality of the investigational product (IP). (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)).

As explained in the INS-CTManual and Res252-2022, the person in charge of the Documentary Processing Area (Área de Trámite Documentario (ATO)) receives the application file and reviews the file with a health professional assigned from the DIIS’s Clinical Trials Subdirectorate (Subdirección de Ensayos Clínicos) (formerly known as the Executive Office of Investigation (Oficina Ejecutiva de Investigación (OEI))) to ensure completeness. The applicant has a maximum of two (2) business days to make any corrections that have been identified. If the corrections have not been made in the required timeline, the file is returned to the applicant, who is reimbursed for any processing fees. If the file is deemed complete and any required corrections have been addressed, the file is assigned a registration number in SIGNANET, the INS’s integrated administrative management system. Res252-2022 further explains that the authorization request procedure is formally initiated when the sponsor is provided with the file registration number. At this stage, an identification number is also assigned to the clinical trial in the Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2).

Per Res252-2022, the file is then forwarded to the Clinical Trial Processing Area (Área de evaluación de Ensayos Clínicos (AEC)). Upon receipt of the application file, the AEC reviewer receives the file and sends the list of clinical trial supplies (PER-42) along with the required documentation in Annex 5 of Decree021-2017 to the Research Product Safety Surveillance Area (Área de Vigilancia de la Seguridad del Producto en Investigación (AVISPI)). AVISPI, in turn, sends this documentation to the ANM to request a binding technical opinion on the IP safety and quality. Concurrent with the request for the ANM’s review, the AEC reviewer evaluates the file, including the ANM binding technical opinion once received, and prepares a draft evaluation report which is reviewed by the Functional Clinical Trials Team (Equipo Funcional de Ensayos Clínicos (EFEC)) coordinator. If agreed to, the EFEC coordinator forwards the file to the Clinical Trials Subdirectorate’s Legal Advice Functional Team (Equipo Funcional de Asesoría Jurídica (EFAJ)) who prepares a report for the Clinical Trials Subdirectorate Executive Director’s review.

The Clinical Trials Subdirectorate Executive Director reviews the evaluation documents and legal report generated by the EFEC and the EFAJ. If the evaluation is agreed to, then the Executive Director signs the report, approves the project, and sends it to the INS’s DIIS, who also reviews and approves the file and signs off on the project. Otherwise, the file is returned to the EFEC to be handled as a non-compliant project. The process is finalized when the sponsor or the CRO is notified of the approval. The DIIS secretary registers the decision in SIGANET and all documentation is registered in PER-89. Per Decree021-2017, the sponsor has the right to appeal when the INS does not grant authorization.

Per Decree021-2017, any modifications of the conditions under which a clinical trial was authorized, and amendments to the research protocol and/or informed consent, require prior authorization from the INS’s DIIS.

Decree028-2023 (which amends Decree021-2017) further specifies that a minor change(s) to the protocol and/or informed consent form (ICF), only requires the approval of the INS registered and accredited EC that originally approved the current version, and the sponsor must communicate the change(s) in writing to the INS’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) within 10 business days prior to its implementation. Per Decree028-2023 and Res184-2023 (which amends Decree021-2017), a minor change does not generate a new version of the protocol or ICF; however, if a subsequent amendment is made to the protocol, it must also contain the minor change(s) made. (See Scope of Assessment and Scope of Review sections for additional information on submitting minor changes to the INS’s DIIS.)

Per Decree021-2017, Res655-2019, PER-72, and PER-93, the sponsor or the CRO should also request a trial extension within 30 calendar days prior to the trial’s expiration. The authorized trial extension will be valid for a maximum of 12 months from the date of issue.

Ethics Committee Approval

The EC review and approval process timeline varies by institution.

Overview

New National Ethics System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings. The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

In accordance with ResNo945 and the G-DDCMManual, a clinical trial can only commence after the sponsor, the designated contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or the sponsor-investigator receives clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). According to LawNo14.874, ResNo945, ResNo466, and OSNo001, research involving human beings is also subject to prior ethical analysis by research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). ResNo945 states that a drug clinical trial may only be initiated after approval is obtained by both the EC (CEP) and 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 National Research Ethics Authority 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).

Per BRA-65, Brazil is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ResNo945 indicates that Brazil has formally adopted the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025.) ResNo945 and the G-DDCMManual also specify that clinical trials should be conducted in compliance with 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 forms indicating the start and end date of the clinical trial in Brazil must be filed as a secondary petition to the corresponding Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) process, within 30 business days after each start and end date. (See Clinical Trial Start Date Form in Brazil (BRA-25)).

Clinical Trial Agreement

As per LawNo14.874, the sponsor is responsible for establishing the contract between the parties involved in the research. Prior to initiating the trial, as described in BRA-28, the sponsor must sign an agreement between all involved parties, including between the investigators, the institution, the EC (CEP), and the CRO, to ensure full compliance with the regulatory requirements. In addition, the sponsor should obtain the investigator’s/institution's agreement:

• To conduct the trial in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC (CEP)
• To comply with procedures for data recording and reporting
• To permit monitoring, auditing, and inspection
• To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement. 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 has developed a clinical trials search tool to obtain detailed information about scientific/academic research or clinical trials authorized by the agency to support the registration of medicines since 2015. The Clinical Trials (Ensaios Clínicos) tool may be accessed via ANVISA’s Consultation System webpage (BRA-44), which 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.

Overview

In accordance with Decree021-2017, Res655-2019 (which amends Decree021-2017), the INS-CTManual, and Res252-2022 (which amends the INS-CTManual), a clinical trial can only commence after the sponsor or the contract research organization (CRO) receives authorization from Peru’s National Institute of Health (Instituto Nacional de Salud (INS)) and approval from an INS-accredited institutional ethics committee (EC) (El Comité Institucional de Ética en Investigación (CIEI)). No waiting period is required following the applicant’s receipt of these approvals.

According to Decree021-2017, Decree016-2011, the INS-CTManual, and Res252-2022, the sponsor or the CRO must also obtain approval from the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)) to manufacture or import investigational products (IPs) and to obtain an import license for the shipment of IPs to be used in the trial. (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)). (See the Manufacturing & Import section for additional information).

Additionally, per Decree021-2017 and Res252-2022, the sponsor must ensure authorization by the research institution where the clinical trial will be carried out. Decree021-2017 further states that the sponsor must inform the INS’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) when the first research participant is enrolled in Peru as well as the enrollment termination date in the country.

The INS-CTManual further specifies that the trials should be conducted in compliance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (PER-53).

Res686-2020, in turn, states that clinical studies of vaccines in humans must be conducted in accordance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (PER-53) and current national clinical trial regulations (Decree021-2017). Refer to Res686-2020 for detailed information and requirements associated with clinical vaccine studies.

Clinical Trial Agreement

According to Decree021-2017, the INS-CTManual, Res252-2022, and PER-71, the sponsor and principal investigator (PI) must sign an affidavit of compliance with the minimum requirements of the research site where the clinical trial will be executed (see PER-35). Further, per Res252-2022 and PER-71, both the sponsor and the PI must sign an affidavit establishing that there is no conflict of financial interest in executing the trial (PER-34).

In addition, per Decree021-2017, the INS’s DIIS refers to the requirements laid down in PER-53 for topics not addressed in Decree021-2017. Accordingly, PER-53 states that prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor or the CRO should provide the investigator(s) with the protocol and an investigator’s brochure (IB), and ensure that they agree to comply with good clinical practices and ethical standards. The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

As per Decree021-2017, the INS-CTManual, Res252-2022, and PER-71, the sponsor or the CRO must register the clinical trial application electronically using the INS’s Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2), at which time, a registration code is assigned to the application.

As specified in PER-89, the REPEC platform should be used to register all requests for procedures related to newly submitted clinical trials, to track the status of the authorization process, to identify critical events that require immediate attention via an alert system (e.g., expiring or expired authorizations and necessary notifications per Decree021-2017, and to obtain updated information on clinical trials being conducted in Peru). However, per PER-88, any requests for procedures related to already active clinical trials must still be submitted using the older REPEC platform via PER-91. See PER-81 for instructional videos on registering with the new REPEC platform. Refer to the Oversight of Ethics Committees section for instructions on EC registration/accreditation and the Submission Process section for instructions on sponsor/CRO registration.

Safety Reporting Definitions

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

• Adverse Event/Experience (AE) – Any adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
• Adverse Drug Reaction or Adverse Reaction (ADR) – 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 investigational product (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 to the sponsor, the health authority, the research ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)), and the National Research Ethics Authority all serious or unexpected AEs. ResNo945, the G-SUSARs, and the AESafetyManual 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 the 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 communicating to the sponsor the occurrence of all AEs. 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. The AESafetyManual further states the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the EC (CEP) with any additional requested information (e.g., autopsy reports and terminal medical reports).

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.

Sponsor Responsibilities

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

• Promptly notifying the investigator, the institution, the competent ethical review entities, and 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 investigator’s brochure (IB), amendments, reports, or early termination of the clinical trial. The G-SUSARs further notes that, as a joint action to submit SUSAR notifications, 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. While the IB is not updated, it is necessary to notify additional occurrences (follow-ups) of SUSARs to ANVISA. (See Quality Requirements section for detailed IB requirements)

ResNo945 and the G-SUSARs also state that if there is a possibility that an event may be a SUSAR, the sponsor must break the blinding for notification to ANVISA, and the break must only be in relation to the designation of the participant who was affected by the SUSAR. Where possible, the blinding should be preserved to 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 in question and 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 states 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 (referred to as fatal or life-threatening SAEs/SADRs by the AESafetyManual) 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 and the AESafetyManual, 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.

