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

Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

As set forth in GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is the regulatory authority responsible for approving all clinical studies in human beings and/or their biological samples, for scientific research purposes. COFEPRIS is authorized to monitor and verify approved clinical studies to be conducted in Mexico in accordance with the provisions of the aforementioned documents.

Under the terms of Reg-COFEPRIS and GenHlthLaw, the Ministry of Health (Secretaría de Salud) supervises the regulation, control, and promotion of health through COFEPRIS. Per MOH-Org, COFEPRIS, a decentralized administrative body, is overseen by the Ministry of Health’s head of the Undersecretariat of Prevention and Health Promotion. Reg-COFEPRIS and GenHlthLaw state that COFEPRIS is headed by a Federal Commissioner appointed by the President of Mexico, upon the Ministry’s recommendation. Per GenHlthLaw, the Ministry of Health is also responsible for supervising COFEPRIS. Per Reg-COFEPRIS and GenHlthLaw, the agency has technical, administrative, and operational autonomy in regulating, evaluating, controlling, promoting, and disseminating the conditions and requirements to prevent and manage health risks in the Mexican population.

Reg-COFEPRIS specifies that COFEPRIS comprises eight (8) administrative units and four (4) government advisory bodies that manage the agency’s organizational and operational responsibilities. Included among COFEPRIS’s administrative units, and central to the research protocol authorization process, is the Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)). As delineated in Reg-COFEPRIS, GenHlthLaw, and MEX-53, CAS is responsible for issuing, extending, or revoking research protocol authorizations. According to MEX-104, CAS’s work is performed by its protocols area.

Other Considerations

Per MEX-41, Mexico is a regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). As indicated in MEX-2, COFEPRIS is in the process of implementing the ICH Guideline for Good Clinical Practice E6 (R2) (MEX-22). However, COFEPRIS-GCP complies with the Guideline for Good Clinical Practice E6 (R1) (MEX-32).

Please note: Mexico is party to the Nagoya Protocol on Access and Benefit-sharing (MEX-5), 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 MEX-35.

Contact Information

As per MEX-71 and MEX-15, COFEPRIS’s contact information is as follows:

Comisión Federal para la Protección contra Riesgos Sanitarios
Oklahoma No. 14
Colonia Nápoles
Del. Benito Juárez
C.P. 03810, Ciudad de México

Note: Per MEX-37, MEX-15, and MEX-25, the preceding address should also be used to contact COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) for technical inquiries or those inquiries requiring an official response.

COFEPRIS Call Center Phone: 01-800-033-5050 (toll free within Mexico) or 55 53 40 09 96 (international calls) (per MEX-37)
Foreign Processing Area Phone (for entry and/or tracking number of procedure): 01-800-420-4224 (toll free within Mexico) (per MEX-25)
Email: contactociudadano@cofepris.gob.mx (per MEX-71 and MEX-37)

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 GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is the regulatory authority responsible for reviewing, evaluating, and approving all requests for research protocol authorization in human beings and/or their biological samples using registered or unregistered investigational products (IPs). Per NOM-257-SSA1-2014, COFEPRIS requires biotechnological drugs used in clinical research studies to follow the same protocol authorization procedure as is required for all IPs. COFEPRIS-GCP and HlthResRegs specify that the scope of COFEPRIS’s assessment includes all clinical trials (Phases I-IV).

As indicated in HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, COFEPRIS’s review and approval of a protocol authorization request is dependent upon obtaining a favorable decision from the health institution’s Research Ethics Committee (REC) and Research Committee where the study is being conducted, and when applicable, the Biosafety Committee. Therefore, the COFEPRIS and EC reviews may not be conducted in parallel. In addition, per NOM-012-SSA3-2012, the REC’s favorable decision is only later submitted to COFEPRIS with the protocol authorization request. Refer to the Ethics Committee section for detailed information on the REC, and the Initiation, Agreements & Registration section for additional information on the Research Committee and Biosafety Committee.

Clinical Trial Review Process

As delineated in Reg-COFEPRIS and MEX-53, COFEPRIS’s Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)) is responsible for recording, evaluating, and issuing opinions on requests for human research protocol authorizations. According to MEX-104, CAS’s work is performed by its protocols area. Per MEX-15, CAS’s technical/protocols area conducts its work via COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37), a public service system established by the Mexican government to facilitate the processing of the agency’s standardized procedures and services.

As indicated in G-HumResProt and G-ResProtocolAmd, the applicant must submit an application to the CIS (MEX-37) to request protocol authorization or modification/amendment of a protocol authorization, and the application is then forwarded to CAS’s technical/protocols area for evaluation. (Note: COFEPRIS refers to applications as requests or procedures). Per G-HumResProt, the designated evaluator reviews and evaluates the information, comparing the information presented to assess whether it complies with current Mexican legislation on the matter. The information is also evaluated for completeness and accuracy and is reviewed to detect deficiencies or anomalies in the documentation or in the study process. Once the evaluator issues a resolution of authorization or a prevention letter, it is forwarded to the head of CAS for signature.

Following its review of the application documentation, per G-HumResProt and G-ResProtocolAmd, CAS’s technical/protocols area issues an official resolution of authorization or a prevention letter (in which additional or missing information is requested). If authorized, the clinical study may begin. However, if a prevention letter is received, the applicant must respond to what is stated in the letter and resubmit a request for continued processing after addressing all of the issues raised. CAS’s technical/protocols area will issue a final resolution following resubmission of the application for protocol authorization or modification/amendment. G-HumResProt also indicates that for in-person submissions, applicants can go to the CIS (MEX-37) to obtain the resolution.

G-ResProtocolAmd specifies that protocol modifications may be submitted to amend the research protocol, amend the informed consent/assent form, update the clinical and/or preclinical sections of the investigator’s brochure (also known as investigator’s manual in Mexico), remove or add research center(s)/research institution(s), or provide updated clinical and/or preclinical security/safety IP information. Refer to G-ObsrvStdies information on submitting applications to conduct risk-free research (observational studies), and G-BioequivStud for information on submitting applications to conduct bioequivalence studies.

Additionally, as indicated in G-DIGIPRiS-ResProts, once an official authorization from COFEPRIS is obtained, some of the data provided by the applicant via COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86), will be migrated to the CIS (MEX-37) and to the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). According to MEX-109, the G-RNECManual is useful for information on registering with RNEC for clinical trial applications submitted in person at the CIS (MEX-37). See also G-DIGIPRiS-DocComp for instructions on validating and comparing resolutions issued through DIGIPRiS (MEX-86) for research protocols). See Submission Process section for detailed DIGIPRiS (MEX-86) submission requirements.

Reg-HlthProd further explains that applicants must submit a request to COFEPRIS to obtain a sanitary registration for biosimilar biotechnological drug products. The specific requirements for the approval of each biosimilar biotechnological drug (e.g., in vitro studies, preclinical study reports, and comparative pharmacokinetic study reports) will be determined by the Ministry of Health, who will take into consideration the opinion of the Committee of New Molecules. When there is no relevant information in the Pharmacopoeia of the United Mexican States (Farmacopea de los Estados Unidos Mexicanos (FEUM)) and its supplements, nor in national guides or monographs, the Ministry may evaluate biosimilar tests using clinical data obtained from biosimilar biotechnological drug studies conducted in other countries. However, clinical trials are required to be conducted in Mexico when an applicant requests the renewal of an approval for a biosimilar biotechnological drug product. According to MEX-91, COFEPRIS’s acceptance of data produced abroad will accelerate the introduction of biosimilar drug products into Mexico. Additionally, per MEX-120, COFEPRIS has implemented modifications to NOM-177-SSA1-2013, the standard which establishes the tests and procedures to demonstrate that generic drugs or biosimilar biotechnological drugs comply with established interchangeability tests and delineates requirements for the authorized third parties that perform these tests. Pursuant to NOM-177-SSA1-2013-Mod, the modification expands the standard to include studies that are carried out in Mexico as well as in other countries to demonstrate interchangeability and biocomparability. MEX-120 also notes the modifications in NOM-177-SSA1-2013-Mod are designed to expedite the registration of generic and biosimilar biotechnological drugs. See NOM-177-SSA1-2013 and NOM-177-SSA1-2013-Mod for details.(Note: In Mexico, biosimilar is also referred to as biocomparable.)

UHAP Evaluations

Per HlthResRegs, prior to submitting an authorization request, applicants may also obtain a pre-assessment evaluation by an authorized third party that helps to facilitate COFEPRIS’s review. MEX-21 and MEX-10 explain that rather than submitting the application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment (third party) evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Speciality Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) or a UHAP within the Mexican Social Security Institute (Instituto Mexicano del Seguro Social (IMSS)). MEX-9 states that the CCINSHAE oversees (12) UHAPs. According to MEX-90, the Faculty of Medicine of the Autonomous University of Nuevo León (Facultad de Medicina de Universidad Autónoma de Nuevo León (UANL)) UHAP is another third-party unit authorized by COFEPRIS to assist in the evaluation and assessment of human research protocols. Refer to MEX-19, MEX-69, and MEX-70 for detailed information on the CCINSHAE, the IMSS, and the UANL UHAP application submission requirements and evaluation process. See also HlthResRegs for information on the third party authorization process by the Secretariat, and MEX-10 and MEX-121 for additional information on authorized third parties. See Timeline of Review section for timeline information on submitting UHAP applications.

According to MEX-10, the UHAP has a maximum of 30 calendar days to respond to an evaluation request. See the Scope of Assessment and Submission Process sections for detailed UHAP information.

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).

Federal Commission for the Protection Against Sanitary Risks (COFEPRIS)

As indicated in G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, MEX-84, G-DIGIPRiS-ResProts, the applicant is responsible for paying a non-refundable fee (also referred to as “Proof of Payment of Rights”) to submit a request for protocol authorization to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)).

According to MEX-37 and MEX-15, applicants may obtain the fee information for a specific procedure or service using COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37). Per MEX-15, CIS is a public service system established by the Mexican government to facilitate the processing of the agency’s standardized procedures and services. MEX-15 and MEX-37 indicate that applicants may call CIS (MEX-37) or schedule an appointment for assistance with determining the COFEPRIS procedure code to obtain the correct processing instructions and fees and for help with submitting the payment. See MEX-37 and MEX-15 for information on scheduling an appointment with CIS.

G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, and MEX-11 provide requirements and corresponding costs to submit requests to COFEPRIS for protocol authorizations or amendments/modifications. The costs linked to these procedures are as follows:

• Request for authorization of research protocol in humans for medicines, biological, and biotechnological: 7,553.00 Mexican Pesos (G-HumResProt and MEX-11)
• Authorization of research protocol in humans (bioequivalence studies): 7,553 Mexican Pesos (G-BioequivStud)

• Authorization of research protocol without risk (observational) in humans: 7,553.00 Mexican Pesos (G-ObsrvStdies)
• Amendment or modification to the research protocol or inclusions to the protocol: 5,665 Mexican Pesos (G-ResProtocolAmd and MEX-11)

In addition, per G-UnregDrugImprts, the fee to request a health permit to import investigational products for research purposes is 6,727.65 Mexican Pesos.

As indicated in MEX-10, the fee for requesting a pre-assessment application evaluation through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Speciality Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) is 60,000 Mexican Pesos. The cost is the same for obtaining a review from any of the UHAPs within CCINSHAE. In addition, if the applicant selects a scientific committee within an institution that has a UHAP, the cost is 40,000 Mexican Pesos. The cost for each amendment is 3,500 Mexican Pesos, and corrections to the pre-assessment document are free.

Payment Instructions

As explained in MEX-50, G-HumResProt, G-BioequivStud, G-ObsrvStdies, and G-ResProtocolAmd, applicants should make payments for these procedures and services through an authorized credit institution using E5cinco (MEX-52). (See also MEX-52 for a link to participating financial institutions). Per MEX-50 and MEX-52, E5cinco is an electronic scheme created to enable users to submit the Payment of Rights, Products and Benefits (Derechos, Productos y Aprovechamientos (DPAs)) to a participating credit institution through its Internet portal or banking window. See also MEX-51 and MEX-6 for detailed DPA payment instructions via E5cinco (MEX-52).

