National Health Surveillance Agency (ANVISA)

As per ResNo9 and ResNo255, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspection of drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of ResNo9 and ResNo255.

LawNo9.782 states ANVISA is an independent administrative agency linked to the Ministry of Health (MOH) that is responsible for regulating, controlling, and supervising products and services involving public health risks. LawNo9.782 and ResNo255 explain that the goods and products under the agency’s purview include medicines for human use and their active ingredients, immunobiologicals and their active substances, and blood and blood derivatives.

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

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

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

Other Considerations

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

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

Contact Information

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

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

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

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

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

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

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

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

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

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

Clinical Trial Review Process

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

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

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

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

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

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

Priority Submissions

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

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

New Drugs for Rare Diseases

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

In addition, per ResNo763, which modifies ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, if the sponsor deems necessary, and ANVISA should hold the meeting within 60 days following this request. Refer to ResNo205 and ResNo811 (which partially amends ResNo205) for additional submission documentation requirements. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.

Equivalent Foreign Regulatory Authority Submissions

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

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

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

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

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

Overview

In accordance with the 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 ResNo9 and ResNo857, the sponsor is responsible for paying a Health Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) to submit a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). As per ResNo857 and BRA-47, once the sponsor has completed the process of submitting a DDCM request (“petition” in Portuguese), ANVISA’s Solicita Electronic Petition Request System (BRA-56) generates a document known as the Union Collection Guide (Guia de Recolhimento da União (GRU)). According to ResNo857, ANVISA uses the GRU as its primary method to generate TFVS fees. In addition to ResNo857, see also BRA-51 for detailed information on the GRU, BRA-69 for information on the TFVS fee, and BRA-10 for additional information on TFVS requirements. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

Per BRA-69, ANVISA determines the TFVS fee based on the company’s size and the subject code assigned to the application request. Per the TFVS fee table provided in ResNo857 and BRA-11, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval. BRA-8 further notes that ANVISA charges a fee for substantial amendments to the clinical protocol. Additionally, per BRA-69, users can also obtain their petition fee prior to submission by searching ANVISA’s Consultation System webpage (BRA-44) using the “Subject Consultation” (Consulta de Assuntos) tool. BRA-44 provides the fee value based on the petition description subject code. See BRA-69 for further information.

Payment Instructions

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

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

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

As per ResNo466, ResNo446, and OSNo001, Brazil has a centralized registration process for research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) and requires institutional level EC (CEP) approval for each trial site. The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs (CEPs), and for registering and accrediting the ECs (CEPs). ResNo466, ResNo446, and OSNo001 state that CONEP is a collegiate advisory body directly linked to the National Health Council (Conselho Nacional de Saúde (CNS)), a permanent body within the Ministry of Health (MOH)’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53).

Both the ECs (CEPs) and CONEP are responsible for evaluating the ethical aspects of all research involving human beings and for approving the research protocols when applicable, as explained in ResNo466, ResNo446, OSNo001, and ResNo706. ResNo466 further notes that institutions conducting research involving human participants may establish one (1) or more ECs (CEPs) according to their particular requirements. For those institutions lacking an EC (CEP), or in the case of an investigator without an institutional affiliation, CONEP is required to suggest an EC (CEP) to conduct the protocol review. Together, the ECs (CEPs) and CONEP represent the ethical review system in Brazil, known as the CEP/CONEP System, as described in ResNo466, OSNo001, G-ClinProtocols-FAQs, and ResNo706. See also BRA-50, BRA-16, and BRA-49 for useful information on CONEP and the CNS.

Ethics Committee Composition

National Research Ethics Commission (CONEP)

As per OSNo001 and ResNo446, CONEP is an independent and multidisciplinary organization consisting of 30 appointed members and five (5) alternate members. The members represent a balanced gender composition; eight (8) members must equally represent various segments of the CNS. In addition, according to BRA-16, five (5) members must have a background in ethical research and health, and eight (8) members must represent the theological, legal, health management, and other related professions. Per ResNo446, CONEP also has an Executive Secretary appointed by the MOH’s Secretariat for Science, Technology and Strategic Inputs and an Assistant Secretary appointed by the CNS to coordinate CONEP’s work and to manage the technical and operational work to be carried out by the Executive Secretary. See ResNo466, OSNo001, ResNo446, and BRA-16 for detailed information on CONEP composition and responsibilities. See also BRA-50 for useful information on CONEP.