Per the AESafetyManual, AEs/ADRs and SAEs/SADRs do not need to be reported to ANVISA under the above timelines when they occur outside of Brazil or are defined in the protocol as a primary or secondary outcome. Additionally, SAEs/SADRs that are categorized as Unlikely, Conditional/Unclassified, or Unassessable/Unclassifiable do not need to be reported under the above timelines. The sponsor should classify all AEs/ADRs and SAEs/SADRs according to the World Health Organization’s Uppsala Monitoring Centre (WHO-UMC)’s standardized causality assessment system (BRA-31). The recommended criterion to categorize each event is as follows: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and Unassessable/Unclassifiable.

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. ResNo945 explains that safety information originating from other countries where clinical development is taking place must be communicated to the 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. The G-SUSARs also notes that information about the late AEs can become part of the IP safety profile. See ResNo945 and the G-SUSARs for additional safety monitoring requirements.

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.

Ethics Committee Responsibilities

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

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

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

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

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

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

Other Safety Reports

As described in ResNo945, the G-SUSARs, and the AESafetyManual, Drug Development Safety Reports (DSURs) must be sent annually to ANVISA, until the end of the clinical development of the IP in Brazil. The DSURs must be filed within a maximum of 60 calendar days of the yearly anniversary of the date that ANVISA approves the clinical trial application (DDCM), or the date determined in the international development. 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 at any time, 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.

Per BRA-37, sponsors of clinical trials that have not yet been registered with VigiMed 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-85 for VigiMed Frequently Asked Questions (FAQs).

Safety Reporting Definitions

According to Decree021-2017, Decree021-2017-Correct, the G-SafeRpt, and the G-CTSafety, the following definitions provide a basis for a common understanding of Peru’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 (or Adverse Experience) (AE) – Any event or situation harmful to the health of the research participant to whom an investigational product (IP) has been administered, which does not necessarily have a causal relationship with its administration
• Adverse Reaction (AR) – Any AE in which there is a clearly defined causal relationship with an IP or there is at least a reasonable possibility of causation, which occurs regardless of any dose administered to that participant
• Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) – Any AE/AR that results in death, is life threatening, requires or extends hospitalization, results in persistent or significant disability/incapacity, or causes a congenital anomaly/birth defect
• Unexpected Adverse Reaction – An AR where the nature or severity is inconsistent with the applicable IP information, i.e., it is not described in the investigator’s brochure (IB) and/or the technical data sheet
• Suspected Unexpected and Serious Adverse Reaction (SUSAR) – Any serious AE/AR in which there is at least a reasonable possibility of a causal relationship with the IP and the nature and severity of the event/reaction is not described in the IB and/or technical data sheet

Safety Reporting Requirements

Investigator Responsibilities

According to Decree021-2017, the INS-CTManual, and the G-SafeRpt, the principal investigator (PI) and the sponsor or the contract research organization (CRO) are responsible for monitoring the safety of the IP. As specified in Decree021-2017 and the G-SafeRpt, the PI is also responsible for notifying the sponsor or the CRO or the ethics committee (EC) of any SAEs/SARs and SUSARs within a period not exceeding one (1) calendar day from the date the event occurs, or, the PI becomes aware of the incident.

Decree021-2017 notes that the PI must also follow up with a detailed written report. Per the G-SafeRpt, the PI must record the SAEs/SARs and notify the sponsor according to the procedure described in the study protocol.

Furthermore, per Decree021-2017, the PI must inform the sponsor or the CRO and the EC of the following:

• Any SAE/SAR that has occurred to a participant following the trial’s completion
• Any non-serious AEs/ARs identified as determinants of safety assessments in the protocol within the periods specified

In addition, the G-SafeRpt states that if the PI becomes aware of SAEs/SARs occurring after the end of the trial, they should notify the sponsor or the CRO and the EC.

Lastly, per Decree021-2017, the PI must provide the sponsor or the CRO, the EC, and the Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) within Peru’s National Institute of Health (Instituto Nacional de Salud (INS)) with any additional safety information requested.

Res233-2020, which regulates human subjects research other than clinical trials of drugs or devices, indicates that investigators should immediately report to the EC and the corresponding authorities any AE or unanticipated risk to research participants related to the research. Furthermore, in cases where protocol or informed consent process changes are necessary to prevent harm to the participants, the investigators must submit report deviations within 24 hours.

Sponsor Responsibilities

According to Decree021-2017, the INS-CTManual, the G-SafeRpt, and PER-72, the sponsor or the CRO should report IP-related AEs/ARs, SAEs/SARs, and SUSARs and provide these reports to the INS’s DIIS. Decree021-2017 also notes that the sponsor or the CRO should also maintain detailed records of all AEs/ARs communicated by the PIs.

Per Decree021-2017, Decree021-2017-Correct, the INS-CTManual, PER-72, and PER-38, the sponsor or the CRO and the PI are required to submit all expected and unexpected SAEs/SARs (related or not per PER-72) and SUSAR reports electronically through the Serious Adverse Events Virtual Reporting System (Sistema de Reporte de Eventos Adversos Serios (REAS-NET)) (PER-69) to the DIIS within seven (7) calendar days from the occurrence of the incident, or as soon as the sponsor is aware of the incident. The G-SafeRpt specifies that the sponsor or the CRO is responsible for evaluating, categorizing, and reporting all SAEs/SARs and SUSARs that occur within the country through REAS-NET (PER-69). The notification should be completed using the online form, FOR-OGITT-046 (PER-38).

Per the INS-CTManual, the electronic form (PER-38) submitted via REAS-NET (PER-69) should be printed and signed by the sponsor or the CRO. The INS-CTManual and the G-SafeRpt state that the submitted information above must be updated with any additional relevant information in a follow-up tracking report within eight (8) calendar days. The G-SafeRpt also notes that if the causality assessment of the SAE conducted by the investigator differs from the causality assessment made by the sponsor, the investigator’s assessment cannot be modified. The INS-CTManual further states that both the follow-up report and the final report completed in REAS-NET (PER-69) should be submitted electronically and in print formats to the DIIS.

In addition, per Decree021-2017, Decree021-2017-Correct, and PER-72, the sponsor or the CRO must notify the DIIS, the ECs, and the PIs within a maximum period of seven (7) calendar days of any findings that could adversely affect the safety of research participants, have an impact on the conduct of the study, or alter the benefit/risk balance. This report should be prepared independently and separately from other required AE/AR submission deadlines outlined in this section. Decree021-2017, Decree021-2017-Correct, PER-4, and PER-12 further state that the sponsor or the CRO is also required to notify the DIIS of critical or very serious and major or serious deviations to the clinical trial protocol within a maximum period of seven (7) calendar days from the time of becoming aware of the incident.

The G-SafeRpt further explains that if the sponsor or the CRO is aware of safety findings that are not covered within the scope of an SAE/SAR or SUSAR, these findings require another measure or action such as a security emergency measure, an amendment to the protocol or informed consent, or the suspension or cancellation of the clinical trial. The sponsor should communicate this information to the DIIS through a detailed report that includes the measures and actions taken at the local and international levels, if already established. The ECs and PI should also be notified within seven (7) calendar days. The information must be written in Spanish and English, be contained in an electronic medium (CD), and be presented in the DIIS’s Document Processing Office. The sponsor is subsequently required to initiate administrative procedures that correspond to the measure or action taken, and in accordance with the requirements established by the clinical trial regulations. Refer to the G-SafeRpt for examples of administrative procedures.

As delineated in Decree021-2017, the G-SafeRpt, and PER-72, the sponsor is also required to submit, electronically on a quarterly or semi-annual basis, SAE/SAR and SUSAR reports occurring internationally, to the DIIS and the Council for International Organizations of Medical Sciences (CIOMS) whether they have occurred in the authorized trial, in other trials with the same IP, or in a context of different use. The G-SafeRpt specifies that the information should be presented on magnetic media. Refer to Annex 1 in the G-SafeRpt for data requirements. PER-72 further indicates that the sponsor should send the SUSAR reports for events that have occurred abroad as soon as possible to the investigator using CIOMS Form I (PER-18). The investigator, in turn, will send the reports to the EC. Further, per Decree021-2017, the DIIS must notify the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)) of any SAEs/SADRs and SUSARs caused by an IP being used in an authorized trial in Peru within a maximum period of 15 working days after receiving notification about the incident. The INS-CTManual also indicates authorized ANM personnel will have access to SAEs/SADRs and SUSARs that have occurred in Peru via REAS-NET (PER-69). (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)). See also the G-CTSafety for information on actions taken by the INS’s DIIS in response to SAEs/SARs, SUSARs, and safety reports.

Other Safety Reports

As delineated in the INS-CTManual and the G-SafeRpt, the sponsor or the CRO must also submit an annual IP safety report (DSUR) to the DIIS. Decree021-2017 further specifies that the DSUR should be sent to the DIIS and the ANM. Per the INS-CTManual, the translation of the annual report summary must be presented in English and Spanish. The G-SafeRpt explains that the DSUR should be prepared after the first authorization of the clinical trial in any country. This is referred to as the Development International Birth Day (DIBD). The report should comply with the ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (PER-52). The sponsor must complete form FOR-OGITT-048 (PER-45) online in Spanish as well as submit a copy of the DSUR to the DIIS on CD.

In addition, per the G-SafeRpt, the sponsor or the CRO must describe in the protocol the SAEs that will not be reported promptly because they are expected to occur in the study population with a frequency independent from their exposure to the IP. The sponsor or the CRO is also required to describe in the protocol the procedures for monitoring SAEs produced by the IP. Moreover, depending on the trial design, the pathology, and the IP, the sponsor or the CRO will describe in the protocol the notification procedures for non-serious AEs. Decree021-2017 also notes that the sponsor or the CRO should continuously evaluate IP safety and implement an IP security monitoring system.