In addition, G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, and MEX-84 provide a website link, Help Sheet for the Generation of the Fee Payment Format, for users to generate a payment form for fees based on their procedure in order to make a payment at the banking institution of their choice. Refer to G-HumResProt, G-BioequivStud, G-ObsrvStdies, G-ResProtocolAmd, MEX-84, and G-DIGIPRiS-ResProts for additional information on this process.

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 delineated in GenHlthLaw, HlthResRegs, REC-Op, REC-Op-Ref, G-RECs-Op-2018, and NOM-012-SSA3-2012, Mexico has a decentralized process for the ethics review and approval of clinical trial research. Accordingly, every health care institution which carries out research activities in human beings is required to have a Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) that is responsible for evaluating and ruling on research protocols in human beings. RECs are subject to current legislation and the criteria established by the National Bioethics Commission (Comisión Nacional de Bioética (CONBIOÉTICA)).

RECs must also comply with guidelines for the ethical evaluation of research involving human beings as delineated in GenHlthLaw, G-RECs-Op-2018, HlthResRegs and NOM-012-SSA3-2012. Pursuant to G-RECs-Op-2018, RECs must adhere to international guidelines relevant to research with human beings including the Declaration of Helsinki (MEX-76) and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MEX-22)).

In addition, per GenHlthLaw, HlthResRegs, and NOM-012-SSA3-2012, every health institution where research is conducted is required to establish a Research Committee and a Biosafety Committee. Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, REC and Research Committee approval is required for each trial site where a study is being conducted, and when applicable, Biosafety Committee approval is required as well.

GenHlthLaw further notes that in addition to establishing an REC, public, social, or private sector health care establishments of the National Health System must have a Hospital Bioethics Committee for the resolution of problems arising from medical care along with engaging in other bioethical and ethical related activities.

As per HlthResRegs, REC-Op, REC-Op-Ref, G-RECs-Op-2018, and NOM-012-SSA3-2012, Hospital Bioethics Committees also operate through CONBIOÉTICA. MEX-47 specifies that CONBIOÉTICA is responsible for registering RECs and Hospital Bioethics Committees. See the Oversight of Ethics Committees section for details on ethics committee registration.

Ethics Committee Composition

Research Ethics Committee Composition

As indicated in GenHlthLaw, RECs must be interdisciplinary gender-balanced groups composed of medical personnel from different specialties; professionals from psychology, nursing, social work, sociology, anthropology, philosophy, or law fields who have bioethics training; and community representatives affected by the health condition under study or other health services users who may or may not be attached to the health unit or institution. In addition to the previously stated criteria, G-RECs-Op-2018 indicates that these professionals should have a professional license and accredited training and experience in research ethics, good clinical practice, bioethics, and have experience related to the research area they will be evaluating. HlthResRegs further notes that the REC must consist of at least three (3) scientists including both genders and recommends that at least one (1) of them be based outside the health institution. The medical professionals should also represent the moral, cultural, and social values of the research groups. By comparison, NOM-012-SSA3-2012 states that REC health professionals should have expertise in the subjects investigated at the institution, regardless of whether the professionals have experience in the scientific methodology applied to the research. Further, the community representatives should embody the moral, cultural, and social values of the research participants.

Per REC-Op and REC-Op-Ref, the REC members must also be recognized and able to document their professional excellence in research/research bioethics, have personal records that prove ethical suitability and conduct, and advanced knowledge in qualitative and quantitative methodology. Additionally, GenHlthLaw, G-RECs-Op-2018, and NOM-012-SSA3-2012 state that REC members may or may not be based at the associated institution where the study is being conducted.

Additionally, NOM-012-SSA3-2012 specifies that the REC should be composed of a minimum of three (3) scientists, plus community representatives, as deemed necessary, with a total of at least six (6) members and a maximum of 20. G-RECs-Op-2018, REC-Op, and REC-Op-Ref note that the REC should comprise a president, at least four (4) members, one (1) of whom will serve as secretary, a representative from the affected study group or other health services users, with at least one (1) member who has expertise in bioethics and research ethics, and internal or external specialists to be included on an as needed basis. G-RECs-Op-2018 also notes that the member acting as a representative is not required to have a professional license in research or medical care and may include individuals with basic education or technical training.

Hospital Bioethics Committee Composition

Per GenHlthLaw and G-CHBs-Op, Hospital Bioethics Committees must be multidisciplinary, diverse, gender-balanced groups composed of medical personnel from different specialties and the health team; professionals from psychology, nursing, social work, sociology, anthropology, and philosophy fields; lawyers with knowledge in health matters, and community representatives affected by the health condition under study or other health services users who may or may not be attached to the health unit or institution. G-CHBs-Op notes that the members must have previous bioethics training or receive the training within the six (6) months after joining the Committee. Administrative personnel, directors of institutions, or people who occupy managerial positions in the institution should not be included, in order to promote an environment of equity.

In addition, per G-CHBs-Op, the Hospital Bioethics Committee should be composed of a president and a minimum of four (4) members with assistance from a secretary, to be appointed from among the members by the president. At least one (1) member not assigned to the health establishment must be included.

Terms of Reference, Review Procedures, and Meeting Schedule

Research Ethics Committees

Per NOM-012-SSA3-2012, the constitution and operation of the REC will be subject to the provisions of current legislation and, where appropriate, to the criteria referred to in article 41 Bis of the GenHlthLaw. REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP specify that RECs should operate within written standard operating procedures (SOPs) to conduct their reviews. REC-Op and G-RECs-Op-2018 indicate that the health institution owner must approve the SOPs and issue a certificate of appointment to each of the REC members. HlthResRegs, G-RECs-Op-2018, and NOM-012-SSA3-2012 note that members must hold office for three (3) years and may be approved for an equal period.

Per REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP, the following minimum requirements must be met (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• RECs must meet at least six (6) times a year, and at least once every two (2) months
• The minimum number of members required to complete a quorum must be greater than 50% of the members, and the president and/or secretary must be present to form a quorum
• In the evaluation of multicenter studies and when otherwise warranted, the REC may meet jointly with other RECs that belong to other establishments in the country, for the assessment and opinion for these protocols
• Minutes must be prepared for legal and administrative purposes in meetings
• An annual report of activities should be presented to the institutional head in the first 30 calendar days of the year
• Avoid conflicts of interest in protocol evaluations or be declared disqualified for that particular review
• Participation is required in initial training and bioethics continuing education
• Liaisons with other RECs within and outside the country to better carry out its functions
• A general policy on the confidentiality of information for protocols reviewed must be established and implemented
• A code of conduct for REC members must be established and implemented
• Members must refrain from participating in the evaluation and opinion of their own research
• Members will remain in office for the time established in each committee’s installation act and may be ratified at the end of each period, if applicable. Members may be replaced in a staggered manner, for which documentary evidence must be kept
• The committee will designate the person who will occupy the position of president and who will be responsible to the head of the institution or establishment and for the committee’s activities
• In the committee sessions, members of external committees may participate or have the support of external advisors, who will have a voice but no vote. In these cases, researchers from the institution or establishment itself may also participate as long as they work in areas related to the subject of the project or research protocol in the opinion phase
• It is the responsibility of the committee to issue the technical opinion on ethics, according to the nature of the proposed investigations

For detailed REC procedures and information on other administrative processes, see REC-Op, G-RECs-Op-2018, NOM-012-SSA3-2012, and COFEPRIS-GCP. See also MEX-72 for information on CONBIOÉTICA’s REC follow-up monitoring reports.

As per G-RECs-Op-2018, the REC should also keep documentation related to its integration, operation, and registration activities for up to three (3) years after the conclusion of the committee’s activities. The committee should also define the procedure for transferring the files and appoint the responsible person at the institution where the REC registration was granted. In addition, the REC will keep all the essential documents reviewed and related to each evaluated investigation, up to five (5) years following the end of the investigation or during the period established in the applicable provisions.

See G-RECs-Op-2018 for additional REC recordkeeping requirements.

Hospital Bioethics Committees

As indicated in G-CHBs-Op, Hospital Bioethics Committees must establish operating rules, which specify member functions as well as the internal mechanisms and procedures for operations during the sessions. In newly created Committees and during the first six (6) months, the members must be trained in bioethics on an ongoing basis. Per G-CHBs-Op and GenHlthLaw, the Committee will also promote, with the head of the hospital, the dissemination, elaboration and implementation of institutional bioethical guidelines and guides for medical care and teaching. It will also promote the ongoing the bioethical education of its members and hospital staff. GenHlthLaw also notes the Hospital Bioethics Committees must comply with current legislation and CONBIOÉTICA guidelines.

G-CHBs-Op further explains that Hospital Bioethics Committees must meet in an ordinary manner, at least six (6) times a year, and in an extraordinary way, at any time, at the President’s request, or when requested by the majority of its members. Quorum requirements to review and decide on a request must include attendance of at least half the number of committee members and the president. Minutes will also be prepared for each of the Committee sessions. The resolutions issued by the Committee are the result of the analysis and deliberation of the members present at the session and must be communicated through a letter addressed to the applicant who presented the case. The recommendations issued by the Committee must not be incorporated into the clinical file. The Committee President is responsible for safeguarding the files. For detailed Hospital Bioethics Committee procedures and information on other administrative processes, see G-CHBs-Op.

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 HlthResRegs, REC-Op, and G-RECs-Op-2018, the primary scope of information assessed by the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) relates to maintaining and protecting the dignity and rights of human research participants and ensuring their safety throughout their participation in a clinical trial. Per HlthResRegs and G-RECs-Op-2018, RECs must also pay special attention to reviewing informed consent and protecting the welfare of certain classes of participants deemed vulnerable. (See Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations.)

HlthResRegs and G-RECs-Op-2018 also state that RECs must ensure 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, and they must verify the adequacy of confidentiality and privacy safeguards. See HlthResRegs and G-RECs-Op-2018 for detailed ethical review guidelines.

Role in Clinical Trial Approval Process

Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the applicant must obtain a favorable decision from the REC and the Research Committee at the health institution where the study is being conducted, and when applicable, a favorable decision from the Biosafety Committee. As per COFEPRIS-GCP, HlthResRegs, and NOM-012-SSA3-2012, the REC must provide a favorable decision for the research protocol and informed consent form prior to the applicant submitting a request for protocol authorization to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Consequently, the REC and COFEPRIS reviews may not be conducted in parallel.

HlthResRegs, GenHlthLaw, and G-HumResProt explain that the REC provides ethics recommendations on protocols for research in human beings, including a review of the research risks and benefits, and per G-HumResProt, assesses the technical quality and scientific merit of the protocol. HlthResRegs further notes that RECs also prepare ethics guidelines for conducting research in humans.

As delineated in G-RECs-Op-2018, the REC agenda and documents corresponding to each session should be delivered at least seven (7) days prior to the meeting. It is then recommended that the REC’s decision be sent within a period not exceeding five (5) working days after the committee has met, or if applicable, not to exceed 30 calendar days from the review request date. G-RECs-Op-2018 and G-DIGIPRiS-ResProts also state that the approval of a new application is valid for one (1) year.

After obtaining a favorable opinion from the REC that validated the initial project or protocol, per NOM-012-SSA3-2012, the principal investigator (PI) must submit an amended protocol to the Ministry of Health (Secretaría de Salud) to request a new authorization for any amendments to be made to the methodological design of the initial research project. In those cases where the lives of research participants are endangered, amendments can be applied immediately, prior to approval by the REC and authorization by the Ministry of Health. However, in these situations, it will be necessary for the PI to provide documentary evidence following the event to the REC and the Ministry.