Research Ethics Committees (CEPs)

As per the PANDRH-GCPs, an institutional EC (CEP) must have at least five (5) members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. By comparison, the OMREC requires the EC (CEP) to be composed of a minimum of seven (7) members having proven expertise in research. ResNo706, in turn, states the EC (CEP) must be composed of at least nine (9) members with at least two (2) Research Participant Representatives (Representantes de Participante de Pesquisa (RPPs)).

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

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

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

Also, as noted in ResNo706, an EC (CEP) is responsible for receiving and considering, from an ethical point of view, the research protocols indicated by CONEP. However, the committee may also refuse the ethical assessment of research protocols indicated by CONEP, upon justification.

Per the PANDRH-GCPs, OMREC, and ResNo706, the majority of committee members must be involved in the review and approval process, and the necessary quorum must be obtained to approve or deny permission to conduct a study as specified in each EC’s (CEP’s) SOPs. As per ResNo706, the term of office of EC (CEP) members is valid for four (4) years, with the possibility of reappointment, at the discretion of the CEP. At the end of the term of office, an EC (CEP) member may remain in this role up to 90 days, until a replacement or reappointment takes place.

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

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

Overview

As 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

As set forth in ResNo466, the PANDRH-GCPs, ResNo251, and the G-ClinProtocols-FAQs, the primary scope of information assessed by research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), jointly known as the CEP/CONEP System, relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial.

Per ResNo466, the PANDRH-GCPs, ResNo251, and OSNo001, the CEP/CONEP System members must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). ResNo304 further establishes specific ethical requirements for research studies involving indigenous populations. Detailed information on documentation and consent requirements for studies involving indigenous populations is available in the Documentation Requirements, Vulnerable Populations, and Consent for Specimen sections.

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

National Research Ethics Commission (CONEP)-Designated Protocol Reviews

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

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

Review Pathways

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

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

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

There are four (4) ways of processing protocols in the CEP/CONEP System: express, simplified, collegiate, and special collegiate; the modulation factors per Annex II of ResNo674 provides additional characteristics to further modify the protocol processing method to be used. See ResNo674, BRA-4, and BRA-5 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures. (Please note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor the Plataforma Brasil webpage for any developments.)

Role in Clinical Trial Approval Process

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

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

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

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

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

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

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

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

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

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

Foreign Research

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

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

Multicenter Research

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

See ResNo346 for additional multicenter protocol processing information and OSNo01 for detailed information on the coordinating center’s role in this process.

Exemption from Review

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

Overview

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 Commission (CONEP)

According to ResNo466, OMREC, and ResNo706, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)), to charge a fee to review clinical trial protocols. OMREC further explains that financing to support ethical reviews should come from a specific scientific committee budget designated within each institution.

Fees are determined by each accredited institutional ethics committee.

Overview

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

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

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

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

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

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

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

Registration, Auditing, and Accreditation

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

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

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

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

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

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

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

See CNSResNo506 for additional documentation requirements.

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

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

High-Risk Research Protocols

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

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

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

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

Suspension and Cancellation of Accreditation

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

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

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

Overview

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

Regulatory Submission

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

As indicated in the G-DDCMManual and BRA-8, ANVISA recommends that the DDCM and associated documents (including the protocol, investigator’s brochure, informed consent form, and sponsor and institutional declarations) be translated into Portuguese. If a translated version of the submission is not provided, ANVISA’s technical area reviewer may issue a requirement for the sponsor to provide a free translation of the submitted documentation.

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

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

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

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

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

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

BRA-59 explains that once the fee is paid, a reference (transaction) number is generated that will be required for the subsequent submission of the associated checklist documents. The processing of this request can take up to two (2) days, which is the time given to the banking network to clear the payment. Refer to BRA-59 for additional instructions. See also BRA-47 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition Request Form. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

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

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

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

Ethics Review Submission

Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the PI must also obtain approval from the EC (CEP). The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional EC review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals. Please refer to Scope of Review and Oversight of Ethics Committee sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. See also CLNo183 for instructions on linking investigator/institutions to the responsible EC in submissions; CLNo062 for guidance on submitting documentation required for CONEP analysis; and CLNo046 for instructions on submitting requests for inclusion/exclusion of research center(s).