According to the INS-CTManual and the G-SafeRpt, in cases of prenatal exposure due to a pregnant woman’s participation in a clinical trial, the PI, the sponsor or the CRO is required to submit form FOR-OGITT-047 (PER-39) to notify the DIIS of the SAE/SAR or SUSAR. Per the G-SafeRpt, the sponsor submits the form and the procedures for monitoring and controlling the pregnancy and newborn on magnetic media. The notification of a pregnancy must be made within seven (7) calendar days. The INS-CTManual also indicates prenatal monitoring reports must also be prepared during pregnancy, childbirth, and for six (6) months postpartum following the occurrence. See the Pregnant Women, Fetuses & Neonates section for additional information on this population.

See Decree021-2017, the INS-CTManual, the G-SafeRpt, and PER-38 for detailed sponsor/CRO reporting requirements.

Form Completion & Delivery Requirements

As per Decree021-2017, the INS-CTManual, the G-SafeRpt, and PER-72, all AEs/ARs, SAEs/SARs, and SUSARs must be reported electronically by the sponsor or the CRO using REAS-NET (PER-69). PER-12 specifies that notifications of very serious and major or serious protocol deviations should be submitted using FOR-OGITT-053 (PER-40) via the INS’s Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2). PER-114 further notes that reports of SAEs (REAs) and deviations can be submitted via PER-89, regardless of the year of trial authorization. However, REAs and deviations that have been submitted via the older REPECv1 platform (PER-91) will remain on this platform for consultation, if required.

(Refer to PER-38 for the DIIS SAE/SAR form, FOR-OGITT-046. All SAEs/SARs and SUSARs must also be reported on the CIOMS Form I (PER-18). The INS-CTManual further notes that the sponsor or the CRO should also submit a printed copy of the CIOMS report in Spanish or English to the INS’s DIIS.

Pursuant to the G-SafeRpt, to report post-study AEs, the sponsor or the CRO should send an email to consultaensayos@ins.gob.be to coordinate with the person in charge of computer systems and grant the person access to REAS-NET (PER-69) to complete and submit the online form FOR-OGITT-046 (PER-38). SAEs/SAR notifications following a trial’s completion should remain in the research site archives.

Interim and Annual Progress Reports

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

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

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

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

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

Final Report

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

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

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

Other Reporting Requirements

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

Interim and Annual Progress Reports

National Institute of Health (INS)

As delineated in Decree021-2017, the INS-CTManual, PER-72, PER-47, PER-8, and PER-14, the sponsor or the contract research organization (CRO) must submit a progress report for each institution in which a trial is conducted from the date of the study’s authorization to the Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) within Peru’s National Institute of Health (Instituto Nacional de Salud (INS)). The report should be submitted quarterly or biannually to the INS’s Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2) for each of the approved research sites. Per the INS-CTManual, this report should be submitted regardless of the enrollment status in each site. The INS-CTManual and PER-14 further specify that the submission deadline is up to seven (7) calendar days after completing the quarterly or half-yearly period. The sponsor or the CRO should print and sign the electronic form and deliver it to the INS’s Document Processing Office within 20 working days. Refer to the INS-CTManual for additional information, and PER-47 and PER-8 for the progress report form and detailed submission instructions.

PER-92 further notes that while the older REPECv1 platform (PER-91) is closed for the entry of progress reports, research center final reports, national final reports, and international final reports, the reports will remain in the system for consultation.

In addition, Decree021-2017 and PER-72 state that the progress report must be sent in print and electronic media, and include the following information:

• Number of patients enrolled in the study and status (e.g., in treatment, retired from study, completed study, or who are not ready to enroll) (Decree021-2017)
• Summary of serious adverse events/adverse reactions (SAEs/SARs) and non-serious adverse events (AEs)/adverse reactions (ARs) related to the investigational product (IP), and deviations occurring in the corresponding period (Decree021-2017)
• Number of patients who failed the screening (PER-72)
• Number of patients with clinical failure (PER-72)

According to PER-72, the following documentation should also be attached to the progress report:

• Quarterly or half-yearly report of deviations/breaches to the protocol that occurred during the stated timeframe for every research site
• Quarterly or half-yearly report of the serious and unexpected adverse reactions (SUSARs) related to the IP that have occurred abroad

Ethics Committees

As per Decree021-2017, the principal investigator (PI) is also responsible for submitting clinical trial progress and final reports to the research institution and the institutional ethics committee (EC) (El Comité Institucional de Ética en Investigación (CIEI)).

Res233-2020, which regulates human subjects research other than clinical trials of drugs or devices, indicates that researchers should submit progress reports, final reports, suspension reports, and early termination reports, among others, to the EC per the terms established by the committee.

Final Report

As delineated in Decree021-2017, the INS-CTManual, PER-72, PER-48, PER-16, and PER-14, the sponsor or the CRO must submit a research site final report via PER-89 for each of the participating sites for a specific clinical trial within 30 calendar days following the closing visit made by the monitor. Per the INS-CTManual, this information should be provided regardless of the enrollment status of each site. The INS-CTManual notes that the electronic form should also be printed and signed by the sponsor or the CRO and delivered to the INS’s Document Processing Office within 20 working days. Refer to the INS-CTManual for additional information, and PER-48 and PER-16 for the final report form and detailed submission instructions.

Decree021-2017 also states that the final report should include the following information:

• Number of screened, enrolled, and retired patients who completed the trial
• Summary of SAEs/SARs and non-serious AEs/ARs related to the IP, and deviations occurring since the date of the last progress report

National Final Reports

Per Decree021-2017, Decree021-2017-Correct, the INS-CTManual, PER-72, and PER-14, national final reports should be submitted via PER-89 for the INS’s DIIS review within 60 calendar days following the date of the final report submission of the last research site. Per the INS-CTManual and PER-72, the national final reports should be electronically submitted (refer to PER-49 and PER-17 for the submission form and instructions).

For clinical trials performed only in Peru, the report must be submitted within a maximum period of six (6) months following the trial’s conclusion as indicated in Decree021-2017, Decree021-2017-Correct, the INS-CTManual, and PER-72. The DIIS will send a copy of the final national report of clinical trials to the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)) within 30 business days following receipt of the report. (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)).

Per the INS-CTManual, the electronic form should also be printed and signed by the sponsor or the CRO and delivered to the INS’s Document Processing Office within seven (7) working days. If applicable, a report of the study results and conclusions must be attached as established in the INS-CTManual. Refer to the INS-CTManual for additional information, and PER-49 and PER-17 for the national final report form and detailed submission instructions.

Decree021-2017 further explains that the national final report should include the following information:

• Number of screened, enrolled, retired patients who completed the trial
• Summary of SAEs/SARs and non-serious AEs/ARs related to the IP, and deviations that occurred
• For trials performed only in Peru, the report should also include the final results and conclusions of the trial

International Final Reports

As delineated in Decree021-2017, the INS-CTManual, and PER-72, international final reports should be submitted to PER-89 within 12 months following the completion of the last clinical trial in all international research sites. Per the INS-CTManual, the sponsor or the CRO should also print and sign the electronic form and deliver it to the INS’s Document Processing Office within 20 working days. In addition, a report of the study results and conclusions should be attached as established in the INS-CTManual. PER-72 notes that the report should include the results and the study conclusions before publication. Refer to the INS-CTManual for additional information, and PER-46 and PER-9 for the international final report form and detailed submission instructions.

Results Publication

Further, according to Decree021-2017, the INS, in coordination with the sponsor, must submit a Results Publication after the final national or international report is completed to provide the results of authorized and performed clinical trials through PER-89 using form FOR-OGITT-058 (PER-23). The sponsor is also obligated to submit an article to a national or international scientific journal that strictly reflects the final report submitted to the DIIS and notify DIIS of this submission using form FOR-OGITT-059 (PER-41). The published article must also be sent to the INS and the research institution in print and electronic media.

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 for submitting 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 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.

Decree021-2017 defines a sponsor as an individual, group of individuals, company, institution, or organization with legal representation in the country, and duly registered in the corresponding public registries. The sponsor takes ultimate responsibility for trial initiation, maintenance, conclusion, and financing. When an independent researcher initiates and takes full responsibility for a clinical trial, then the role of sponsor is assumed.

Decree021-2017 also states that sponsors not based in Peru are required to appoint a legal representative who channels all the communication with the Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) within Peru’s National Institute of Health (Instituto Nacional de Salud (INS)) for the trial’s duration.

Decree021-2017 also explains that a sponsor can authorize a contract research organization (CRO) with legal status and an office in Peru to carry out certain work and obligations regarding the trial. However, the sponsor is ultimately responsible for the execution of the research protocol and the results of the trial.

Overview

As set forth LawNo14.874 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the sponsor is responsible for selecting the investigator(s) and the institution(s) for a clinical trial. The sponsor must also ensure that the investigator(s) are qualified by education, training, and experience to assume responsibility for the proper conduct of the trial. BRA-28 also notes that the investigator(s) should provide evidence of all the qualifications specified by the applicable regulatory requirements through up-to-date curriculum vitae(s) (CVs) and/or other relevant documentation requested by the sponsor, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), and/or the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).

As delineated in BRA-28, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. See the Submission Content section for additional information on clinical trial application requirements. See also CLNo046 for the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidance on submitting requests for inclusion/exclusion of research center(s).

Foreign Sponsor Responsibilities

As specified in the 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

BRA-28 indicates that for multicenter trials, the sponsor should ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by ANVISA, and given approval/favorable opinion by the EC (CEP)
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites. For investigators collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data
• The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards for the assessment of clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

Per BRA-28, the sponsor must also organize a coordinating committee or select coordinating investigators.

Overview

Per Decree021-2017, the National Institute of Health (Instituto Nacional de Salud (INS))’s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))), follows the requirements provided in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (PER-53) for topics not addressed in Decree021-2017. Accordingly, PER-53 states that the sponsor or the contract research organization (CRO) is responsible for selecting the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. Investigators should also be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial. Decree021-2017 further specifies that, in addition to professional competence, the sponsor or the CRO should also ensure that investigators have enough time to conduct the trial and agree to comply with good clinical practices (GCP) and ethical standards. Res233-2020 also requires investigators to have basic training in ethical research with human beings. PER-53 may also be referred to for additional information on investigator requirements.