In addition, G-RECs-Op-2018 indicates that the REC should establish procedures for monitoring approved studies, from the point at which the decision was made until the completion of the investigation and reporting of results. Per NOM-012-SSA3-2012 and G-RECs-Op-2018, the REC must assess and approve the research protocol at the beginning of the project, and periodically throughout the project’s duration to ensure conformance with ethical principles and applicable regulations. NOM-012-SSA3-2012 further specifies that the REC must propose to the head of the institution or establishment where health research is carried out that the research be suspended or cancelled in the presence of any adverse effect that is an impediment from an ethical or technical point of view to continue with the study.

(See Submission Process and Timeline of Review sections for detailed REC 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.

As set forth in G-RECs-Op-2018, COFEPRIS-GCP, and REC-Op, Research Ethics Committees (RECs) (Comités de Ética en Investigación (CEIs)) do not charge sponsors/investigators for their review. Rather, the health institution must finance REC operating expenses, without this causing any conflict of interest in the committee’s functions.

G-RECs-Op-2018 further states that the institution may also receive support from external sources for evaluating protocols. However, this funding should not be given directly to any of the REC members, and the contributions should not lead to a conflict of interest between the funding source and the REC’s functions. Similarly, the committee’s evaluations should not result in financial gains as a result of these contributions.

Per G-RECs-Op-2018, REC financial support should not be used for purposes other than for its operation, and all activities should be handled with full transparency. Support is provided for the following activities:

• Time for participation in committee meetings
• Work recognition for their performance in the REC
• Support for training in bioethics and research ethics inside and outside the institution
• Physical space for the REC headquarters, both for meetings and receipt of documents, and safeguarding of documentation protocols, opinions, and minutes
• Administrative assistance for REC activities

No information is available on Hospital Bioethics Committee fees.

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

The National Bioethics Commission (Comisión Nacional de Bioética (CONBIOÉTICA)) was established as a decentralized entity of the Ministry of Health (Secretaría de Salud) in 2005, as specified in D-CONBIOETICA. According to D-CONBIOETICA and MEX-55, the agency has technical and operational autonomy in defining and establishing national bioethics policies in medical care and health research. Per D-CONBIOETICA, GenHlthLaw, G-RECs-Op-2018, and MEX-57, CONBIOÉTICA is also responsible for promoting the organization and operation of Research Ethics Committees (RECs) (Comités de Ética en Investigación (CEIs)) and Hospital Bioethics Committees in public and private health institutions, for establishing and disseminating criteria to support development of REC activities, and for providing committee member training support.

In addition, per D-CONBIOETICA, CONBIOÉTICA’s other roles include:

• Exercising the Commission’s legal authority and head Commission operations
• Presiding over the Commission’s Advisory Council
• Issuing positions on bioethical issues relevant to society
• Establishing links with federal entities to promote the creation and operation of state bioethics commissions
• Signing and implementing collaborative agreements with organizations and opportunities that favor the development and consolidation of bioethical culture
• Carrying out activities assigned by the Secretary of Health
• Providing information and technical cooperation required by the Ministry of Health’s administrative units and other dependencies/entities within the Federal Public Administration

Registration, Auditing, and Accreditation

Research Ethics Committees

As delineated in HlthResRegs, REC-Op, REC-Op-Ref, REC-Op-Amd, G-RECs-Op-2018, G-RECReg, and MEX-57, all RECs are required to register with CONBIOÉTICA in order to conduct health research in humans.

G-RECs-Op-2018, and G-RECReg further state that CONBIOÉTICA has 10 working days from the business day following application receipt to accept the application, or require the applicant to correct omissions in the application within 15 working days from the business day following the date when the applicant is notified. If the applicant fails to respond within this timeframe, the application must be deemed not filed. Once the application has been admitted for processing, the Commission has 30 working days to notify the applicant of receipt, and if appropriate, to issue the corresponding registration certificate, which will be valid for three (3) years. The registration record must also be visibly displayed in the institution where REC operations occur and on its website, if applicable. Additionally, the registration number must be included in all official committee communications.

Per REC-Op-Amd, MEX-58, and G-RECReg, the REC registration form (MEX-29) is available for completion or download via MEX-58 or G-RECReg, and should be submitted in person according to the requirements outlined in REC-Op-Amd, MEX-58, and G-RECReg. The application must include the REC’s health institution identification data, an email address in order to receive Commission notifications, and the name and signature of the responsible person heading the REC. G-RECReg specifies that the applicant may request an appointment by phone or email to deliver all the documentation in printed form to CONBIOÉTICA, or send the application documentation via certified mail.

Refer to REC-Op-Amd, G-RECs-Op-2018, MEX-58, and G-RECReg for detailed registration application instructions and documentation requirements. See also MEX-57 for a list of registered RECs.

As delineated in REC-Op-Amd, G-RECs-Op-2018, and G-RECRegRenew, a registration renewal application must be submitted by the principal or owner of the health establishment or by the legal representative to CONBIOÉTICA within 45 working days prior to the expiration of the validation period covered by the registration certificate. From this point, the timing requirements are the same as for the initial application. See REC-Op-Amd, G-RECs-Op-2018, and G-RECRegRenew for detailed registration renewal application requirements and the application form.

In addition to CONBIOÉTICA’s REC registration requirement, per GenHlthLaw, G-RECs-Op-2018, REC-Op, and REC-Op-Ref, RECs must be installed under the responsibility of the head of the health institution where the study is taking place. They are required to sign a REC Installation Certificate (MEX-27), which stipulates its characteristics and functions. Refer to G-RECs-Op-2018 for detailed certificate requirements. See also MEX-72 for information on CONBIOÉTICA’s REC follow-up monitoring reports.

According to NOM-012-SSA3-2012, the research institution owner must also register the REC with the Ministry of Health (Secretaría de Salud), and report on the modification, designation, or substitution of any of its members. Additionally, an annual report documenting the integration and activities of these committees must be submitted to the Ministry during the first 10 business days of June each year.

Hospital Bioethics Committees

G-CHBs-Op and G-CHBReg indicate that Hospital Bioethics Committees must also register with CONBIOÉTICA, who is, in turn, required to issue a registration record within a maximum of 15 business days. CONBIOÉTICA’s registration is valid for three (3) years. Per G-CHBs-Op, the Hospital Bioethics Committee registration form must be submitted electronically through CONBIOÉTICA’s website. The application for registration renewal can be submitted one (1) month prior to the registration’s expiration date. Refer to G-CHBs-Op, MEX-56, MEX-59, and G-CHBReg for additional Hospital Bioethics Committee registration information.

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 GenHlthLaw, Reg-COFEPRIS, HlthResRegs, and NOM-012-SSA3-2012, Mexico requires the applicant to obtain research protocol authorization from the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the applicant must also obtain a favorable decision from the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee at the health institution where the study is being conducted, and when applicable, a favorable decision from the Biosafety Committee. Because COFEPRIS’s review and approval of a protocol authorization request is dependent upon obtaining a favorable decision from the REC and Research Committee, the COFEPRIS and ethics committee (REC and Research Committee) reviews may not be conducted in parallel.

Regulatory Submission

MEX-15 states that applicants may submit research authorization requests or protocol modification/amendment requests in person or by mail to COFEPRIS at the Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37), a public service system established by the Mexican government to facilitate the processing of the agency’s standardized procedures and services. According to G-HumResProt, G-ResProtocolAmd, MEX-109, and MEX-37, however, requests should be submitted to the CIS (MEX-37) in person or electronically via COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86). (Note: COFEPRIS refers to applications as requests or procedures).

Pre-submission Registrations

As delineated in G-DIGIPRiS-Regis and G-DIGIPRiS-SystAccess, prior to submitting a request for research protocol authorization via DIGIPRiS (MEX-86), an applicant must first register in (MEX-86) using an e.signature (also known as e.firma) digital certificate. MEX-49 explains that the signature is a secure, encrypted digital file that identifies an applicant, and can be used to carry out procedures electronically with various government agencies. An e.signature can be obtained from the Tax Administration Service (Servicio de administración tributaria (SAT)) as described in MEX-105. G-DIGIPRiS-Regis and G-DIGIPRiS-SystAccess further explain that an e.signature is used to validate the natural person or legal entity registering in MEX-86. DIGIPRiS’s Terms of Use, which is accessible via MEX-86, also notes that the applicant is required to be registered with the Federal Taxpayer Registry (Registro Federal de Contribuyentes (RFC)). See G-DIGIPRiS-Regis, G-DIGIPRiS-SystAccess, and DIGIPRiS’s Terms of Use for details on registering in MEX-86. See also MEX-106 for an instructional tutorial on registering in MEX-86, and see G-DIGIPRiS-FAQs for frequently asked questions on using MEX-86.

DIGIPRiS Submissions

DIGIPRiS’s Terms of Use further explains that the application process is carried out entirely electronically via DIGIPRiS (MEX-86), unless the user is required to present printed documents with a handwritten signature or a physical inspection is required. The application request will be considered active when the documentation is signed and submitted, otherwise it will only remain in the system for 90 calendar days. When the request is active, the user receives a “Procedure Entry Receipt” through which COFEPRIS assigns a procedure number and the entry date and time is recorded. Once the procedure has begun, the user will be notified in MEX-86 of all request related administrative acts (e.g., requirements, actions, preventions or missing information, and resolutions). Authorizations issued via MEX-86 will take effect on the date and time indicated in the corresponding document. The email address the user provides during registration will be used to send notices of notification availability related to submitted applications. Refer to DIGIPRiS’s Terms of Use for detailed information on the administrative act notification process via MEX-86. See also G-DIGIPRiS-SystAccess for instructions on registering and updating emails in MEX-86.

Pursuant to G-DIGIPRiS-SystAccess and G-DIGIPRiS-ResProts, users can view the flow and status of the entire application process (application, evaluation, verification, signature and resolution) in DIGIPRiS (MEX-86), as well as view previously authorized applications. Additionally, multiple requests and procedures can be in process simultaneously in MEX-86. See also G-DIGIPRiS-DocComp for instructions on validating and comparing documents issued through MEX-86 for research protocols. Refer to MEX-96, MEX-97, and MEX-108 for additional background information on MEX-86. Per G-HumResProt, electronic submissions via MEX-86 are tracked via the applicant’s e.signature (MEX-105). See also G-DIGIPRiS-Reqs&Amdts for instructions on submitting requests for protocol amendment/modification via MEX-86.

CIS Submissions

As indicated in MEX-37 and MEX-15, applications submitted in person at the CIS (MEX-37) can be tracked via a CIS assigned reference number in the COFEPRIS Electronic Procedures Portal (MEX-103). MEX-109 specifies that the Electronic Procedures Portal (MEX-103) is only to be used for procedures submitted in person at the CIS (MEX-37) while procedures submitted via DIGIPRiS (MEX-86) should be tracked through the DIGIPRiS platform.

As per MEX-15, and MEX-71, applications as well as technical inquiries, or those inquiries requiring an official response, should be submitted to the CIS (MEX-37) at:

COFEPRIS
Centro Integral de Servicios
Oklahoma No. 14
Colonia Nápoles
Del. Benito Juárez
CP 03810, Ciudad de México

COFEPRIS Call Center Phone: 01-800-033-5050 (toll free within Mexico) or 55 53 40 09 96 (international calls) (per MEX-37)
Foreign Processing Area Phone (for entry and/or tracking number of procedure): 01-800-420-4224 (toll free within Mexico) (per MEX-25)
Email: contactociudadano@cofepris.gob.mx (per MEX-71 and MEX-37)

Per G-DIGIPRiS-ResProts, all documents uploaded to DIGIPRiS (MEX-86) must be in “.pdf” format (unrestricted text file), unless another format is specified.

Per G-HumResProt, G-ResProtocolAmd, and MEX-18, the Authorizations, Certificates and Visits form (MEX-25) should also be included in the application submission, as well as the original proof of payment of rights with two (2) copies of the receipt for protocol authorization and protocol modification/amendment requests. See the Submission Content section for detailed submission documentation requirements.