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

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

Overview

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

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

• Health Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResNo857 (fee required by individuals and companies engaged in clinical research)
• Drug development plan (known as experimental drug dossier) (See the G-BioIProdManual for instructions on completing a biological products dossier and the G-SynthDrugProdManual for completing a synthetic/semi-synthetic products dossier)
• Certified copy of the clinical agreement (contract or statement) that has been written, dated, and signed by the sponsor or the CRO
• Clinical research protocol
• Investigator’s Brochure (IB)
• Summary of the investigational product (IP)’s safety aspects based on previous research in humans
• Information on any discontinued development or withdrawal of IP
• IP dossier
• Specific dossier for each clinical trial to be conducted in Brazil
• Proof of clinical trial registration in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE) (Note: the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.) Per ResNo449, which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25). Note that per ResNo205, the ResNo9 requirement to include the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval in the initial DDCM or in any protocol amendment submission has been revoked.

Substantial Protocol Modifications

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

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

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

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

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

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

Ethics Committee Requirements

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

• Cover Sheet for Research Involving Human Beings (BRA-20)
• Clinical research protocol (in Portuguese)
• Background, justification, and registration in the country of origin for drug and device health products
• Description of materials, methods, rationale, expected results, and bibliography
• Critical risk and benefit analysis
• Duration
• Responsibilities of investigator, institution, and sponsor
• Criteria for project suspension or termination
• Location of implementation of various project steps
• Necessary infrastructure and agreement of the institution
• Statement of Commitment from the principal investigator (PI)
• Informed consent form (ICF) (See Informed Consent topic for additional information)
• Detailed research financial budget and investigator remuneration
• Ownership of information
• Characteristics of the participant population, and justification for the use of vulnerable groups
• Number of participants locally and globally (multicenter)
• Description of methods that affect research participants
• Sources of material and details of the specific collection
• Recruitment plans, inclusion and exclusion criteria
• PI/investigator(s) Curriculum Vitaes (CVs)
• Research project schedule
• Foreign Research or Foreign Cooperation documentation (commitments and advantages for research participants and the country; identification of the national investigator and co-responsible institution; EC approval document in the country of origin or justification; response to the need for personnel training in Brazil; and lists of participating centers abroad and in Brazil)
• Research with new drug, vaccine, and diagnostic test document requirements (current clinical trial phase and demonstration of compliance with previous clinical trial phases; drug substance registration in the country of origin and status of research; IB; clinical information from previous trial phases; justification for using placebo or wash out period; access to the drug, if its superiority is proven; investigator’s statement to agree to comply with BRA-20; justification for inclusion of healthy participants; forms of recruitment)

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

Clinical Protocol

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

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

For complete protocol requirements, refer to the PANDRH-GCPs, OMREC, and OSNo001.

Regulatory Authority Requirements

As 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

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

Regulatory Authority Approval

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

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

Priority Submissions

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

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

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

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

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

See also ResNo811 (which partially amends ResNo205), BRA-8, and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.

Ethics Committee Approval

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

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

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

CLNo040 further explains that new investigational brochure (IB) versions to be uploaded to the CEP/CONEP System via Plataforma Brasil (BRA-34) are often limited to updates pertaining to the investigational product’s efficacy and safety data and research team instructions. Updates should not alter research that has already been approved and must be processed as notifications in BRA-34. However, CLNo040 specifies that if the IB changes result in modifications to the detailed protocol and/or the informed consent form (ICF), it is necessary to submit a protocol amendment. In this case, the EC (CEP) will analyze the IB together with the other documents pertaining to the amendment, and, if necessary, the required amendments and/or clarifications will be requested. If the project needs to go through CONEP’s appraisal, the deadline for Document Validation is 15 days and for Ethical Review, 45 days.