Per Decree021-2017 and Res655-2019 (which amends Decree021-2017), research institutions must also register with the INS’s Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2), but are no longer required to provide proof of this registration in the clinical trial authorization application. As delineated in Res655-2019, the research institution’s legal representative must submit an application for registration that includes the following:

• A code from the National Registry of Institutions that Provide Health Services (Registro Nacional de Instituciones Prestadoras de Servicios de Salud (RENIPRESS)) (Refer to PER-80 for instructions on how to register a health service provider institution in RENIPRESS.)
• Details of the categorization level assigned to the health institution interested in obtaining registration as a research center to conduct clinical trials (per Res546-2011, categorization is based on the institution’s levels of complexity and functional characteristics)
• Number and date of proof of payment of processing fees

Decree021-2017 also requires research centers to register with REPEC (PER-89) to carry out clinical trials at the research institution’s request. According to PER-73, research centers should apply electronically via REPEC (PER-89), submit the printed application form, FOR-OGITT-022 (PER-19) per Res0423-2019, and complete the printed affidavit form, FOR-OGITT-023 (PER-44). Research center registration is valid for three (3) years. Refer to PER-73 for detailed registration instructions and PER-90 for a research center registration checklist. According to PER-73, public and private sector research centers must also be registered in (REPEC) (PER-89), at the request of the research institution, to carry out clinical trials.

Per PER-113, the INS’s DIIS has established the Validity of the Record of Registration of Research Center in compliance with Law1452 (which amends Law27444). In accordance with Law1452, any Research Center Registration Certificate (Constancia de Registro de Centros de Investigación (RCI)) that is valid as of September 16, 2018, and all those certificates subsequently issued, are valid for an indefinite period, and are therefore exempt from the registry renewal process delineated in Decree021-2017. However, the DIIS may continue to carry out subsequent scheduled or unscheduled audits in accordance with its authority, and may revoke the certificate, if it verifies changes in the conditions essential to obtaining the registration.

PER-131 further states that the RCIs are no longer valid for research centers that do not have active clinical trials and whose RCI was issued prior to September 16, 2015. Research institutions that intend to continue carrying out clinical trials may request an update of the RCI validity by completing and signing the printed application form, FOR-OGITT-022 (PER-19), and affidavit form, FOR-OGITT-023 (PER-44), and submitting via REPEC (PER-89). Research institutions must also notify the Virtual Submission Platform (Mesa de Partes Virtual (MPV)) (PER-106) of the submitted procedures, and attach PER-19 and PER-44. Additionally, as indicated in PER-130, sponsors or CROs are obligated to verify that the research center where a clinical trial will be conducted is authorized in the specialty related to the proposed trial. If the research center did not provide the related specialty information in its REPEC registration, the research institution’s legal representative, as research center administrator, must submit a request to the INS’s DIIS to modify the registration to include the required specialty. The new RCI must also include the required specialty. All of these procedures must be carried out prior to the request for authorization of a clinical trial.

Foreign Sponsor Responsibilities

Decree021-2017 states that the sponsor is required to appoint a legal representative in the country for the trial’s duration when based outside of Peru. Per Decree021-2017, the in-country legal representative channels all communication with the INS’s DIIS during the study’s execution, unless this responsibility is delegated to a CRO. As specified in Decree021-2017, the sponsor may transfer any or all of the study related duties and functions to a CRO. However, the sponsor is ultimately responsible for the execution of the research protocol and results of the clinical trial.

See PER-7 for detailed documentation submission requirements for a foreign sponsor to delegate an in-country legal representative or for a local sponsor to appoint a legal representative. Decree021-2017 further explains that the in-country representative must also be registered in REPEC (PER-89) for the trial’s duration. Refer to the Submission Process section for additional REPEC registration instructions.

Data and Safety Monitoring Board

Decree021-2017 requires the sponsor to provide data on the Data Safety Monitoring Board (DSMB) including its composition, a summary of its role and notification procedure, a statement of independence from the sponsor, and any conflicts of interest. Additionally, the sponsor should specify where to find other details about the by-laws not included in the protocol or explain why a DSMB is not necessary.

Multicenter Studies

Per Decree021-2017, multicenter clinical trials are carried out by more than one (1) investigator and require an appointed coordinator responsible for processing all of the data and analyzing the results.

In addition, according to PER-53, in the event of a multicenter clinical trial, the sponsor must ensure that:

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

In addition, the sponsor is responsible for the organization of a coordinating committee and/or selection of coordinating investigator(s), if they are to be utilized.

Insurance

As set forth in the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the sponsor is responsible for providing insurance or should indemnify the investigator/institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

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 research, 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 with regard to 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 prior material provision
• Other types of compensation required, depending on the research project

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

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

Post-Trial Access

Pursuant to LawNo14.874, before the start of the clinical trial, the sponsor and the investigator must submit a post-study access plan to the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), presenting and justifying the need or otherwise to provide free access to the investigational product (IP) after the trial’s completion. If there is a need to supply post-trial access to the IP, a post-study supply program must be prepared, in accordance with the regulations. In order to guarantee the receipt of the IP after the end of the clinical trial, the post-study supply program must ensure the continuity of the participant's safety monitoring. The program should only be initiated after regulatory approval, the request for which must be submitted in a timely manner so that the research participant can transition to the post-study period without prejudice to the continuity of treatment.

Additionally, per LawNo14.874, at the end of the clinical trial, the investigator, after hearing from the sponsor and the research participant, must carry out an assessment on an individual basis to determine the need to continue the IP for each participant. The free provision of the IP after the trial must be implemented whenever it is considered the best therapy or treatment for the participant’s clinical condition and presents a more favorable risk-benefit ratio in comparison with other available treatments. The assessment of the need for continued supply of the IP 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-study 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
• 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.

In addition, per ResNo466, at the end of the study, the sponsor much ensure free and indefinite access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective. Access must also be guaranteed to participants between the time they stop their participation in the trial and the end of the study.

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. ResNo311, which amends 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-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (CNS)). The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Study Medicine Supply Programs (see 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-study drug supply. See ResNo903 for additional information. See also the Submission Content section for specific documentation requirements, and the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

Insurance

As set forth in Decree021-2017, the G-EC-CTRev, and PER-71, it is a legal requirement for the sponsor or the contract research organization (CRO) to carry a valid insurance policy for the expected duration of the study for any unforeseen injury to research participants. Per Res0423-2019, the sponsor or the CRO should sign an affidavit (PER-51) guaranteeing an active insurance policy is in place according to requirements in the INS-CTManual.

Decree021-2017 also specifies that the sponsor or the CRO must obtain insurance coverage in Peru or have a legal representative in Peru who will represent the sponsor or the CRO, if the policy is from a foreign company. The insurance policy must be in force until the date of submission of the National Final Report. At the end of this period, it should be renewed whenever there is still a possibility of late damages arising from the adjudication of injuries resulting from the clinical trial.

Compensation

Injury or Death

According to Decree021-2017 and PER-71, in addition to guaranteeing an active insurance policy is in place, the affidavit (PER-51) submitted by the sponsor or the CRO also certifies a financial fund is immediately and conveniently available. The fund ensures free medical treatment to participants who suffer any trial-related injuries as long as the insurance policy is activated.

In addition, as described in Decree021-2017, compensation will be awarded in the following circumstances:

• Any damage to the research participant as a result of participation in the clinical trial
• Any damage that occurred during pregnancy or that would have occurred to the newborn in the case of pregnancy in a female research participant or in the couple of the male research participant, as long as it is a result of their participation in the trial
• Economic damages derived directly from earlier stated damages, provided that the damage is not inherent to the pathology under study, or to the individual evolution of the research participant

The sponsor’s obligation to award compensation is independent of the validity or available coverage of the contracted insurance.

Trial Participation

Per Decree021-2017, research participants may receive reasonable compensation from the sponsor for extraordinary expenses incurred and loss of productivity arising from their participation, which will be specified in the informed consent. The institutional ethics committee (EC) (El Comité Institucional de Ética en Investigación (CIEI)) will evaluate this form of compensation on a case-by-case basis and determine whether it unduly influences the consent of the research participant.

PER-15 further states the following:

• Research participants may receive compensation in order to reimburse them for expenses (e.g., transportation, accommodation, communication, food expenses) and/or compensate the loss of productivity, time, among others, derived from their participation. Any compensation to the participants of the investigation must be reasonable and proportionate and, in no case, may it constitute undue influence.
• In order to safeguard the rights of research participants, researchers and sponsors should take into account the personal and specific considerations of each research participant for the calculation of compensation for expenses incurred arising from their participation and,
• ECs must evaluate the compensation amount, paying special attention to the information that appears in the informed consent forms, in order to ensure that the established compensations consider the possible conditions of each research participant

Post-Trial Access to the Investigational Product

As delineated in Decree021-2017, the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)) is also responsible for authorizing post-study access to the investigational product (IP) by study participants when it is demonstrated to be beneficial. ANM authorization is granted on a case-by-case basis through the following procedures:

• Authorization of a clinical trial corresponding to a Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))) approved extension study
• ANM authorization for an IP which must have proved to be beneficial to a participant, at the PI’s discretion, and its use will be maintained as soon as there is benefit

The PI should communicate to the sponsor the IP’s benefit to the participant, and the sponsor must, in turn, request ANM authorization (See Title X of Decree021-2017 for documentation submission requirements) (Note: The ANM is also referred to as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)).

Decree021-2017 also notes that participants must be ensured free access to the IP following the trial’s conclusion. Before the study commences, post-study access should be anticipated, and this information must be provided during the informed consent process.