G-HumResProt and G-ResProtocolAmd state that all documentation related to submitting applications for research protocol authorization and protocol modification/amendment is required to be in Spanish. MEX-84 also specifies that the protocol, investigator’s brochure (known as the researcher’s manual in Mexico), and the informed consent forms should be in Spanish.

Enabled Pre-Assessment Support Unit (UHAP) Evaluation Submissions

Per MEX-21 and MEX-10, rather than submitting the application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Speciality Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) or a UHAP within the Mexican Social Security Institute (Instituto Mexicano del Seguro Social (IMSS)). See Scope of Assessment section for detailed information on UHAPs.

Ethics Review Submission

As earlier stated, per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, all requests for research protocol authorization in human beings and/or their biological samples in Mexico require the applicant to obtain a favorable decision from the REC and the Research Committee, and when applicable, a favorable decision from the Biosafety Committee. Because the submission process at individual institutional RECs 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 GenHlthLaw, HlthResRegs, NOM-012-SSA3-2012, COFEPRIS-GCP, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the following documentation must be submitted to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) as part of the approval process (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Authorizations, Certificates and Visits form (original and two (2) copies) (MEX-25)
• Proof of payment of rights (original and two (2) copies)
• Request letter (in editable format (.docx) containing study data (title, investigator’s name, etc.), description of study risk level and duration (including estimated start and end dates (DD/MM/YYYY), and documents submitted for research protocol authorization (original)
• Response to COFEPRIS prevention letter requesting missing or additional information should be submitted in a new request letter
• Research protocol (original and one (1) copy)
• Acceptance letter from research institution head and responsible principal investigator (PI)
• Sponsor letter of acceptance of position and delegation of responsibilities (must include at least sponsor contact information, description of obligations and protocol rights, sponsor legal representative/authorized person signature, protocol number, when applicable, a certified copy of the apostilled, notarized, and translated power of attorney) (one (1) copy)
• Letter of No Conflict of Interest from the sponsor (one (1) copy)
• Document proving applicant’s legal identity (e.g., health license, operating notice or, where appropriate, the Federal Taxpayer Registry (Registro Federal de Contribuyentes (RFC)) (one (1) copy)
• Follow-up letter from sponsor providing monitoring/auditing plan
• Model letter of informed consent in Spanish
• Informed consent of the research participant or, where appropriate, the legal representative (original and one (1) copy)
• Study schedule (original and one (1) copy)
• Health warehouse license for operation of storage and distribution warehouse for biological products for human use, with handling of medications: narcotics, psychotropics, vaccines, toxoids, serums and antitoxins of animal origin and/or blood derivatives (one (1) copy)
• Letter of acceptance of responsibility from the importer (signed by legal representative of the importer)
• Importer name, license number, and address
• Sanitary license of the warehouse for storage and distribution of the research product (only narcotics, psychotropics, biologicals, radiopharmaceuticals, and vaccines)
• Letter of import supplies providing approximate total quantity and description of investigational products (IPs) requiring importation at each stage of the study; letter serves as acknowledgement of information, not authorization (original and one (1) copy)
• IP route of administration
• Insurance policy or current document from the financial fund that covers all study participants at the local level (one (1) copy)
• Current Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and Research Committee registration and Biosafety Committee registration, where applicable (one (1) copy)
• Favorable opinion of REC, Research Committee, and where appropriate, Biosafety Committee (original and one (1) copy)
• REC member list
• REC member letters recusing themselves if on research team (one (1) copy)
• REC letter describing study follow-up monitoring process (one (1) copy)
• Letter of No Conflict of Interest and Confidentiality signed by REC members (one (1) copy)
• Institution’s or establishment’s sanitary license or notice of operation (one (1) copy)
• Letter of authorization to carry out the research, signed by institutional head or health institution owner (must include protocol title/number, PI name, institution/establishment head signature and position, research center name/address) (original and one (1) copy)
• Where applicable, copy of agreement between research centers that have agreements for emergency medical care with other institutions
• Acceptance letter from the head of the institution or establishment describing resources available for emergency management (original and one (1) copy)
• Health license of the establishment to carry out medical emergency care
• Agreement or contract of the establishment for the care of medical emergencies of the research (must include at least title/protocol number; PI name; scope, clauses, and validity; signature of holders and legal representatives of both institutions; statement establishing the care of medical emergencies)
• Agreement or contract with institution or establishment to provide care for research related medical emergencies (one (1) copy)
• Letter of acceptance, confidentiality, and commitment to report suspected adverse reactions and events signed by the PI (original and one (1) copy)
• Summary of PI’s professional record/official professional documentation issued and registered by competent educational authorities (original and one (1) copy)
• Professional background of the PI (one (1) copy)
• Summary of academic preparation and experience of medical personnel, paramedics, and other experts involved in study (include updated Curriculum Vitae (CV), dated and signed, for each member; include a copy of documentation issued and registered by competent educational authorities accrediting academic preparation) (original and one (1) copy)
• Express letter of No Conflict of Interest to conduct the research, signed by the PI and research team
• PI letter describing research team’s delegation of responsibilities (must including protocol title/number, detailed description of activities, PI name/signature, team member signatures) (one (1) copy)
• Investigator’s Brochure (IB) (original and one (1) copy) (also known as investigator’s manual in Mexico)
• Letter describing the sponsoring institution’s or establishment’s resources for the study’s development (include institution/establishment name, PI name, protocol title/number, type of support required (e.g., human, material, financial, advisory information, equipment, auxiliary laboratory services, cabinets, and other resources), and how support will be provided and distributed) (original and one (1) copy)
• Document indicating drugs used in study comply with Good Manufacturing Practices (GMPs) and have the expected quality characteristics for IPs to be used in study, or letter documenting GMPs (one (1) copy)
• Status of stability studies, or letter documenting IP stability studies comply with applicable regulations (one (1) copy)
• Basic pharmacological and preclinical product information
• Additional study information (countries where research will be conducted, health conditions/problems, public consultation contact, scientific consultations contact)
• Optional pre-assessment evaluation opinion (See Scope of Assessment and Submission Process sections for details on pre-assessment evaluations)

See also Scope of Assessment and Timeline of Review sections for additional COFEPRIS review process and timeline information.

Refer to GenHlthLaw, HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, G-DIGIPRiS-ResProts, and MEX-18 for more detailed submission information. See also MEX-36 for information on obtaining a certificate of GMPs.

Ethics Committee Requirements

As indicated in MEX-84 and G-DIGIPRiS-ResProts, the following documentation should be submitted to obtain the favorable opinion of the REC, the Research Committee, and where appropriate, the Biosafety Committee:

• Full title and number of the research protocol
• Research protocol with the version and date in Spanish
• IB with the version and date in Spanish
• Full name of the IP corresponding to the research center
• Research center company name and address
• Informed consent forms with the version and date in Spanish
• Protocol summary
• Detailed description of the documents evaluated and approved in Spanish, citing version and date
• Validity of the approval opinion (not greater than one (1) year)
• Name, position, and signature of the person responsible who supports the opinion
• Confirmation of the evaluation of aspects of a scientific nature, the risk/benefit of the protocol as well as the guarantee and well-being of the participants

Additionally, a signed opinion issued on letterhead should be submitted that includes:

• Committee name and address (in accordance with its current registration)
• Date the opinion was issued
• PI name
• Company name and address of the research center
• Title of the study and protocol number
• Status/result of the evaluation of the documents (must be approved)
• Date of issue of the opinion (day, month, and year)
• Name and position of the signatory who supports the opinion (must be the President or the Secretary Member)

G-DIGIPRiS-ResProts, also notes that only the opinions with the signature of the President of the REC (or, where appropriate, the Secretary-Vocal) will be accepted with a letter attached stating “NO VOTE” or a justification for the absence of the president. See MEX-84 and G-DIGIPRiS-ResProts for additional ethics committee requirements.

Clinical Protocol

As set forth in MEX-84 and G-DIGIPRiS-ResProts, which are in compliance with the Guideline for Good Clinical Practice E6 (R2) (MEX-22), and NOM-012-SSA3-2012, the research protocol should include the following elements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Title, acronym, and protocol number (corresponds to the opinion of the committee(s) evaluators)
• Document version and date, and amendments (if applicable) (corresponds to the opinion of the committee(s) evaluators)
• Sponsor name/address and monitor, if different from sponsor
• Theoretical framework (IP name/description, preclinical findings summary, etc.)
• Definition of problem
• Participant selection and withdrawal criteria
• Statement that the clinical trial will be conducted in accordance with the protocol, good clinical practices, and local regulatory requirements
• Background
• Rationale
• Hypotheses (if applicable, includes statistical hypotheses)
• General objective (if applicable, includes specific, primary, secondary, or exploratory objectives)
• specific objectives)
• Materials and methods
• Study design (e.g., inclusion/exclusion and elimination criteria; information input, processing, analysis, and interpretation)
• Phase and type of study
• Study duration
• Sample size (global and local, as appropriate)
• Countries where the research will be carried out
• Health conditions or problems studied
• Capture, processing, analysis, and interpretation of the information obtained
• Route of administration, dose, dosing regimen, and treatment period(s) and justification
• Accountability procedure for handling the IP and placebo (if applicable)
• Mechanisms for maintaining randomization and blinding (if applicable), and codes for breaking them (e.g., criteria for premature unblinding, etc.)
• Statistical considerations
• Ethical considerations
• Efficacy and safety assessments
• Study schedule (document detailing activities to be carried out during the investigation)
• Bibliographic references and relevant trial data
• Names and signatures of PI and associate researchers (no more than five (5), classified according to their involvement in the research project)
• Other documents related to the research project or protocol
• Optional pre-assessment evaluation opinion (See Scope of Assessment and Submission Process sections for details on pre-assessment evaluations)

In addition to the protocol submission, per NOM-012-SSA3-2012, an additional letter should accompany the application. Please refer to NOM-012-SSA3-2012 for more specific letter instructions. See also MEX-84 and G-DIGIPRiS-ResProts for more detailed protocol requirements.

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

As delineated in HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS))’s review and approval of a protocol authorization request is dependent upon obtaining a favorable decision from the health institution’s Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee, and where applicable, the Biosafety Committee. Therefore, COFEPRIS and ethics committee (REC, Research Committee, and Biosafety Committee) reviews may not be conducted in parallel. However, per HlthResRegs, the REC, the Research Committee, and the Biosafety Committee may meet together to decide whether to authorize a protocol to conduct research on humans, as appropriate.

Regulatory Authority Approval

Pursuant to HlthResRegs, COFEPRIS must approve a request for research protocol authorization within 30 working days from the day following an application’s filing. However, according to G-HumResProt, COFEPRIS is required to complete its review of a research protocol authorization request and notify the applicant within three (3) months.

According to Reg-COFEPRIS and MEX-53, COFEPRIS’s Sanitary Authorization Commission (Comisión de Autorización Sanitaria (CAS)) is responsible for recording, evaluating, and issuing opinions on requests for human research protocol authorizations. Per G-HumResProt, the evaluator in CAS issues a resolution of authorization or a prevention letter, and it is forwarded to the head of the area (CAS) for signature. If a prevention letter is issued in which additional or missing information is requested, the applicant is required to address the issues within 30 calendar days. See Submission Process section for details on tracking submitted procedures via the Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) or COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86).

Per G-ResProtocolAmd, G-ObsrvStdies, and G-BioequivStud, COFEPRIS’s review deadlines (three (3) months or 90 calendar days) to notify applicants are also applicable to requests for authorization of protocol amendments or modifications and requests for authorization to conduct risk-free research (observational studies) and bioequivalence studies. Refer to G-ResProtocolAmd, G-ObsrvStdies, and G-BioequivStud for details. See Submission Process section for detailed submission requirements.

Additionally, per Reg-HlthProd and G-UnregDrugImprts, COFEPRIS has 10 days to approve import requests for investigational drug products. If COFEPRIS does not respond within this timeframe, the request is deemed approved. G-UnregDrugImprts also notes that COFEPRIS has four (4) business days to send the applicant a prevention notification regarding missing or additional information required. The applicant, in turn, has five (5) business days to respond.