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

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

Overview

Based on 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

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

In addition, per ResNo9, the sponsor or the designated CRO is required to obtain an import license from ANVISA for the shipment of the investigational product (IP) to be used in the trial. (See the Manufacturing & Import section for additional information). The trials should be conducted in compliance with the PANDRH-GCPs, ResNo466, and ResNo9. Clinical trials must also be conducted in a laboratory complying with the Organisation for Economic Co-operation and Development (OECD)’s Principles on Good Laboratory Practice (GLP) (BRA-15) as mandated by Brazil’s National Institute of Metrology, Quality and Technology (INMETRO). Refer to BRA-15 and BRA-48 for additional information on GLP requirements.

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

Clinical Trial Agreement

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

Clinical Trial Registration

As delineated in ResNo9, the sponsor must register the clinical trial in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE). According to BRA-52, the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)) (BRA-45) is a primary registry in the ICTRP network. See also BRA-45 and BRA-46 for further information about ReBEC. Per ResNo449 which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25).

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

Overview

In accordance with 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 the PANDRH-GCPs, ResNo9, the AESafetyManual, and CLNo13, the following definitions provide a basis for a common understanding of Brazil’s safety reporting requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

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

Safety Reporting Requirements

Investigator Responsibilities

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

Sponsor Responsibilities

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

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

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

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

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

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

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

Ethics Committee Responsibilities

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

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

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

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

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

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

Other Safety Reports

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

Form Completion & Delivery Requirements

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

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

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

Safety Reporting Definitions

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 ResNo9 and the G-CTReptsManual, the sponsor must file a progress report, known as an annual clinical trial protocol monitoring report, to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) in the form of a secondary petition electronically attached to the respective protocol to which it is linked. ResNo9 indicates that the annual report should contain the following information for each clinical trial protocol, in tabulated form, exclusively from Brazilian centers:

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

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

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

Final Report

ResNo9 and the G-CTReptsManual state that the sponsor should submit a final report to ANVISA in the form of a secondary petition electronically attached to the respective protocol to which it is linked. The final report must be filed within 12 months of the clinical trial end date. Per ResNo9 the final report should contain at least the following:

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

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

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

Other Reporting Requirements

As stated in ResNo9 and the G-CTReptsManual, in addition to submitting a final report, the sponsor is also responsible for submitting clinical trial start and end date forms for trials conducted in Brazil. The forms with the trial start and end dates must be filed as a secondary petition to the corresponding trial dossier within 30 calendar days after each start and end date. The secondary petition should be submitted to ANVISA using the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) Petition Request Form (BRA-21). See BRA-56 to access ANVISA’s Solicita Electronic Petition Request System website that allows users to submit these forms electronically, and BRA-25 and BRA-24 for links to the notification forms. See also BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

Interim and Annual Progress Reports

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

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

As delineated in ResNo9, when a clinical trial is developed by a sponsor-investigator, the institution with which the individual is linked is the primary sponsor. The primary sponsor may delegate responsibilities to the investigator, who will be responsible for conducting the clinical trial at the institution, and the sponsor-investigator will serve as the secondary sponsor. See also BRA-79 for additional information on sponsor and CRO requirements in Brazil.

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

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

Foreign Sponsor Responsibilities

As specified in the PANDRH-GCPs and ResNo9, the sponsor may transfer any or all of the sponsor’s study related duties and functions to a contract research organization (CRO). However, the sponsor is ultimately responsible for the study data’s quality and integrity. Any study related duties, functions, or responsibilities transferred to and assumed by a local representative or CRO must be specified in writing. Other duties, functions, or responsibilities not specifically transferred shall be deemed as retained by the sponsor. However, as per ResNo9, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

Data Safety and Monitoring Board

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

Multicenter Studies

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

Overview

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

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

Compensation

Injury or Death

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

Trial Participation

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

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

Post-Trial Access

According to ResNo563, for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining ANVISA registration. In addition, per ResNo466, at the end of the study, the sponsor much ensure free and indefinite access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective. Access must also be guaranteed to participants between the time they stop their participation in the trial and the end of the study.

Furthermore, ResNo311, which amends ResNo38, states that the sponsor/CRO should guarantee access to the post-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (CNS)). The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Study Medicine Supply Programs (see Annex VI of ResNo38). See also BRA-79 for additional information on sponsor/CRO insurance coverage.