Quality Assurance/Quality Control

As set forth in LawNo14.874 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil adopted per ResNo945, the sponsor is responsible for the implementation and maintenance of quality assurance (QA) and quality control (QC) systems, based on standard operating procedures (SOPs), in order 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, with a view to ensuring its reliability and correct processing; 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). Per BRA-28, the CRO should also implement a QA/QC plan.

As delineated in BRA-28, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

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

In addition, BRA-28 states that the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. See the Initiation, Agreements & Registration section for additional information on sponsor agreements with investigator(s), institution(s), and any other parties.

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 quality assurance and monitoring.

Monitoring Requirements

As part of its QA system, BRA-28 notes that the sponsor or the CRO should ensure the trial is adequately monitored and determine the appropriate extent and nature of monitoring, based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. Monitors, which are appointed by the sponsor, should be appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.

BRA-28 also explains that if or when the sponsor performs audits as part of implementing QA, the following should be considered:

• The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and other applicable regulatory requirements
• The sponsor should appoint auditors to review the clinical trial who are independent of the clinical trial/data collection system(s)
• The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented
• Auditing procedures that ensure the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written SOPs
• The auditor’s observations and findings should be documented

LawNo14.874 also 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, and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)); allowing the sponsor to monitor and audit the research; and allowing ANVISA, the National Research Ethics Authority, and the EC (CEP) to conduct inspections.

BRA-28 does not provide a specific timeframe for the audit process. Regulatory authorities may seek access to an audit report on a case-by-case basis when evidence of serious GCP noncompliance exists, or in the course of legal proceedings. Additionally, noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution or member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identify serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/ institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify the regulatory authorities promptly. Refer to BRA-28 for detailed audit requirements.

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.

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

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.

Premature Study Termination/Suspension

Pursuant to LawNo14.874, the sponsor is responsible for promptly communicating to the investigators involved, the executing institution, and ANVISA regarding the reasons for the suspension or premature termination of the research, where applicable. ResNo945 further explains that, at any time, the sponsor may 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 clinical trial has 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. If a DDCM or clinical trial is canceled for safety reasons, the sponsor must describe the reasons for the cancellation and present the measures to minimize/mitigate risk to the clinical trial participants in compliance with the requirements detailed in the AESafetyManual. 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, 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 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.

BRA-28 also explains that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The EC (CEP) should be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). Additionally, if the investigator terminates or suspends a trial without the sponsor’s prior agreement, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the EC, and should provide the sponsor and the EC a detailed written explanation of the termination or suspension.

Quality Assurance/Quality Control

As stated in Decree021-2017, the sponsor or the contract research organization (CRO) is responsible for ensuring that all information on the investigational product (IP) and additional documentation corresponds to the research protocol and complies with good clinical practices (GCPs) as provided in the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (PER-53), as well as the requirements established in Decree021-2017. PER-53 further explains that the sponsor or the CRO is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, documented (recorded), and reported in compliance with the protocol, PER-53, Decree021-2017, and other applicable regulatory requirements.

Declaration of the sponsor guaranteeing that the researchers will allow the monitoring, audits, supervision of the institutional ethics committee (EC) (El Comité Institucional de Ética en Investigación (CIEI)) and inspections of the clinical trial by the National Institute of Health (Instituto Nacional de Salud (INS))'s Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT))), including direct access to the documentation of the clinical trial. Per Decree021-2017, the sponsor or the CRO is responsible for obtaining agreement from the investigators to ensure that they will allow monitoring, audits, ethics committee (EC) monitoring, and trial inspections by the DIIS, including direct access to the clinical trial documentation. PER-53 further states the sponsor is responsible for securing agreements from all involved parties to ensure direct access to all trial related sites, source data/documents, and reports for the purpose of monitoring and auditing by the sponsor and inspection by domestic and foreign regulatory authorities.

In addition, PER-53 states that the sponsor or the CRO should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

• During protocol development, identification of processes and data that are critical to ensure participant protection and the reliability of trial results
• Identification of risks to critical trial processes and data
• Evaluation of the identified risks against existing risk controls
• Decisions on which risks to reduce and/or which risks to accept
• Documentation of quality management activities and communication to those involved in or affected by these activities
• Periodic review of risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, a description of the quality management approach implemented in the trial and a summary of important deviations from the predefined quality tolerance limits and remedial actions taken

Monitoring Requirements

As part of the clinical protocol requirements, Decree021-2017 notes that the following data collection and monitoring activities should be implemented:

• Develop plans to evaluate and collect baseline, outcome, and other study data, including a process to improve data quality and a description of instruments used in the study along with their reliability and validity, if known
• Prepare plans to promote participant retention and complete follow up, including a list of data to be collected from participants who leave the trial or deviate from it
• Document (or provide) data monitoring committee details including its composition, a summary of its role and notification procedure, a statement of its independence from the sponsor, and its conflicts of interest. Details about by-laws not included in the protocol should be specified, or an explanation about why this committee is not needed
• Describe trial monitoring arrangements/audits and sponsor’s statement to ensure that investigators will allow monitoring, audits, EC monitoring, and INS’s DIIS trial inspections, including direct access to clinical trial documentation
• Provide plans to enter, encode, protect, and save data, including any process to improve its quality
• Specify where data management procedure details not included in the protocol can be found

No specific timeframe is provided for the audit process.

The G-CTInspec explains that the INS’s DIIS inspection team carries out GCP inspections in accordance with Decree021-2017. Trial inspection findings are based on the severity of the clinical trial conditions, practices, or processes and their potential to affect adversely the rights, safety, or well-being of the research participants and/or data quality and integrity. Inspections are carried out through ordinary and extraordinary inspections, with qualified personnel (multidisciplinary, if applicable) and may be conducted at the beginning, the middle, or the end of the trial. Ordinary inspections are conducted according to the DIIS’s Annual Schedule of Ordinary Inspections. Extraordinary inspections are performed in response to a complaint received by phone, written communication, formal document submitted through the INS reception desk, or from any relevant information received through safety reports, progress reports, and/or a justified request by a clinical trial evaluation team that has obtained DIIS approval. If required, the DIIS coordinates with the National Authority for Pharmaceutical Products, Medical Devices and Medical Products (la Autoridad Nacional de Productos Farmacéuticos, Dispositivos Médicos y Productos Sanitarios (ANM)) for the agency’s assistance in verifying compliance with good manufacturing practices standards, good storage practices, and other IP related standards. (Note: The ANM is also known as the General Directorate of Medicines, Supplies and Drugs (La Dirección General de Medicamentos Insumos y Drogas (DIGEMID)) (PER-109)).

In addition, during an inspection, the evaluation of biological samples is conducted in accordance with the provisions in Decree021-2017. Please refer to the G-CTInspec for detailed clinical trial inspection procedures. See also PER-100 for the clinical trial inspection sheet form (FOR-OGITT-049). The INS-CTManual and the G-CTInspec indicate that when a regulatory medicines agency of high health surveillance notifies a research site to carry out an inspection visit in Peru, the sponsor or the contract research organization (CRO) is required to inform the INS’s DIIS of the date and time of this visit within five (5) business days of receiving the notification. The DIIS will then coordinate with the regulatory medicines agency of high health surveillance to arrange for their participation in the inspection visit as an observer.

Per the INS-CTManual, for regular clinical trial inspections scheduled by the INS’s DIIS, when inspection findings are critical, the sponsor or the CRO is required to submit a defense within a period of no more than seven (7) working days following receipt of the inspection report. If the inspection observations are minor or major, the sponsor or the CRO should submit their defense within a period of no more than 15 working days, after receiving the inspection report. The inspector will issue an official notice of compliance within a period of no more than 15 business days if the sponsor or the CRO addresses the issues identified in the report in a timely way. Please refer to section 7.9 of the INS-CTManual for detailed information on preparing for the INS’s DIIS scheduled clinical trial inspections and responding to the inspection reports received.

Per Decree021-2017, Res064-2021, and the G-CTSanction, in the event of a DIIS inspection during which violations in the implementation of a clinical trial are identified, the sponsor or the CRO will be subject to the following sanctions: a warning(s) and a fine for the infraction(s). In addition to the warning(s) and fine, the sponsor will also be required to cancel the trial. See also G-CTFines for additional information on how fines are assessed and graded.

As explained in Res064-2021 and the G-CTSanction, once an investigation is initiated, the DIIS’s Clinical Trials Subdirectorate (Subdirección de Ensayos Clínicos) (formerly known as the Executive Office of Investigation (Oficina Ejecutiva de Investigación (OEI)) notifies the participant(s) responsible for conducting the trial of the possible sanction(s) and the charges being made. The participant(s) then has five (5) business days from the date of notification to dispute the charges. The Clinical Trials Subdirectorate may subsequently carry out an examination to determine the existence of the liability(ies) subject to sanction within a maximum period of 30 business days. A final instructional report by the Clinical Trials Subdirectorate is prepared within no more than 15 business days and submitted to the DIIS. Once the report is received, within a maximum term of 15 business days, the DIIS decides on the application of the sanction and may order the performance of complementary actions if considered essential to resolving the procedure. Within a term not exceeding 15 business days, the DIIS then issues a resolution that applies the sanction or the decision to archive the procedure and the participant will be notified. The participant has 15 business days to file an appeal to the DIIS which will then be resolved within 30 business days.

Premature Study Termination/Suspension

Decree021-2017 states that the sponsor or the CRO is responsible for submitting the required documentation to Peru's INS to request a trial’s suspension. Per Decree021-2017 and Res655-2019 (which amends Decree021-2017), an application must be submitted that substantiates the reasons for the suspension and describes the data obtained until the time of the suspension. Refer to PER-43 for the clinical trial research site closure application form, PER-30 for the clinical trial suspension application form, and PER-31 for the clinical trial cancellation request form.

Electronic Data Processing System

As set forth in the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, when using electronic trial data processing systems, the sponsor must ensure that the system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human participant protection and reliability of trial results. In addition, the sponsor must maintain standard operation procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties should be clear, and the system users should be provided with training. Refer to BRA-28 for additional information.