Per HlthResRegs and G-RNECManual, once the applicant obtains an official authorization from COFEPRIS, the applicant has a maximum of five (5) working days to enter this information into the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). The RNEC is in charge of the CAS’s Clinical Trials technical area and serves as the interface through which applicants are required to submit their application documentation in order to maintain an updated national inventory of clinical studies involving humans and/or their biological samples.

Enabled Pre-Assessment Support Unit (UHAP) Evaluations

Per HlthResRegs, prior to submitting an authorization request, applicants may also obtain a pre-assessment evaluation by an authorized third party that helps to facilitate COFEPRIS’s review. MEX-21 and MEX-10 explain that rather than submitting an application directly to the CIS, the applicant has the option of first choosing to obtain a pre-assessment (third party) evaluation of the application through an Enabled Pre-Assessment Support Unit (Unidad Habilitada de Apoyo al Predictamen (UHAP)) (MEX-69) within the Coordinating Commission of National Institutes of Health and High Specialty Hospitals (Comisión Coordinadora de Institutos Nacionales de Salud y Hospitales de Alta Especialidad (CCINSHAE)) (referred to as the UHAP-CCINSHAE) or a UHAP within the Mexican Social Security Institute (Instituto Mexicano del Seguro Social (IMSS)). According to MEX-10, the UHAP has a maximum of 30 calendar days to respond to an evaluation request. See MEX-10 and MEX-121 for additional information on authorized third parties. See the Scope of Assessment and Submission Process sections for detailed UHAP information.

Ethics Committee Approval

As delineated in G-RECs-Op-2018, the REC agenda and documents corresponding to each session should be delivered at least seven (7) days prior to the meeting. It is then recommended that the REC’s decision be sent within a period not exceeding five (5) working days after the committee has met, or if applicable, not to exceed 30 calendar days from the date of request for its review. G-RECs-Op-2018 and G-DIGIPRiS-ResProts also state that the approval of a new application is valid for one (1) year.

In addition, G-RECs-Op-2018 indicates that the REC should establish procedures for monitoring approved studies, from the point at which the decision was made until the completion of the investigation and reporting of results. RECs should conduct at least one (1) review a year.

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 GenHlthLaw, Reg-COFEPRIS, HlthResRegs, NOM-012-SSA3-2012, COFEPRIS-GCP, G-HumResProt, and MEX-84, a clinical trial can only commence after an applicant receives authorization from Mexico’s Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)). Per HlthResRegs, G-HumResProt, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, the applicant must also obtain a favorable decision from the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee at the health institution where the study is being conducted, and when applicable, a favorable decision from the Biosafety Committee. No waiting period is required following the applicant’s receipt of these approvals.

As per GenHlthLaw, an applicant must be a resident of Mexico and is required to obtain an import license from COFEPRIS for the shipment of an investigational product to be used in the trial. The applicant must be a resident of Mexico or have a legal representative submit the application on their behalf. (See the Manufacturing & Import section for additional information).

As set forth in NOM-220-SSA1-2016, the health record holder, principal investigator (PI), sponsor, or person responsible for a study authorized by COFEPRIS must also issue a notice of a study’s commencement (e.g., first visit of the first patient) and a notice of its completion (e.g., last visit of the last patient).

Clinical Trial Agreement

Prior to initiating the trial, as set forth in NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, if applicable, the sponsor must sign a letter of acceptance that serves as an agreement to assume the project obligations and rights stated in the letter. G-DIGIPRiS-ResProts also notes that the letter must include the sponsor’s delegation of activities to other institutions and/or companies duly authorized to accept the obligations, responsibilities, and rights imposed by the development and conduct of the study. Per G-DIGIPRiS-ResProts and NOM-012-SSA3-2012, in the case of corporate entities, this position must be accepted by an individual authorized to do so or by a corporation’s legal representative, according to its organizational structure or incorporation regime.

Additionally, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts state that the sponsor must sign a letter to ensure there are no conflicts of interest that could lead to the interruption of treatment for the research participant. NOM-012-SSA3-2012, further specifies that when the research is sponsored by a public or private organization, that it must be guaranteed that this will not generate conflicts of interest that could cause the interruption of treatment for the research participant. A detailed explanation of the resources available and the way in which they will be provided and distributed must also be attached in the research protocol.

According to COFEPRIS-GCP, COFEPRIS requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. COFEPRIS-GCP indicates that the sponsor must establish in writing each of the research team member functions and responsibilities, and the financial agreement with the PI. The sponsor or the CRO must also establish a declaration of financing, sponsorship, affiliations, contracts of agreements with other institutions involved, and procedures for handling any conflict(s) of interest, and a system for providing incentives and quantity/payments to research participants. MEX-32 specifies that the financial aspects of the trial should be documented in an agreement between the sponsor and the investigator and the institution.

Further, per MEX-32, 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 and should provide sufficient time for the investigator and institution to review the protocol and the information provided.

COFEPRIS-GCP further states that in the case of delegating investigation-related activities to a CRO, the sponsor must also establish in writing each of the activities that are delegated. However, the ultimate responsibility for all CRO activities remains with the sponsor. Additionally, COFEPRIS-GCP indicates that the sponsor or the CRO must establish a declaration of financing, sponsorship, affiliations, contracts, or agreements with other institutions involved, handling of any conflict of interest, incentives, and quantity and payments to the research participants.

According to MEX-32, the sponsor or the CRO must also obtain the investigator(s)’s and the institution(s)’s agreement to:

• Conduct the trial in compliance with MEX-32 and the protocol agreed to by the sponsor and approved by the ethics committee
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor informs them that they are no longer needed

Per MEX-32, the sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

Clinical Trial Registration

Per G-DIGIPRiS-ResProts, once an official authorization from COFEPRIS is obtained, some of the data provided by the applicant in COFEPRIS’s digital procedures and services platform, DIGIPRiS: Online Regulation (MEX-86), will be migrated to COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37) and to the National Registry of Clinical Trials (Registro Nacional de Ensayos Clínicos (RNEC)) database (MEX-68). According to MEX-109, the G-RNECManual is useful for information on registering with RNEC for clinical trial applications submitted in person at the CIS (MEX-37).

Governance

Per GenHlthLaw, HlthResRegs, and NOM-012-SSA3-2012, every health institution where research is conducted is required to establish a Research Committee and a Biosafety Committee. Per HlthResRegs, NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts, REC and Research Committee approval is also required for each trial site where a study is being conducted, and when applicable, Biosafety Committee approval is required as well.

HlthResRegs explains that the Research Committee evaluates the technical quality and scientific merit of the proposed research, and its opinion must contain the REC opinion and, where applicable, the Biosafety Committee opinion. The Biosafety Committee, in turn, is responsible for determining and regulating the use of ionizing radiation or genetic engineering techniques within the health institution as indicated in HlthResRegs, GenHlthLaw, and NOM-012-SSA3-2012. Pursuant to HlthResRegs, NOM-012-SSA3-2012, and G-HumResProt, the Biosafety Committee issues a technical opinion on the biosafety aspects of the proposed research and ensures that research study staff, research participants, the community, and the environment are protected against radiological risks.

Additionally, per MEX-47, COFEPRIS is responsible for registering Research Committees and Biosafety Committees. Refer to MEX-47, G-BiosafetyReg, and G-ResCommReg for detailed Research Committee and Biosafety Committee registration requirements. See MEX-26 for COFEPRIS’s Research Committee and Biosafety Committee registration form.

Safety Reporting Definitions

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

Sponsor Responsibilities

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

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

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

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

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

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

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

Ethics Committee Responsibilities

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

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

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

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

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

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

Other Safety Reports

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

Form Completion & Delivery Requirements

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

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

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

Safety Reporting Definitions

In accordance with NOM-220-SSA1-2016, NOM-012-SSA3-2012, G-ClinResPV, and G-PharmPerSafRpt, the following definitions provide a basis for a common understanding of Mexico’s safety reporting requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event/Experience (AE) – Any undesirable medical event that may occur in a research participant during the clinical investigation stage of a drug/vaccine, but does not necessarily have a causal relationship to it
• Adverse Drug Reaction or Adverse Reaction (ADR) – An unwanted response to a drug, in which the causal relationship with it is, at least, reasonably attributable
• Unexpected Adverse Drug Reaction – One whose nature or severity is inconsistent with the applicable product information, or in the documentation presented for its sanitary registration
• Suspected Adverse Drug Reaction (SRAM) – Any clinical or laboratory manifestation that occurs after administration of one (1) or more drugs

Safety Reporting Requirements

As specified in NOM-220-SSA1-2016-Mod, for clinical study related incidents involving health professionals (public and private) or institutions conducting health research, notifications to the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS))’s National Pharmacovigilance Center (CNFV) must be submitted according to the following timelines:

• Serious SRAMs or serious AEs/ADRs must be reported within a maximum of seven (7) calendar days, if fatal, and within a maximum of 15 days, if not fatal (severe cases from abroad should only be included in the final study safety report, if the study has a research center in Mexico)
• Not serious SRAMs or AEs/ADRs must be reported at the end of the study
• Two (2) or more serious cases, in the same place with the same drug and the same batch, must be reported immediately, and no later than 48 hours
• When a review of scientific literature shows a safety issue, it should be reported within a maximum of 30 calendar days from first knowledge of the AE/ADR

HlthResRegs and NOM-012-SSA3-2012 state that the institution must notify and provide a report to the Ministry of Health (Secretaría de Salud) within a period of 15 days after the suspension or cancellation of the research has been agreed upon. The report should specify the effect(s) detected, all medical care steps adopted, and the consequences produced. A detailed report on the research participant(s) physical condition should also be included. NOM-012-SSA3-2012 indicates that all serious or deadly adverse reactions or effects must be immediately reported to the Ministry. Per NOM-012-SSA3-2012, the principal investigator (PI), the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), the institutional head(s), or the Ministry of Health must also suspend or cancel the research as soon as any AE representing an ethical impediment to research is identified.

Additionally, per NOM-220-SSA1-2016, institutions must notify the CNFV of a study’s suspension or cancellation within a maximum of 15 days. If the study is resumed, the CNFV must also be notified within a maximum of 15 working days following the study’s recommencement.

Per MEX-2, COFEPRIS has also implemented the following International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines:

• Guideline E2B (R3) on Electronic Transmission of Individual Case Safety Reports (ICSRs) – Data Elements and Message Specification – Implementation Guide (MEX-79)
• ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (MEX-80)
• ICH Harmonised Tripartite Guideline: Pharmacovigilance Planning (E2E) (MEX-82)

Investigator Responsibilities

As specified in HlthResRegs, NOM-012-SSA3-2012, and COFEPRIS-GCP, the PI must report to the REC all probable AEs or any AEs directly related to the research study. Per NOM-012-SSA3-2012, the investigator is also responsible for submitting safety reports to the CNFV.

Other Safety Reports

As indicated in NOM-220-SSA1-2016, a pharmacovigilance study protocol should be prepared and submitted to the Executive Director of Pharmacopeia and Pharmacovigilance through COFEPRIS’s Comprehensive Service Center (Centro Integral de Servicios (CIS)) (MEX-37).

Per NOM-220-SSA1-2016, a clinical safety report is also required to be submitted to the CNFV for all trials, sponsored or not, that have at least one (1) site or research center in Mexico. In addition, G-ClinResPV explains that a final safety report must be submitted to the CNFV in the following circumstances:

• A study is completed that has included at least one (1) research center in Mexico
• A study has been cancelled, discontinued, or definitively suspended
• A bioequivalence, bioavailability, and pharmacokinetics study is concluded

Refer to G-ClinResPV and G-PharmPerSafRpt for additional report writing instructions and criteria that align with the safety reporting requirements delineated in NOM-220-SSA1-2016 and NOM-220-SSA1-2016-Mod. See also G-PharmRptReq for detailed pharmacovigilance reporting guidelines and to extend sanitary registrations for drug products.