Insurance

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

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

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

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

Monitoring Requirements

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

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

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

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

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

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

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

In the event of a routine inspection, RegNo122 states that ANVISA will notify the institution at least 15 calendar days in advance of the visit. Both the sponsor and/or the CRO are responsible for preparing for the inspection. ANVISA shall also notify the principal investigator (PI) of the scheduled visit to the center to be inspected, when applicable, by means of a GCP Inspection Notification Letter. For more detailed information on ANVISA’s inspection process, refer to RegNo122.

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

GuideNo35-2020 and GuideNo36-2020 explain that GCP inspections of sponsors and CRO representatives and in clinical trial centers may be carried out before, during, or after a clinical trial has been conducted and will be classified as either a routine inspection or complaint/suspected irregularity, per RegNo122. In addition, per GuideNo35-2020 and GuideNo36-2020, the inspections will involve at least two (2) ANVISA inspectors, one (1) of whom will be the lead inspector and the focal point for communication with either the clinical trial center or the sponsor/CRO(s). The inspections for both entities will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.

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

Premature Study Termination/Suspension

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

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

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

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

Quality Assurance/Quality Control

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

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

Records Management

As set forth in ResNo9, the sponsor or the CRO should maintain the clinical trial data on file in physical or digital format for a period of five (5) years after the last approval of a request for registration in Brazil. ResNo9 and the PANDRH-GCPs also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, a marketing application receives the last approval, or there are no pending or contemplated marketing applications. Per the PANDRH-GCPs, the sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

Electronic Data Processing System

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 and precisely and in Portuguese. Additionally, the exercise of activity of the person in charge does not presuppose registration with any entity or any specific certification or professional training. See CD-ANPD-No18 for details on the activities and duties of the person in charge and how conflicts of interest are handled. See also BRA-116 for additional information.

Data Protection

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

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

The LGPD also provides a definition for sensitive personal data or information that encompasses health related considerations. Sensitive personal data refers to personal data about racial or ethnic origin; religious belief; political opinion; union membership or organization of a religious, philosophical, or political nature; data relating to health or sexual life; and genetic or biometric data, when linked to a natural person.

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Children/Adolescents

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

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

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

Responsible Parties

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

As per the PANDRH-GCPs, ResNo466, the G-ClinResSubjectRts, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by an research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and provided to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) with the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). CLNo51 further clarifies that the ICF should be written as an invitation rather than as a statement as this may reduce the participant’s autonomy. Refer to CLNo51 for detailed information. See the Required Elements section for details on contents to be included in the form.

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the investigator, or their designated representative, must provide detailed research study information to the participant or legal representative/guardian. As delineated in ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, OMREC, and the G-ClinProtocols-FAQs, the ICF content should be presented in a clearly organized format using practical and non-technical language commensurate with the participant’s level of understanding. Per the PANDRH-GCPs and the G-ClinResSubjectRts, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. The PANDRH-GCPs further explains that none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. ResNo466 and the G-ClinResSubjectRts further note that the investigator must bear in mind that the prospective participant’s ability to understand the information required to give consent depends on their maturity, ethics, intelligence, education, and cultural beliefs. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and the G-ClinProtocols-FAQs, the information should be in both written and oral form, and the participant and the legal representative/guardian should also be given adequate time to consider whether to participate. See also BRA-29 for additional information on informed consent.

Re-Consent

According to the PANDRH-GCPs and CLNo17, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by the EC (CEP) and submitted to ANVISA before such changes are implemented. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and CLNo51, the investigator must ensure that the participant or legal representative/guardian sign the revised ICF and any other updated information. CLNo17 further notes that changes made to the ICF through separate documents are not considered acceptable. The update requires the investigator to generate a single and complete version of the new document, free of addenda and/or other documents associated with it. The investigator or their delegated representative should also emphasize the changes contained in the updated ICF. The clarifications delineated in CLNo17 also apply to assent forms.

Language Requirements

As earlier stated, the PANDRH-GCPs and the G-ClinResSubjectRts require the ICF to be presented orally and in writing at a level that the participant is able to understand. Per the PANDRH-GCPs, the investigator should provide the ICF in the participant’s own language when they do not speak the language currently spoken in the country. The G-ClinProtocols-FAQs further notes that the ICF must be adequately adapted and be fully revised in Portuguese to ensure that the document is properly translated.

Documenting Consent

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

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

Waiver of Consent

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

Obtaining Consent

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

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