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. ResNo945 and BRA-28 also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, or a marketing application receives the last approval. Per BRA-28, the sponsor should also inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

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

Electronic Data Processing System

No information is currently available.

Records Management

As set forth in Decree021-2017, the sponsor or the contract research organization (CRO) is required to possess a documented monitoring record, including the provision of specially selected and specialized personnel (monitors). Additionally, the sponsor or the CRO is responsible for filing in the country all documentation and data obtained for at least 10 years after the conclusion of the study. After two (2) years, the documentation/data may be filed electronically, after communication with the National Institute of Health (Instituto Nacional de Salud (INS)).

Per Decree021-2017, Peru also complies with the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (PER-53), which provides guidance to sponsors on records management. PER-53 further specifies that sponsor-specific essential documents should be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

In addition, PER-53 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.

Responsible Parties

For the purposes of data protection requirements, the LGPD delineates that the sponsor acts as the “controller” who is responsible for decisions regarding the processing of personal or sensitive personal research data. Within this context, the controller (sponsor) may carry out studies as a research body, guaranteeing, whenever possible, the anonymization of personal data.

Per CD-ANPD-No18, which regulates the performance of the person responsible for processing data, the person in charge is appointed by the controller and operator to act as a communication channel between the controller, data subjects, and the National Data Protection Authority (Autoridade Nacional de Proteção de Dados (ANPD)). The person in charge may be a natural person, member of the organizational structure of the processing agent or external to it, or a legal entity, and must be able to communicate with the holders and with the ANPD, clearly, 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. See also BRA-116 and BRA-119 for additional information.

Data Protection

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

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

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

See the LGPD and BRA-76 for detailed information on data protection requirements in Brazil.

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

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

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

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

In the event of a security incident, per CD-ANPD-No15, the controller must communicate to the ANPD and the data holder the occurrence of a security incident that could cause significant risk or damage to the holders in compliance with Article 48 of the LGPD. CD-ANPD-No15, which defines a security incident as any confirmed adverse event, related to the violation of the confidentiality, integrity, availability, and authenticity properties of personal data security, 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, establishes the procedures and rules applicable to international data transfer operations for countries or international organizations that provide a level of personal data protection adequate to that provided for in the LGPD, upon recognition of adequacy by the ANPD; or, when the controller verifies compliance with the principles, rights of the holder, and the data protection regime in the form of specific contractual clauses for a given transfer; standard contractual clauses; or global corporate standards as provided for in the LGPD and CD-ANPD-No19. Refer to Chapter V of the LGPD, CD-ANPD-No19, and BRA-118 for detailed international data transfer requirements.

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

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Children/Adolescents

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

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

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

Responsible Parties

Law29733 provides that the “person in charge of the personal data bank” is any natural person, private legal entity, or public entity that, alone or acting in conjunction with another, performs the processing of personal data on behalf of the owner of the personal data bank. Law1353 and Decree003-2013 modify the definition provided by Law29733 by stating that the entity “responsible for processing personal data” is any natural person, private legal entity, or public entity that, alone or acting jointly with another, performs the processing of personal data on behalf of the owner of the personal data bank by virtue of a legal relationship that binds him to it and defines the scope of its performance.

RegDir294-2020 (approved by Res688-2020), similarly defines the “holder of the personal data bank” as the natural person, private legal person or public entity, responsible for determining the purpose and content of the personal data bank, its treatment and the security measures. As described in RegDir294-2020, personal data bank holders specifically refer to public, private, or mixed entities in the health sector that are overseen by the Ministry of Health of Peru (Ministerio de Salud del Perú (MINSA)).

Data Protection

As delineated in Law29733, the person in charge of the personal data bank, is required to protect the confidentiality and background of the owner of the personal data. This obligation continues even after the conclusion of the relationship between the owner of the personal data and the person in charge. However, the person in charge of the personal data may be relieved of the obligation to uphold the owner’s confidentiality when there is prior, informed, explicit, and unequivocal consent by the owner, or when there are justifiable reasons related to national defense, public safety, or public health.

According to Law29733, the person in charge of the personal data bank (also referred to as the person in charge of processing personal data, as per Law1353) has the following obligations:

• To carry out the processing of personal data, only with prior informed, explicit, and unequivocal consent of the owner of the personal data
• To not collect personal data by fraudulent, unfair, or illegal means
• To collect personal data that is updated, necessary, relevant, and adequate, in relation to specific, explicit, and lawful purposes for which the data was obtained
• To not use the personal data processed for purposes other than those that motivated its collection, unless there is an anonymization or dissociation procedure
• To store personal data in a way that allows the exercise of the owner’s rights
• To delete and replace, or where appropriate, correct the personal data subject to processing once aware of its inaccurate or incomplete nature, without prejudice to the rights of the owner in this regard
• To delete personal data subject to processing when it is no longer necessary or relevant to the purpose for which it had been collected, or the deadline for its treatment has expired, unless there is an anonymization or dissociation procedure
• To provide the National Authority for the Protection of Personal Data with information related to the processing of personal data that it requires, and allow access to the personal data banks that it manages, for the exercise of its functions, within the framework of an administrative procedure in case it is requested by the affected party

RegLaw1353, which regulates the application of Law1353 and strengthens the personal data protection requirements delineated in Law29733, further establishes the terms of personal data protection violations provided in Law29733. Please refer to RegLaw1353 for information on sanctions imposed on personal data violations that include, but are not limited to, failing to treat personal data without the free, express, unequivocal, prior, and informed consent of the personal data holder and conducting sensitive personal data processing in breach of established security measures.

RegDir294-2020 (as approved by Res686-2020), in turn, establishes administrative criteria for the adequate treatment of personal data related to health or personal data in health in accordance with Law26842, Law29733, and Law27806. Pursuant to RegDir294-2020, MINSA classifies information relating to the problems, situation, or health conditions of the population in the health sector into two (2) categories: Personal Health Data (DPS) or Personal Data related to Health, and Health Information (IS). DPS are those related to the health or disease situation of a person that identifies or makes the person individually identifiable, corresponding to the past, present, or predicted health and disease, physical or mental, of a person, including the degree of disability and their genetic information.

RegDir294-2020 further explains that DPS are generated in any medical or health act, or any health care received in a health facility or outside of it, including the DPS generated in health-related research. DPS also includes information related to the medical act or health information that may affect personal and family privacy or self-image, national security, and foreign relations. When subjected to the proper anonymization and dissociation procedures, DPS become IS, where it is not possible to know the identity of the owners of the original DPS. In this case, health establishments may transmit health information related to the health of its users. Additionally, information generated from the care of patients in health emergency or pandemic situations, insofar as it corresponds to DPS, must receive the same treatment that DPS receive under normal conditions per the requirements specified in RegDir294-2020. See RegDir294-2020 for more information on the treatment of DPS.

Consent for Processing Personal Data

Prior to the collection of personal data, the entity responsible for processing this data must obtain the data holder’s consent for the collection and use of personal data per the provisions of Law29733, Law1353 (which amends Law29733), and Decree003-2013.

Law29733 and Decree003-2013 provide definitions to address health related data. Per Law29733 and Law1353, sensitive data is defined as personal data constituted by biometric data that by themselves can identify the holder; data referring to racial and ethnic origin; economic income, opinions, or political, religious, philosophical or moral convictions; union affiliation; and information related to health or sexual life. Decree003-2013, in turn, provides the following definitions:

• Personal data related to health – information concerning the past, present, or forecasted physical or mental health of a person, including the degree of disability and their genetic information
• Sensitive data – information related to personal data referring to physical, moral, or emotional characteristics, facts, or circumstances of an individual’s emotional or family life; personal habits that correspond to the most intimate sphere; or information related to physical health or mental or other analogs that affect an individual’s privacy

Law29733 and Law1353 further explain that prior to the data collection, the holder of the personal data has the right to be informed of the following information in a detailed, simple, express, and unambiguous manner:

• The purpose for which the personal data will be processed
• Recipient identity
• The existence of the databank in which the holder’s data will be stored, as well as the identity and address of the owner, and, if applicable, the person in charge of processing the personal data
• The obligatory or optional nature of the holder’s answers to the questionnaire that is presented, especially regarding sensitive data
• The transfer of personal data
• The consequences of the holder providing personal data and the refusal to do so
• The time during which the holder’s personal data is kept, and
• The possibility of exercising the rights granted by law and the means provided for it

Decree003-2013 states that in cases involving sensitive data, consent must be granted in writing, through the personal data holder’s signature, digital signature, or any other authentication mechanism that guarantees the unequivocal will of the holder.

Law29733 and Law1353 also indicate that sensitive data is subject to special protection, and consent for the purposes of its treatment must also be made in writing. Even if the owner does not consent, the processing of sensitive data can be carried out when authorized by law, provided that it addresses important reasons of public interest.

Law29733 further states that the owner of the personal data bank, the person in charge, and others involved in any way with processing an individual’s personal data are obligated to protect the confidentiality of the individual’s background and data. This obligation continues even after the conclusion of the relationship between the personal data holder and the entity responsible for the data. However, the person in charge of the personal data may be relieved of the obligation to uphold the owner’s confidentiality when there is prior, informed, explicit, and unequivocal consent by the owner, or when there are justifiable reasons related to national defense, public safety, or public health.

In addition, per RegDir294-2020, the DPS owner’s written consent is required to process their personal data. Further, even when the owner’s consent is not obtained, sensitive data processing can be carried out when authorized by law, provided that it meets important reasons of public health interest. These reasons refer to the exceptional access to the DPS of a person(s), without their consent, when that information is necessary to protect the population. In no case does this exception extend to the entire population or groups of populations, as this would require the written and express consent of each person per Law29733.