Form Completion & Delivery Requirements

G-ClinResPV specifies that clinical safety reports must be written in Spanish and submitted electronically (in PDF format) to the CNFV. In addition, reports should be submitted by either the health record holder or the sponsor or the legal representative to avoid sending duplicate information to the CNFV. G-PharmPerSafRpt states, in turn, that the safety report must be written in Spanish in the sections delineated in Annex 1 of G-PharmPerSafRpt and submitted electronically via CD or USB in editable PDF format. As indicated in G-ClinResPV and G-PharmPerSafRpt, the annual safety report submission date is determined by the date of the study’s first national authorization by COFEPRIS.

As per MEX-117, the E-Reporting Industry platform, which is linked to VigiFlow (MEX-43), was developed by the World Health Organization (WHO)’s Uppsala Monitoring Centre for the pharmaceutical industry to manage individual case safety reports at the national level. Reports are submitted by pharmaceutical industry professionals including health registration holders or their legal representatives and institutions/establishments where research is conducted as well as contract research organizations, distributors, and marketers. MEX-117 also specifies the CNFV is responsible for granting access to the E-Reporting Industry tool, and requests can be made via email: xmlvigiflow@cofepris.gob.mx. Refer to MEX-117 for details. Additionally, per MEX-77, state centers, institutional coordinating centers, institutional centers, and pharmacovigilance units of the National Health System should also report AE/ADRs, SRAMs, ESAVIs, and other safety issues via MEX-43.

MEX-78, in turn, provides patients, consumers, and health professionals instructions on reporting ADRs via VIGIRAM (MEX-118). See MEX-12 for instructions on using MEX-118, see MEX-30 for the form to be completed via MEX-118, and see MEX-119 for additional information on MEX-118. See also G-ADR-PatientRpt for information on how patients, consumers, and/or family members report suspected ADRs.

Refer to NOM-220-SSA1-2016 for detailed reporting requirements, and the G-AENotif, MEX-44, and MEX-117 for submitting safety reports via VigiFlow (MEX-43). See also MEX-54 for additional CNFV issued pharmacovigilance guidelines and requirements.

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

Per HlthResRegs, NOM-012-SSA3-2012, and MEX-28, the principal investigator (PI) must prepare and submit a progress report (also referred to as a partial technical or technical-descriptive report) (MEX-31) to the Ministry of Health (Secretaría de Salud) at any time, but at least once a year, to communicate progress and partial research study results. In addition, per NOM-012-SSA3-2012, information related to any investigation that the PI submits to the Ministry of Health must be classified as confidential. NOM-012-SSA3-2012 further states that the PI must also provide a copy of every report to the head of the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee, and if applicable, the Biosafety Committee of the institution where the research takes place.

NOM-012-SSA3-2012 specifies that the progress reports should describe the results obtained and at a minimum should include the following elements:

• Identification data
• Materials and methods
• Results
• Conclusions
• Bibliographic references
• Any relevant exhibits

In accordance with NOM-012-SSA3-2012, a report should be submitted annually to the Ministry of Health on the integration and activities of the REC, the Research Committee, and, if applicable, the Biosafety Committee, during the first 10 business days of June.

Final Report

As set forth in HlthResRegs, NOM-012-SSA3-2012, and MEX-28, the PI is also required to submit a final report to the Ministry of Health in order to communicate the final results of a research protocol or project as well as the major findings obtained throughout the course of the study. Additionally, per NOM-012-SSA3-2012, the PI must deliver a copy of this report to the research team members, the REC, the Research Committee, and the Biosafety Committee, as applicable, where the study was conducted.

As per NOM-012-SSA3-2012, the final reports should describe the results obtained and at a minimum should include the following elements:

• Identification data
• Summary
• Introduction
• Materials and methods
• Results
• Discussion
• Conclusions
• Bibliographic references
• Any relevant exhibits/Annexes

See section 7.4 of NOM-012-SSA3-2012 for additional required report information.

HlthResRegs further states that the PI is also required to submit a final report to the Research Committee at the institution where the study was conducted. Refer to MEX-31 for the reporting form.

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

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

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

As set forth in NOM-012-SSA3-2012, COFEPRIS-GCP, and MEX-84, a sponsor is defined as an individual or corporation willing to undertake responsibilities to participate and finance a research project or protocol, in full or in part.

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. Per COFEPRIS-GCP and MEX-32, a sponsor is an individual, company, institution, or organization which takes responsibility for the initiation, management, and/or financing of a clinical trial. A sponsor may also hire a CRO to conduct one (1) or more of the activities related to health research that are sponsored in the country. The sponsor must specify in writing any trial-related duty and function that is transferred to and assumed by a CRO. However, the ultimate responsibility for all CRO activities remains with the sponsor. Additionally, MEX-32 notes the ultimate responsibility for the quality and integrity of the trial data always resides with the sponsor, and any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. COFEPRIS-GCP also indicates that CROs of foreign origin must also have a registered address in Mexico, and an authorization to carry out clinical research activities in the country.

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

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. COFEPRIS-GCP states the sponsor or the CRO is responsible for selecting each research center and ensuring that COFEPRIS has authorized its operation as well as the human and material resources needed to conduct research. MEX-32 indicates the sponsor should ensure the investigator(s) have adequate resources to properly conduct the trial for which they are selected. Additionally, MEX-32, explains the investigator should have available an adequate number of qualified staff and adequate facilities for the foreseen duration of the trial to conduct the trial properly and safely.

Per COFEPRIS-GCP, the sponsor must establish in writing each of the research team member functions and responsibilities, and the financial agreement with the principal investigator (PI). G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts also note the sponsor or the CRO must specify in a letter the human and material resources that will be allocated for the research and the way in which they will be provided and distributed to the research sites.

As stated in the HlthResRegs and NOM-012-SSA3-2012, all investigators must possess appropriate qualifications, training, and experience. Per COFEPRIS-GCP, the PI is also responsible for selecting a research team with knowledge, education, and training in MEX-32, and in the process of the investigation in which the investigator is involved. Per MEX-32, the sponsor must ensure each investigator is qualified by education, training, and experience to assume responsibility for the proper conduct of the trial; meets all the qualifications specified by the applicable regulatory requirement(s); and provides evidence of such qualifications through updated curriculum vitae (CV) and/or other relevant documentation requested by the sponsor, the ethics committee (EC), and/or COFEPRIS. G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts also indicate the PI should provide legally issued and registered documentation delineating appropriate academic training and experience appropriate to the research to be conducted, which includes academic preparation, representative scientific production, and clinical practice.

G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts also indicate that institutions in charge of providing medical care for study related medical emergencies are required to sign an agreement or contract to provide these services, and a provide letter stating the institution’s acceptance, authorization, and description of the available resources.

Foreign Sponsor Responsibilities

COFEPRIS-GCP indicates that foreign CROs must have a registered address in Mexico, and an authorization or notice specifying the activities to be carried out in the country.

Data Safety Monitoring Board

According to COFEPRIS-GCP, the sponsor or the CRO is responsible for the continuous monitoring of the study which should be established based on the nature of the study, and must ensure study monitoring is carried out in compliance with MEX-32. Per MEX-32, the sponsor or the CRO may consider establishing an independent data monitoring committee to assess the progress of a clinical trial, the safety data, the critical efficacy endpoints, and to recommend to the sponsor whether to continue, modify, or stop a trial. The committee should have written operating procedures and maintain written records of its meetings.

Multicenter Studies

As delineated in MEX-32, in the event of a multicenter clinical trial, the sponsor or the CRO must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and, if required, by COFEPRIS, 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 between investigators is facilitated

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 COFEPRIS-GCP, the sponsor or the contract research organization (CRO) must establish a financial fund or have insurance to cover serious adverse events that result from the medication or the research study.

Additionally, per COFEPRIS-GCP, which requires the sponsor or the CRO to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/institution against claims arising from the trial, except for those claims arising from malpractice and/or negligence. Per MEX-32, if required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator and the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

Compensation

As specified in COFEPRIS-GCP, the sponsor or the designated CRO must establish a statement of funding and describe the quantity and payments to be allocated for research participants.

Per MEX-32, the ethics committee (EC) should review both the amount and method of payment to participants to ensure that neither presents problems of coercion or undue influence on the trial participants. Payments to a participant should be prorated and not wholly contingent on the completion of the trial by the participant.

Injury or Death

Although NOM-012-SSA3-2012 does not specifically ascribe responsibility to the sponsor, it indicates that the research budget must include the availability of a financial fund as well as mechanisms to guarantee continuity of medical treatment and indemnity of the research participant, in the event of trial-related injuries. Additionally, the head of the institution or establishment, the, Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), Research Committee, or Biosafety Committee, the PI, and, where applicable, the sponsor, must be responsible, in accordance with their area of ​​competence, for the damage to health resulting from the development of the research as well as damage resulting from the interruption or early suspension of treatment for reasons not attributable to the research participant.

Per HlthResRegs and GenHlthLaw, the health care institution and the sponsor or the CRO must provide medical attention to injured participants, and where appropriate, legally required compensation, if the injuries are directly related to the study. Medical attention that is provided to such participants will not prejudice the compensation that may be legally due from the study.

In addition, per COFEPRIS-GCP, the sponsor or the CRO is also responsible for ensuring that research institutions provide urgent care resources, or where appropriate, have a written agreement with the health institution that will handle the emergencies. The agreement must comply with NOM-206-SSA1-2002, which establishes the criteria for the operation and attention in providing emergency services in health care institutions

MEX-32 explains the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s). In addition, when study participants receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s).

In addition, per G-DIGIPRiS-ResProts and G-HumResProt, the sponsor should provide the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) with a copy of the financial fund or current insurance policy, which guarantees the continuity of the medical treatment and the compensation to which the participant will be legally entitled in the event of suffering damages directly related to the development of the research. MEX-84 specifies that the insurance policy or current document from the financial fund should cover all study participants at the local level. The document guarantees coverage to the participant in case of any injury or damage related to the research. The insurance policy and certificate must indicate the number of participants that will be covered, study title, protocol number, and must be on behalf of the license holder and the sponsor.

Trial Participation

Per COFEPRIS-GCP, the sponsor or the CRO must ensure that each and every treatment, clinical analysis procedure, and other study procedures are delivered in a timely manner, in good condition, and free of charge to the research participant.

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

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32), and to ensure and control the quality of the research during a study. Per COFEPRIS-GCP and MEX-32, the sponsor or the CRO is also responsible for establishing written standard operating procedures (SOPs) for each stage of the investigation. In addition, the sponsor or the CRO must implement and maintain quality assurance (QA) and quality control (QC) systems to make certain the trial is conducted, and data are generated, recorded, and reported in compliance with the protocol.

MEX-32 further delineates the sponsor or the CRO is required to obtain 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. The sponsor and investigator(s) agreement should be confirmed in writing prior to the trial. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

Monitoring Requirements

According to COFEPRIS-GCP, the sponsor or the CRO must ensure and control the quality of the research through periodic monitoring visits and audits to ensure compliance with the protocol and the SOPs, and if necessary, compliance with reports derived from inspections or verifications by COFEPRIS. The principal investigator (PI) is responsible for reporting and guaranteeing the quality and validity of the data obtained during the investigation. MEX-32 indicates the sponsor should ensure that the trials are adequately monitored and determine the appropriate extent and nature of monitoring, which should be based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial.

Additionally, per MEX-32, the sponsor should also appoint the monitors who should be appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented. Monitors should also be thoroughly familiar with the investigational product(s), the protocol, written informed consent form, and any other written information to be provided to research participants, the sponsor’s SOPs, COFEPRIS-GCP, and the applicable regulatory requirement(s).