RegDir294-2020 further explains that all DPS have an owner to whom they belong and can exercise their rights of access, rectification, cancellation, opposition, right to guardianship, objective, treatment, among others as indicated in Law29733. As long as the DPS owner gives prior and explicit written consent, the public, private, and mixed health sector entities may share the DPS owner’s information. The health sector entities must also designate an area to respond to DPS holder requests to exercise their rights regarding their information. The DPS owners must be provided the appropriate conditions to grant their consent through handwritten or digital signature, or any other authentication instrument that guarantees the owner’s unequivocal will. The DPS owner may revoke consent to the treatment of their DPS at any time, and the health professional or person who treats them must respect their will.

Refer to PER-3 for additional information on Law29733, and PER-99 and PER-101 for information on RegDir294-2020.

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, OMREC, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, state that the investigator, or their designated representative, must fully inform the participant or the legal representative/guardian of the relevant aspects of the research, including the EC’s (CEP)’s approval. As delineated in LawNo14.874, ResNo466, OMREC, the G-ClinProtocols-FAQs, and BRA-28, 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. Per BRA-28, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. Further, per LawNo14.874 and BRA-28, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive their legal rights, or, per BRA-28, that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. 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, the G-ClinProtocols-FAQs, and BRA-28, the information should be in both written and oral form. Also, per the G-ClinProtocols-FAQs and BRA-28, 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.

Re-Consent

According to LawNo14.874 and BRA-28, 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 BRA-28 and CLNo51, the investigator must ensure that the participant or legal representative/guardian sign the revised ICF and any other updated information. CLNo17 further notes that changes made to the ICF through separate documents are not considered acceptable. The update requires the investigator to generate a single and complete version of the new document, free of addenda and/or other documents associated with it. The investigator or their delegated representative should also emphasize the changes contained in the updated ICF. The clarifications delineated in CLNo17 also apply to assent forms.

Language Requirements

As earlier stated, LawNo14.874, ResNo466, the G-ClinProtocols-FAQs, and BRA-28 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, BRA-28, and OMREC state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. In addition, LawNo14.874 and BRA-28 explain 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.

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 available on consent waivers for research participants. See the Consent for Specimen section for information on waivers pertaining to a participant’s stored genetic materials.

Obtaining Consent

In all Peruvian clinical trials, a freely given informed consent must be obtained from each participant in accordance with the principles set forth in Law26842, Decree021-2017, the G-EC-CTRev, and the Declaration of Helsinki (PER-76). Decree011-2011 further states that all scientific and technological research and applications will be developed with respect for the prior, free, express, and informed consent of the person concerned, based on adequate information. Consent in such terms implies the recognition of the patient's right to be treated as a free person and capable of making their own decisions.

Per Decree021-2017 and the G-EC-CTRev, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an National Institute of Health (Instituto Nacional de Salud (INS))-registered institutional ethics committee (EC) (El Comité Institucional de Ética en Investigación (CIEI)) and provided to the INS with the clinical trial application. PER-83 further specifies that the sponsor or the contract research organization (CRO) must provide copies of the research protocol and ICF that are stamped and signed by the EC in its entirety as evidence that the approved version is being presented. (See the Required Elements section for details on what should be included in the form.)

As delineated in Decree021-2017, RegLaw29414, the G-EC-CTRev, and Res233-2020, investigator(s) must provide detailed research study information to the participant or legal representative/guardian. The ICF content should be presented briefly and clearly in writing, in a manner that is easy to understand, commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and the legal representative/guardian should also be given adequate time to consider whether to participate. Per Decree021-2017, when drafting and presenting the ICF, special consideration must be taken with regard to the participant’s culture, traditional values, intelligence, and education.

Res233-2020, which regulates human subjects research other than clinical trials of drugs or devices, states that investigators must also submit any modifications or amendments to the initially approved research project and informed consent processes in a report to the EC in a timely manner, except in cases where these changes are necessary to prevent harm to the research participants when ECs must be informed within 24 hours. Furthermore, participants must be kept constantly informed about the changes, progress, and results of the research according to the applicable regulations.

Re-Consent

As indicated in Decree021-2017, the participant or legal representative/guardian is required to sign a revised ICF if any changes occur in the protocol or in the treatment methods or procedures.

Language Requirements

Per Decree021-2017, the ICF must be written in Spanish and in the language of the research participant.

Documenting Consent

Decree021-2017 and the G-EC-CTRev state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. Where the participant is illiterate or the legal representative/guardian is illiterate, a fingerprint will serve as a signature, and should be obtained in the presence of and countersigned by an impartial witness who does not belong to the research team. Before participating in the study, the participant should receive a copy of the signed and dated ICF.

Waiver of Consent

No information is available regarding waiver of consent.

Based on ResNo466, OMREC, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

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

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

As delineated in Decree021-2017 and the G-EC-CTRev, 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):

• Trial title (include version and date)
• Sponsor(s), research institution, principal investigator (PI), ethics committee (EC), and the National Institute of Health (Instituto Nacional de Salud (INS)) contact information
• Explicit invitation to participate in an experimental research study and the voluntary nature of participation
• Trial rationale, objectives, and purpose
• Trial treatments or interventions
• Randomization and blinding procedures
• Trial procedures and purpose
• Expected duration of research participant’s involvement in the trial
• The approximate number of participants in the study
• Expected or unforeseeable risks and discomforts arising from the trial
• Free treatment and procedures used as part of the trial design
• The expected benefits that can be obtained from the study
• If there are alternative procedures that could be advantageous to the participant
• The commitments assumed by the participant when agreeing to participate in the study
• The guarantee of receiving answers to any questions and clarification for any doubts about the procedures, risks, benefits, and other trial related matters and the treatment of the participant
• In the event of trial-related injuries, contact information for the PI, the EC president, and the Directorate of Health Research and Innovation (Dirección de Investigación e Innovación en Salud (DIIS)) (formerly known as the General Office for Research and Technology Transfer (Oficina General de Investigación y Transferencia Tecnológica (OGITT)))
• Participant’s right to withdraw consent at any time and to stop participating in the study without creating any detriment to continue care and treatment
• The participant and/or the legal representative agrees to authorize access to personal data to verify procedures and/or trial data without violating the participant’s confidentiality
• The extent to which confidentiality of records identifying the participant will be maintained, and the possibility of record access by the INS and the EC
• The commitment to provide up-to-date information about the investigational product (IP) or procedure, or when the participant requests this information, although this may affect the participant’s willingness to continue participating
• Foreseeable circumstances and/or reasons under which the investigator(s) may remove the participant without consent
• Medical treatment and compensation available to the participant in the case of trial-related injuries and proof of the sponsor’s insurance contract
• Economic compensation for additional expenses (e.g., transportation, accommodation, communication, and food)
• Specify when final trial results will be provided to the participant
• Inform the participant of post-study access to the IP after trial completion
• Provide a trial description in the INS’s Peruvian Clinical Trials Registry (Registro Peruano de Ensayos Clínicos (REPEC)) (PER-89) (also referred to as REPECv2)

Additionally, the G-EC-CTRev states that the participant should be provided with detailed information on the biological samples to be collected and stored. Per Decree021-2017, if biological sample storage and collection is being considered for future use, then this point should be made explicit in an additional ICF. Refer to the Consent for Specimen section for further information on participant consent requirements for use of biological samples.

See also the Vulnerable Populations section 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.

The Right to Participate, Abstain, or Withdraw

As set forth in the LawNo14.874, ResNo466, OMREC, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, 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, OMREC, and BRA-28, 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, OMREC, and BRA-28, 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

BRA-28 and OMREC explain that the research participant or legal representative/guardian, should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of their rights.

The Right to Safety and Welfare

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.

Overview

In accordance with Law26842, Decree021-2017, the G-EC-CTRev, Res233-2020, the PeruConstitution, Decree011-2011, and the Declaration of Helsinki (PER-76), Peru’s ethical standards promote respect for all human beings and safeguard the rights of research participants. Per Decree021-2017, the G-EC-CTRev, and Res233-2020, a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

Decree021-2017, RegLaw29414, and the G-EC-CTRev state that the participant or the legal representative/guardian should be informed that participation is voluntary, that study withdrawal may occur 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 explained in Decree021-2017, RegLaw29414, and the G-EC-CTRev, 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

Pursuant to Decree021-2017 and the G-EC-CTRev, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The ICF must also incorporate the following items related to privacy:

• Data the participant will have access to and what information will be collected
• How collected data will be used, stored, and protected, and who will have access
• That representatives of the sponsor, ethics committee (EC), and the National Institute of Health (Instituto Nacional de Salud (INS)) will have access to the data
• How biological data and samples are handled if consent is withdrawn
• That participants’ data will be de-identified in the case of publications and presentations of the clinical trial results

The Right of Inquiry/Appeal

Per Decree021-2017 and the G-EC-CTRev, 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 the participant's rights.

The ICF must guarantee that the participant will receive answers to any questions and clarification to any doubts about the procedures, risks, benefits, and other matters related to the clinical trial and the treatment of the participant. There must also be a commitment to provide up-to-date information about the product or procedure under investigation when the participant requests it.

The Right to Safety and Welfare

Decree021-2017, the G-EC-CTRev, and Decree011-2011 indicate that the research participant’s dignity, safety, and welfare must be guaranteed while ensuring the quality of the research process in developing new products. The G-EC-CTRev further states that the interests of science cannot take precedence over the interests of the research participants.

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.

In addition, according to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible, and the legal representative/guardian is not available, enrolment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), to protect the participant’s rights, safety, and well-being and to ensure compliance with applicable regulatory requirements. The participant or the legal representative/guardian should be informed about the trial as soon as possible. Consent to continue and other consent as appropriate, should be requested. OMREC and ResNo251 similarly state that the EC (CEP) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner about participation in the study.

No information is currently available.

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 also 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 free and informed consent.

According to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, vulnerable participants are characterized as those who may be unduly influenced by the expectation, whether justified or not, of the benefits associated with their involvement in a clinical trial, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. These participants may include those who are members of a group with a hierarchical structure, such as medical, dental, chemistry, pharmacy, biology, and nursing students, subordinate personnel in a hospital or laboratory, employees of the pharmaceutical industry, members of the armed forces, and individuals who are arrested or imprisoned. Some other vulnerable participants may include those with incurable diseases, people in convalescent homes, the unemployed or indigent, patients in emergency situations, ethnic minorities, homeless people, seasonal workers, refugees, minors, and those who cannot give their consent.

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, ResNo466, and BRA-28, specify 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.

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

Indigenous Peoples

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

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

Overview

As per Decree021-2017, in all Peruvian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Additionally, the G-EC-CTRev specifies that the ethics committee (EC) should identify the vulnerabilities of the research participants to determine the additional protections required and to protect their welfare and rights.

Decree021-2017 defines vulnerable populations as those who are relatively (or absolutely) incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes. This may include those in subordinate groups, indigenous or native peoples, and those who cannot give their consent. In addition, per Decree011-2011, in the case of individuals who do not have the capacity to exercise their autonomy, measures will be taken to safeguard their rights, always ensuring what is most favorable to them. The protection of human life considers the protection of health, as well as taking into account vulnerability and personal integrity. Decree011-2011 further explains that the cultural and plural diversities of Peru cannot represent a justification for transgressing legitimate limits established by the recognition of the principle of respect for human dignity.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations. Information on the other vulnerable populations specified in Decree021-2017 is provided below.

Indigenous Peoples

As explained in Decree021-2017, clinical trials involving participants from indigenous communities may only be conducted under the following conditions:

• When the expected benefit is reasonably assured; that is, when the product or knowledge generated by research is available or applied for the benefit of the community
• The principal investigator (PI) has the approval to conduct the trial from the regional health authority and other authorities in the community, in addition to obtaining informed consent from trial participants
• Sponsors and investigators develop culturally appropriate ways through working with anthropologists, sociologists, and translators to communicate the necessary information, and to meet the standards required in the informed consent process. In addition, the research protocol must describe and justify the methods the investigators plan to use to communicate information to research participants
• Investigators agree to discontinue using individual participants when the community does not have the capacity to understand the implications of the participants’ involvement in the trial, despite the use of a translator or interpreter
• In the case of including biological storage samples, it must have the authorization of the corresponding regional and local government, and of the respective community authorities, who must consider the interest of the community involved

The G-EC-CTRev further notes that the EC should ensure it has adopted all the appropriate measures when running a clinical trial in a community to minimize the potentially negative effects on the group and to ensure the community’s active involvement in the trial. The G-EC-CTRev also references Decree021-2017’s provision pertaining to indigenous communities, which requires approval by the community’s authorities to conduct the study prior to obtaining individual informed consent. However, approval by the community authorities may not replace the consent of each individual research participant within the group.

Persons in Dependent Groups

Per Decree021-2017, clinical trials involving participants in subordinate or dependent relationships must meet the following requirements:

• One (1) or more of the EC’s members must represent the population under study or work with someone who has expertise in addressing social, cultural, and other issues related to the group in question
• Refusal or withdrawal of consent during the trial should not affect a participant’s performance review or result in any negative consequences to the participant

These relationships include participants who are in junior or subordinate positions in hierarchically structured groups, such as students and teachers, employees and their supervisors, and soldiers and their superiors in military settings.

Persons with Physical Disabilities

Per Decree021-2017 and Decree021-2017-Correct, in clinical trials involving participants with physical disabilities that prevent them from signing the informed consent form (ICF), but with the mental capacity to provide their consent, their legal representative(s) may grant their written consent by printing their fingerprint. This consent must be provided in the presence of at least one (1) witness designated by the participant and does not belong to the research team, and who in turn will sign the ICF. If the participant is unable to sign or provide a fingerprint, another means may be used that the participant approves. In this case, the legal representative(s) are required to sign the ICF with a witness present who is not a member of the research team. The participant and/or the legal representative(s) may withdraw consent at any time without negative consequences as long as the withdrawal does not jeopardize the participant’s health.

Additionally, in the case of participants who, due to disabilities, are unable to give their informed consent and have not given consent prior to the onset of their disability, the following provisions must be met:

• The informed consent must comply with the requirements delineated in the Required Elements section
• The protocol must be approved by an EC that has experts in the disease under study, or has consulted on the clinical, ethical, and psycho-social aspects in the area of the disease and the group of patients affected

The G-EC-CTRev also notes that, per Law1384 which amends Law295, persons with disabilities have an equal capacity to exercise their rights in all aspects of life, including the right to choose to be a participant in a research study with the support of a legal representative(s), if applicable. In addition, Law1384 states that any person with a disability that requires reasonable adjustments or support to exercise their legal rights may request or designate a legal representative(s) of their choosing for assistance. Persons with disabilities who cannot communicate their own wishes will receive support and safeguards from judicially designated entities.

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, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, states that when a clinical trial includes minors who can only be enrolled with the consent of the participant’s parent/legal guardian, the participant should be informed about the trial to the extent compatible with the participant’s understanding and, if capable, the participant should sign and personally date the written informed consent.

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.

Pursuant to Law27337, Law295, Law1384, and the G-EC-CTRev, the age of majority is 18 years of age. Per Law295 and the G-EC-CTRev, children under 16 are considered to be absolutely incapable of providing consent, except for those acts determined by law. Individuals who are over 16 and under 18 are considered to be relatively incapable of providing consent. However, individuals older than 16, who are married, or have obtained an official title authorizing them to practice a profession or trade, are exempt from this regulation. Per Law295 and Law1384, females over 14 who are married are also exempt from this regulation. If a marriage is terminated, individuals who acquire this capacity by marriage do not lose this right. Law1384 further clarifies that individuals over 14 and under 18 who marry, or who become parents are considered fully capable of providing consent.

Per Decree021-2017, for studies involving minors, an ethics committee (EC) that has a specialist in pediatrics, or has obtained advice on the clinical, ethical, and psycho-social aspects of the trial from a pediatric expert, if applicable, must approve the protocol.

Assent Requirements

Per Decree021-2017 and the G-EC-CTRev, the assent of a pediatric participant from the age of eight (8) and under 18 years of age must be obtained to participate in an investigation.

In addition to a minor providing assent, Decree021-2017 and the G-EC-CTRev state that the consent of both parents or the minor’s legal guardian is required. Per Decree021-2017, the consent of the legal guardian may only be dismissed in the case of death, loss of rights according to Decree requirements, or proven impossibility to obtain consent has been documented appropriately. In the event that one (1) parent is a minor, the consent of the direct ascendant relative is also required unless the parent is a minor of 16 years of age or more, the participant has gotten married, or has obtained an official professional or trade title as earlier noted per Law295.

Decree021-2017 further explains that all pediatric participants should be fully informed about the trial and its risks and benefits in language and terms that they are easily able to understand. The investigator(s) must also accept the withdrawal of informed consent at the request of the child’s legal guardian at any time, provided that the child’s health will not be jeopardized. A minor who is a teenager must also be excluded from a trial when a conflict of views exists between the legal guardian and the teenager. A minor who reaches the age of majority during a trial must provide consent before continuing to participate in the study.

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.

As per Decree021-2017, studies involving women of childbearing age or who are pregnant require additional safeguards to ensure 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.

Clinical trials may only be conducted under the following conditions:

• The informed consent of the woman and her spouse or partner is obtained, and they are given information about any potential risks to the embryo, fetus, or newborn prior to the trial
• The spouse’s or partner’s consent may only be dismissed in the case of death; their inability to provide reliable consent; loss of rights; or when there is imminent risk to the health or life of the woman or the embryo, fetus, or newborn
• Informed consent may be withdrawn by the woman or spouse’s or partner’s request at any time, without detriment to them, provided the woman or fetus is not endangered
• The research must be preceded by trials in non-pregnant women to demonstrate their safety, except for specific tests that require pregnant participants
• The research must be aimed at improving the health of pregnant women and represent only a minimal risk to the embryo or fetus and the participant
• During the study, investigators will not have the authority to decide on the timing, method, or procedure used to terminate the pregnancy, or to participate in decisions about the viability of the fetus
• Informed consent for pregnant teenagers complies with the requirements stated in the Children/Minors section

Clinical trials may only be carried out in women in labor, postpartum, or breastfeeding when the following conditions are met:

• Consent must be obtained before labor starts
• Research will be authorized in postpartum women and breastfeeding only when there is minimal risk to the infant
• Informed consent may be withdrawn at the request of the participant, spouse, or partner at any time, without detriment to them, provided they do not affect or endanger the mother or the fetus or infant
• The clinical trial has the potential to generate direct benefits greater than the risks to the nursing woman or child after birth

See Title III (Article 23) of Decree021-2017, for additional details on embryos, fetuses, and newborns.

Research Involving Men and Women with Reproductive Capacity

Clinical trials involving men and women with reproductive capacity are only permitted under the following conditions:

• For women, the principal investigator (PI) must conduct a pregnancy test to rule out any pregnancies, and to secure commitment from the women to use effective contraceptive methods. The sponsor will provide free access and a list of contraceptive methods to the participant(s) to be selected by the participant(s) and consistent with the trial
• In the event of pregnancy during the study, the protocol should establish the exclusion of the mother; the application of procedures to monitor and control the pregnancy as well as monitoring and control of the newborn until at least six (6) months of age to identify any effects related to the investigational product
• For men, the PI must secure a commitment from the men to prevent conception, and to use effective contraceptive methods to be provided free of charge to the participant(s) by the PI/sponsor, as specified in the protocol and the informed consent form

According to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, prisoners are included as an example of a vulnerable population that may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

ResNo466 also 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.

No information is currently available.