MEX-32 further indicates the sponsor should appoint individuals, who are independent of the clinical trials/systems, to conduct audits and ensure the auditors are qualified by training and experience to conduct audits properly. An auditor’s qualifications should be documented. The sponsor should also ensure the auditing of clinical trials/systems is conducted in accordance with the sponsor's written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports. The sponsor's audit plan and procedures for a trial audit should be guided by the importance of the trial to submissions to regulatory authorities, the number of study participants, the type and complexity of the trial, the level of risks to the study participants, and any identified problem(s). Auditor(s) observations and findings of the auditor should be documented.

Pursuant to MEX-32, noncompliance with the protocol, SOPs, good clinical practice, and/or applicable regulatory requirement(s) by an investigator/institution, or by member(s) of the sponsor's staff should lead to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identifies serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator's/institution’s participation in the trial and notify promptly the regulatory authority(ies). Also, upon the request of the monitor, auditor, ethics committee (EC), or COFEPRIS, the investigator/institution should also make available for direct access all requested trial-related records. See MEX-32 for detailed monitoring and auditing requirements.

Per NOM-012-SSA3-2012, the institutional head, the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), Research Committee, or Biosafety Committees, the PI, and, where applicable, the sponsor, must be responsible, in accordance with their area of competence, for monitoring the research. NOM-012-SSA3-2012, G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts further require the sponsor or the CRO to provide a follow-up letter to COFEPRIS describing the monitoring and auditing plan to be carried out during the investigation. G-HumResProt, MEX-84, and G-DIGIPRiS-ResProts specify the letter must contain the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Type of plan: audit or monitoring
• Frequency of application
• Responsibility for monitoring, and where appropriate, cite the third party to carry out the activity
• Objective and scope of monitoring
• Evaluation tools and methodology implemented
• Methodology to carry out the scientific, technical, and ethical monitoring
• Communication and notification strategies between investigator, sponsor, ECs, and COFEPRIS
• Profile of the monitor or auditor
• Classification of findings and decision-making
• Decision-making derived based on severity classification
• Notification mechanism to the PI, ECs, and COFEPRIS
• Design of the Action Plan: Corrective, Improvement, or Preventive
• Reporting results through the partial and annual technical report (See MEX-31 for the partial reporting form)

COFEPRIS-GCP also states that the PI is responsible for reporting and guaranteeing the quality and validity of the data obtained during the investigation.

Premature Study Termination/Suspension

Per HlthResRegs the PI, the REC, the institutional head or other authorized institutional officers, or the Ministry of Health (Secretaría de Salud) must order the immediate suspension or cancellation of a research study as soon as any adverse effect is identified that might become an ethical or technical impediment to continuing with the study. The health care institution will submit a report to the Secretariat within 15 business days following the day in which the suspension or cancellation of the study was agreed, specifying the effect noticed, the measures adopted, and consequences produced. NOM-012-SSA3-2012 similarly states the head of the institution or establishment, the REC, the Research Committee, the Biosafety Committee, or PI must order the immediate suspension or cancellation of research, in the presence of any severe adverse effects, which become an ethical or technical impediment to continue with the study and notify the Secretariat in detail. The institutional head must notify the Secretariat of any adverse effect resulting from the experimental research within a maximum period of 15 working days from the event occurrence, including the care measures adopted, the identified sequelae, as well as a detailed report on the physical condition of the patient, which mentions whether the patient is free of any risk at the time of notification. In such case, the resumption of the research will require a new authorization. The investigator is also responsible for suspending the investigation if there is a risk of serious injury, disability, or death of the research subject in accordance with GenHlthLaw. Additionally, per NOM-220-SSA1-2016, institutions must notify the National Pharmacovigilance Center (CNFV) of a study’s suspension or cancellation within a maximum of 15 days. If the study is resumed, the CNFV must also be notified within a maximum of 15 working days following the study’s recommencement. The investigator is responsible for submitting safety reports to the CNFV.

MEX-32 delineates 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). The EC should also be provided with a detailed written explanation of the termination or suspension.

MEX-32 further indicates that if the trial is prematurely terminated or suspended for any reason, the investigator/institution should promptly inform the trial participants, ensure appropriate therapy and follow-up for the participants, and, where required by the applicable regulatory requirement(s), inform the regulatory authority(ies). If the investigator terminates or suspends a trial without prior agreement of the sponsor, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the EC and provide the sponsor and the EC with a detailed written explanation of the termination or suspension. If the EC terminates or suspends its approval/favorable opinion of a trial, the investigator should inform the institution where applicable, and the investigator/institution should promptly notify the sponsor and provide the sponsor with a detailed written explanation of the termination or suspension.

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

According to COFEPRIS-GCP, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) requires the sponsor or the contract research organization (CRO) to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) for conducting clinical trials. Per MEX-32, the sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

In addition, per MEX-32, when using electronic trial data processing or handling systems or remote electronic trial data systems, the sponsor should:

• Ensure and document that the electronic data processing system(s) conform(s) to the sponsor's established requirements for completeness, accuracy, reliability, and consistent intended performance
• Maintain standard operating procedures (SOPs) for using these systems
• Ensure that the systems are designed to permit data changes in such a way that the data changes are documented and that there is no deletion of entered data
• Maintain a security system that prevents unauthorized access to the data
• Maintain a list of the individuals who are authorized to make data changes
• Maintain adequate backup of the data
• Safeguard the blinding, if any

See MEX-32 for additional data processing requirements.

Records Management

As indicated in MEX-32, the sponsor, or other owners of the data, should retain all of the sponsor-specific essential documents pertaining to the trial (see section 8 of MEX-32). The sponsor should retain all sponsor-specific essential documents in conformance with the applicable regulatory requirement(s) of the country(ies) where the investigational product (IP) is approved, and/or where the sponsor intends to apply for approval(s). If the sponsor discontinues the clinical development of an IP (i.e., for any or all indications, routes of administration, or dosage forms), the sponsor should maintain all sponsor-specific essential documents for at least two (2) years after formal discontinuation or in conformance with the applicable regulatory requirement(s).

MEX-32 also states the essential documents should be retained until at least two (2) years after the last marketing approval or at least two (2) years have elapsed since the formal discontinuation of clinical development of the IP. These documents should be retained for a longer period, however, if required by the applicable regulatory requirement(s) or if needed by the sponsor. The sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) when trial-related records are no longer needed.

In addition, as delineated in COFEPRIS-GCP, the principal investigator (PI) is responsible for preparing, integrating, using, filing, and ensuring the safekeeping of the research participant’s clinical file for a minimum of five (5) years in accordance with NOM-004-SSA3-2012, MEX-32, and Good Documentation Practices per NOM-164-SSA1-2015.

Per NOM-004-SSA3-2012, clinical records are the property of the institution or the medical services provider that generates them. However, the patient/participant has ultimate ownership rights over this information to protect their health and the confidentiality of their data. Consequently, because the documents are prepared in the interest and benefit of the patient/participant, they must be kept for a minimum period of five (5) years, which is calculated from the date of the last medical procedure/visit.

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

According to the PDP-PrivateLaw, the PDP-Reg, the PDP-Public, and MEX-4, a private entity that processes personal data is called the “responsible person or entity” or “controller.” Federal, state, or local authorities are referred to as “obliged subjects” and make decisions about the processing of personal data. The private and public entities must protect personal data in accordance with the above laws and regulations.

Data Protection

PDP-PrivateLaw, PDP-Reg, and PDP-Public provide the requirements, responsibilities, and restrictions for handling personal data in the public and private sectors. The PDP-Public regulates the processing of personal information in the public sector by “obliged subjects”. The PDP-PrivateLaw and the PDP-Reg regulate the processing of personal information in the private sector by an individual or legal entity of a private nature.

Per the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public, the sponsor or the sponsor’s representative(s) must comply with the principles of data protection: legality, purpose, loyalty, consent, quality, proportionality, information, and responsibility in the processing of personal data.

According to the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public, the sponsor is also required to protect the confidentiality of the owner of the personal data and their background. The PDP-PrivateLaw further notes that this obligation will remain in place even after the data processing activities have been completed and the relationship between the sponsor or the sponsor’s representative(s) and the data owner has concluded.

Additionally, the PDP-PrivateLaw and the PDP-Public provide definitions to address health related data. Sensitive personal data refers to the most intimate sphere of its owner, whose improper use may result in discrimination, or carries a serious risk of resulting in discriminatory activities. More specifically, data considered to be sensitive may reveal personal information such as racial or ethnic origin, present or future health status, genetic information, religious, philosophical, and moral beliefs, political opinions, and sexual preferences.

Per the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public, data owners have the right to be informed about the collection and use of their personal data. Per the PDP-Reg, the person responsible must also inform the information owner regarding the existence and main characteristics of the treatment to which their personal data will be subjected through the consent document, known as the “privacy notice,” in accordance with the provisions of the PDP-PrivateLaw and the PDP-Reg.

Please refer to the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public for detailed information on the principles guiding the protection and handling of personal data. See also MEX-3 and MEX-4 for additional information on data protection requirements.

Consent for Processing Personal Data

As explained in the PDP-PrivateLaw and the PDP-Public, the consent document or “privacy notice” is a physical document, electronic, or any format generated by the sponsor, that is made available to the data owner prior to processing the owner’s personal data. The PDP-Reg further explains that the privacy notice must be characterized as simple, with necessary information expressed in clear and understandable language, and with a structure and design that facilitates the owner’s understanding.

The PDP-PrivateLaw states that in the case of sensitive data, the sponsor is required to obtain the express and written consent of the data owner for the sponsor’s use, through a written or electronic signature, or any authentication mechanism established for that purpose. In cases where sensitive personal data is being processed, the sponsor must make reasonable efforts to limit processing to the minimum period necessary to complete the goal as delineated in the privacy notice. Moreover, databases containing sensitive personal data may not be created without justifying their creation for legitimate, concrete purposes, and if they are not in accordance with the specified activities delineated and pursued by the sponsor. The PDP-Reg also notes that sponsors may only create databases containing sensitive personal data when they obey a legal mandate; are justified pursuant to the territorial scope of the regulation; or are required by the sponsor for legitimate, concrete purposes, and in accordance with the activities or explicit purposes indicated in the privacy notice.

The PDP-Reg, whose focus is on regulating the process of personal data held in physical or electronic media, further indicates that the sponsor must obtain prior consent to process the data when acquired personally or directly from its owner. Whether tacit or express, the consent process must be:

• Free: without error, bad faith, violence, or intent, which may affect the manifestation of the owner’s will
• Specific: referring to one (1) or more specific purposes that justify the treatment, and
• Informed: the owner has knowledge of the privacy notice prior to granting consent to the processing of their data

The sponsor must obtain the owner’s express consent when their data is deemed sensitive. The express consent must also be unequivocal; that is, there are elements that indisputably demonstrate its granting.

As delineated in the PDP-Public, the sponsor will not be required to obtain consent when processing sensitive data in the following cases:

• When an applicable law authorizes such processing, and is consistent with and does not contravene the bases, principles, and provisions set forth in the PDP-Public
• When sensitive personal data transfers are made between those responsible, the transfers are compatible with the original purpose that motivated the processing of personal data
• When there is a judicial order, resolution, or well-founded and motivated mandate of the competent authority
• For the recognition or defense of the owner's rights before the competent authority
• When personal data is required to exercise a right or fulfill obligations derived from a legal relationship between the owner and the person in charge
• When there is an emergency that could potentially harm an individual or the individual’s property
• When personal data is necessary to carry out a treatment for the prevention, diagnosis, or provision of health care
• When the personal data appear in publicly accessible sources
• When personal data is subject to a prior dissociation procedure
• When the owner of the personal data is a person reported missing under the terms of the law on the matter

Please refer to the PDP-PrivateLaw, the PDP-Reg, and the PDP-Public for detailed consent and privacy notice requirements.

Consent for Processing Personal Data of Minors

Per the PDP-Public, in processing the personal data of minors, the best interest of the children and adolescents must be prioritized in accordance with the applicable legal provisions. MEX-4 further states legal guardians must always give consent when processing children’s personal data. This applies to any individual younger than 18 years of age.

(See the Children/Minors section for additional information on consent requirements for children/minors.)

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 Mexican clinical trials, a freely given informed consent is required from each participant in accordance with the requirements set forth in HlthResRegs, GenHlthLaw, NOM-004-SSA3-2012, and COFEPRIS-GCP. Per COFEPRIS-GCP, the principal investigator (PI) is required to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32) in obtaining and documenting informed consent, and per G-RECs-Op-2018, the PI must also comply with consent requirements as delineated in the Declaration of Helsinki (MEX-76). (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (MEX-22)).

As per HlthResRegs and G-RECs-Op-2018, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by a Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and provided to COEFPRIS with the request for research protocol authorization. (See the Required Elements section for details on what should be included in the form.)

HlthResRegs, COFEPRIS-GCP, and NOM-012-SSA3-2012 state that the PI must provide detailed research study information to the participant or legal representative/guardian. As delineated in HlthResRegs, G-RECs-Op-2018, NOM-012-SSA3-2012, MEX-32, and MEX-84, the ICF content should be presented with a clear explanation and provided in a format that facilitates understanding. Per NOM-012-SSA3-2012 and MEX-32, the participant or legal representative/guardian should also be given adequate time to consider whether to participate. GenHlthLaw and MEX-84 further note the ICF should be expressed in writing in an accessible, timely manner and in understandable language, using accurate and complete information, including the possible benefits and expected risks, and the treatment alternatives, to ensure that services are provided on the basis of free and informed consent. Once comprehension of the information is guaranteed through the necessary means and supports, individuals have the right to accept or reject consent. G-DIGIPRiS-ResProts, MEX-84, and G-HumResProt indicate the ICF and/or assent form, as applicable, is a document through which the research participant agrees to voluntarily participate in a research study and to undergo experimental procedures when the information is presented in a sufficient, timely, clear and truthful manner regarding the expected risk and benefits.

As per HlthResRegs, G-RECs-Op-2018, and MEX-32, 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 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.

Re-Consent

According to G-RECs-Op-2018 and MEX-32, any change in the ICF that is relevant to the participant’s consent should be approved by the REC prior to implementing any changes. Per G-RECs-Op-2018 and MEX-32, the participant or legal representative/guardian should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participating in the trial. MEX-32 further states the communication of this information should be documented.

Language Requirements

G-HumResProt states that the applicant must submit the request for protocol authorization application and all associated documentation (including the protocol and the ICF) in Spanish.

Documenting Consent

As delineated in HlthResRegs, G-RECs-Op-2018, and MEX-32, the participant or legal representative/guardian, as well as two (2) witnesses, must sign the ICF. MEX-32 specifies that the ICF should be dated, and any updates must also be signed, and a copy of the amendments provided to the participant or legal representative/guardian. If the participant does not know how to sign, the participant will provide a fingerprint and will also need to designate someone to sign the participant’s name on their behalf. A copy of the signed ICF will be provided to the participant or legal representative/guardian. Per G-DIGIPRiS-ResProts, which complies with MEX-22, the ICF version and date must coincide with what is recorded as approved in the opinions of the ethics committees (ECs). G-HumResProt further specifies the ICF should be signed by the PI, the participant and the participant’s family, or a legal representative and two (2) witnesses. The names of the witnesses, the addresses, and the relationships the witnesses have with the research participant must be indicated. MEX-84 also notes a section in the ICF should be provided for the participant or the legal representative to sign the document to indicate express acceptance. The section must include general data (full name, address, relationship with the participant) and signatures of two (2) witnesses.

Waiver of Consent

No information is currently available regarding waiver requirements.

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

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

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

As delineated in G-RECs-Op-2018 and MEX-84, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Identification data (Title, protocol number, version, version date, research institution data, principal investigator (PI) name, medical emergency establishment data, and Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)), and this data must coincide with the opinions of the ethics committees)
• The study rationale and objectives
• Purpose and procedures, including all invasive procedures
• Identification of experimental aspects of the study
• Trial duration
• Participant’s responsibilities
• Investigator responsibilities
• Approximate number of participants
• Circumstances that may terminate the study
• Duration of study
• Any expected risks or discomforts to the participant
• Any expected benefits to the participant; if no benefit is expected, the participant should be informed of this point (physical examination, laboratory tests and imaging should not be considered as benefits to the participant)
• Alternative treatments that may be beneficial to the participant
• Trial treatment(s) and the probability for random assignment to each treatment
• Explains the blinding of the study (if applicable) and what it consists of
• Allocation method
• Compensation and/or treatment available for the participant by the health care institution in the case of trial-related injury
• All drugs, products, and procedures are free
• 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
• Assurance that the participant will not be identified and that their confidential information relating to their privacy will be maintained
• Confidentiality of records identifying the participant will be maintained (including sensitive personal data and data derived from the study), and permission given to monitors, auditors, the REC, and the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) 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
• Contact information for the sponsor and PI in the event of participant problems or trial-related injuries
• Communication channels and data to request clarification and to guarantee a response to questions and clarification of concerns about procedures, risks, benefits, and other matters related to the investigation and treatment of the participant
• Foreseeable circumstances under which the PI(s) may remove the participant without their consent
• Commitment to provide updated information throughout the study although this may affect the participant’s willingness to continue
• Notification that any additional research study expenses will be absorbed by the research budget

The Guideline for Good Clinical Practice E6 (R1) (MEX-32) also mentions the following required elements:

• Any expected risks or discomforts, when applicable, to the embryo, fetus, or nursing infant
• Any anticipated prorated payment to the participant for participating in the trial
• Any expenses the participant needs to pay to participate in the trial

Additionally, per NOM-012-SSA3-2012, the investigator must ensure that the ICF explicitly states the compensation to which the research participant is entitled in the event of suffering damage to their health directly attributable to the research, and the availability of free medical treatment, even in the event the participant decides to withdraw from the study before it is concluded.

See HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, and MEX-32 for additional details related to ICF requirements. (Note: Per MEX-2, COFEPRIS is in the process of implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

Also, see the Vulnerable Populations and Consent for Specimen sections for further information.

Overview

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

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

The Right to Privacy and Confidentiality

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

Overview

In accordance with HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, and the Guideline for Good Clinical Practice E6 (R1) (MEX-32), Mexico’s ethical standards promote respect for all human beings and safeguard the rights of research participants. (COFEPRIS-GCP requires the principal investigator (PI) to comply with MEX-32). HlthResRegs and MEX-32 state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation's Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

The Right to Participate, Abstain, or Withdraw

As stated in HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, MEX-32, and MEX-84, the participant or legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As per HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, MEX-32, and MEX-84, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to G-RECs-Op-2018, MEX-32, and MEX-84, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. In addition, per NOM-004-SSA3-2012, although clinical records are the property of the institution or the medical services provider that generates them, the participant has ultimate ownership rights over this information to protect their health and the confidentiality of their data.

The Right of Inquiry/Appeal

MEX-32 states that the research participant or legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or their rights. G-RECs-Op-2018 further specifies that the names and contact information of the PI and the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI))’s president, including a 24-hour telephone number in case of emergency, should be provided.

The Right to Safety and Welfare

HlthResRegs, NOM-012-SSA3-2012, G-RECs-Op-2018, COFEPRIS-GCP, and MEX-32 that upholds the Declaration of Helsinki (MEX-76), clearly state that a research participant’s right to safety and the protection of their health and welfare must take precedence over the interests of science and society.

See the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

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

The HlthResRegs and the Guideline for Good Clinical Practice E6 (R1) (MEX-32) make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies (COFEPRIS-GCP requires the principal investigator (PI) to comply with MEX-32). (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation’s Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

According to HlthResRegs, in an emergency, when it is deemed necessary to use an investigational drug, or a known drug with indications, doses, or routes of administration other than the established uses, the treating physician must obtain the favorable opinion of the Research Ethics Committee (REC) (Comité de Ética en Investigación (CEI)) and the Research Committee, and an informed consent form (ICF) signed by the research participant or legal representative/guardian. The terms under which this documentation is obtained must meet the following requirements:

• The REC and Research Committee will be informed of the use of the investigational drug in advance if the researcher can anticipate the need for use in emergency situations. If this is not possible, an opinion must be obtained after the situation occurs. In both cases, the committees will issue an opinion in favor or against approving the planned or recurring unintended use of the drug.
• A signed ICF must be obtained from the participant or legal representative/guardian unless the participant’s condition prevents them from signing the form, the legal representative/guardian are not available to sign the form, or stopping use of the drug constitutes an almost absolute risk of death to the participant.

Per MEX-32, in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant or legal representative/guardian cannot be obtained, the ethics committee must provide documented approval in order to protect the participant’s rights, safety, and well-being, pursuant to the applicable regulations. The participant or legal representative/guardian should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

In addition, per GenHlthLaw, in cases of medical emergency, and when the terminally ill patient is unable to express their consent, and in the absence of family members, a legal representative, guardian or trusted person, the specialist doctor and/or the institution’s Bioethics Committee will make the decision to apply a necessary surgical medical procedure or treatment.

Overview

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

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

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

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

Indigenous Peoples

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

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

Overview

As delineated in G-RECs-Op-2018, in all Mexican clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. G-RECs-Op-2018 characterizes vulnerable populations as individuals or groups experiencing diminished autonomy due to imposing social, political, and/or economic situations that prevent them from having control over their quality of life. Populations traditionally viewed as vulnerable include minors, women, persons with disabilities, the elderly, those suffering from mental illness, immigrants, those who are illiterate, those belonging to ethnic or racial minorities, the unemployed, the homeless, and reclusive individuals.

As per COFEPRIS-GCP, the principal investigator (PI) is required to comply with the Guideline for Good Clinical Practice E6 (R1) (MEX-32), which similarly characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from not participating. Examples are members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; employees of the pharmaceutical industry; members of the armed forces; and persons kept in detention. Other vulnerable subjects include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent. (Note: Per MEX-2, the Federal Commission for the Protection Against Sanitary Risks (Comisión Federal para la Protección contra Riesgos Sanitarios (COFEPRIS)) is in the process of implementing the International Council for Harmonisation’s Guideline for Good Clinical Practice E6 (R2) (MEX-22)).

G-RECs-Op-2018 specifies that Research Ethics Committees (RECs) (Comités de Ética en Investigación (CEIs)) should ensure that additional security mechanisms are implemented to minimize the specific risks for each group. MEX-32 similarly states that ethics committees must pay special attention to protecting participants who are from vulnerable populations.

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

Persons in Dependent Groups

As indicated in HlthResRegs, for clinical trials involving participants who are involved in subordinate or dependent relationships, the REC must ensure the following:

• Participation or refusal of individuals to participate or withdrawal of consent during the study, will not affect their school, work, military status, or that which is related to the judicial process and any conditions of compliance with a sentence, if applicable
• Research results are not used to the detriment of the individuals involved
• The health institution and sponsors take responsibility for dangers associated with medical treatment, and where appropriate, provide legally required compensation for the harmful consequences of the investigation

Per G-RECs-Op-2018, the following criteria must also be met to conduct a study with a subordinate population:

• The PI must clearly define the reasons for planning to recruit a subordinate population
• Protocol approval must also be obtained in which a written statement from the immediate boss or corresponding authority of the subordinate participant(s) verifying that no coercion has existed
• If resident doctors or partners are recruited for the study, the program director must provide the REC with a letter of support issued by a person without ties to the study
• Confidentiality of research data for the group of subordinate and student participants is important to consider to avoid negatively impacting the participants’ employment possibilities, professional development, study plans, or social relationships. The REC will also need to pay special attention to the PI’s plans to safeguard data security

The HlthResRegs and G-RECs-Op-2018 further specify that these relationships include participants who are in junior or subordinate positions in hierarchically structured groups, such as students, employees, workers in laboratories and hospitals, members of the armed forces, prisoners, social rehabilitation centers, and other members of special population groups in which informed consent can be influenced by some authority.