Brazil
Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Authorizing Body
Clinical Trial Lifecycle
Submission Process
Submission Content
Timeline of Review
Trial Initiation
Safety Reporting
Progress Reporting
Sponsorship
Definition of Sponsor
Trial Authorization
Insurance
Compensation
Quality, Data & Records Management
Site/Investigator Selection
Informed Consent
Documentation Requirements
Required Elements
Compensation Disclosure
Participant Rights
Special Circumstances/Emergencies
Vulnerable Populations
Children/Minors
Pregnant Women, Fetuses & Neonates
Prisoners
Mentally Impaired
Investigational Products
Definition of Investigational Product
Manufacturing & Import
IMP/IND Quality Requirements
Labeling & Packaging
Product Management
Specimens
Definition of Specimen
Specimen Import & Export
QUICK FACTS
Clinical trial application language Portuguese
Regulatory authority & ethics committee review may be conducted at the same time Yes
Clinical trial registration required Yes
In-country sponsor presence/representation required No
Age of minors Unspecified
Specimens export allowed Yes
Regulatory Authority > Regulatory Authority
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1 and 2
(2) (Regulation) ) Resolution of the Board of Directors – RDC No. 61 of February 3, 2016 (ResolutionNo61 – Portuguese (February 5, 2016)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-3, 4-6, 60-61, 63, 88, 91, 97, 103, 208, and Annex III
(3) (Regulation) Resolution of the Board of Directors – RDC No. 176 of September 15, 2017 (ResolutionNo176 - Portuguese) (Effective September 19, 2017)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-2, 4, and Annex III amending ResolutionNo61
(4) (Legislation) Law N. 9.782, of January 26, 1999 (LawNo9.782 - Portuguese) (Effective Date: January 27, 1999)
Presidency of the Federative Republic of Brazil, House Civil Cabinet Subcommittee for Legal Affairs
Relevant Sections: Articles 3-4, 8-10, and 15
Summary

Overview

As per ResolutionNo9, ResolutionNo61, and ResolutionNo176, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspections for drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accord ance with the provisions of ResolutionNo9, ResolutionNo61, and ResolutionNo176.

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 ResolutionNo61 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 ResolutionNo61, ANVISA is headed by a Collegiate Board of Directors composed of up to five (5) members, one 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 sanitary surveillance objectives.

LawNo9.782 and ResolutionNo61 further indicate that ANVISA has an Advisory Board and an Ombudsman. Per ResolutionNo61 and Additional Resource (A), 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. According to Additional Resource (B), the Ombudsman’s Office acts independently from the Collegiate Board and the Advisory Board. The Ombudsman’s activities, as described in ResolutionNo61 and Additional Resource (B), include receiving and registering criticisms, complaints, claims, and suggestions from users and participating in the monitoring and evaluation of ANVISA’s customer service policy. Refer to LawNo9.782, ResolutionNo61, and Additional Resources (A) and (B) for detailed Collegiate Board, Advisory Board, and Ombudsman responsibilities.

As delineated in ResolutionNo61, ANVISA oversees five (5) directorates including the Sanitary Authorization and Registration Board, the directorate responsible for granting approval to conduct clinical trials for drugs to be registered in Brazil. Per ResolutionNo61 and ResolutionNo176, the Sanitary Authorization and Registration Board oversees the administration of the General Management of Medicines and Biological Products (Gerência-Geral de Medicamentos e Produtos Biológicos (GGMED)). The 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 inputs, medicines, and clinical research involving human beings. The Coordination of Clinical Research on Drugs and Biologicals (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 ResolutionNo61 and ResolutionNo176 for detailed information on ANVISA’s organizational structure and administrative units.

Contact Information

ANVISA
Setor de Indústria e Abastecimento (SIA)
 
Bloco 5, Area Especial 57, Lote 200, Bloco A, Uniap
Brasília (DF)
CEP: 71205-050

Phone: (61) 3462 6700
protocol@anvisa.gov.br

Additional Resources
(A) (Website) ANVISA – Advisory Board (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(B) (Website) ANVISA – Meet the Ombudsman (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(C) (Website) ANVISA – Who's Who (Portuguese) (Last Updated June 19, 2019)
ANVISA, Ministry of Health
(D) (Website) ANVISA – Agency Alerts Businesses About Mail (Portuguese) (Last Modified June 25, 2015)
ANVISA, Ministry of Health
Regulatory Authority > Scope of Assessment
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-3, 6, 33, 35-36, 38, and 78
(2) (Regulation) ) Resolution of the Board of Directors – RDC No. 61 of February 3, 2016 (ResolutionNo61 – Portuguese (February 5, 2016)
ANVISA, Ministry of Health
Relevant Sections: Articles 91, 103, and Annex III
(3) (Regulation) Resolution of the Board of Directors – RDC No. 176 of September 15, 2017 (ResolutionNo176 - Portuguese) (Effective September 19, 2017)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-2, and Annex III amending ResolutionNo61
(4) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5.1, 7, and 9
(5) (Regulation) Resolution RDC No. 260, of December 21, 2018 (ResolutionNo260 - Portuguese) (Effective February 26, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1, 2, 4, 7, and Chapters III-IV
(6) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: Sections VI-XI
(7) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.3, 3.1, 5.5, 6.10-6.11, and Chapter 9
(8) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 1, 2.1, 3.1, and 3.4
(9) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 5-11
(10) (Regulation) CNS Resolution No. 292 of July 8, 1999 (ResolutionNo292 – Portuguese) (July 8, 1999)
National Health Council, Ministry of Health
Relevant Sections: Preamble and I
(11) (Regulation) CNS Resolution No. 446 of August 11, 2011 (ResolutionNo446 - Portuguese) (Effective Date: August 29, 2011)
National Health Council, Ministry of Health
Relevant Sections: Article 16
(12) (Regulation) Resolution of the Board of Directors – RDC No. 204 of December 27, 2017 (ResolutionNo204 – English, unofficial translation) (Portuguese) (Effective Date: February 25, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1, 3-6, and 10-13
Summary

As delineated in ResolutionNo9, ResolutionNo61, and ResolutionNo176, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications for drugs to be registered in Brazil. In addition, per ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the clinical trial application (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) must contain at least one (1) Specific Clinical Trial Dossier in order for the DDCM to be approved. ResolutionNo9 and the G-DDCM Manual define a Specific Clinical Trial Dossier as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCM Manual, the Specific Clinical Trial Dossier may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM.

Per ResolutionNo9 and Additional Resource (A), 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 also ResolutionNo260 for detailed information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced research therapy products in Brazil. Advanced research therapy products include medicines for human use that are based on genes, tissues, or cells.

As set forth in ResolutionNo9, ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013, institutional ethics committees (ECs) (referred to as Comitês de Ética em Pesquisas (CEPs)) must evaluate and approve clinical protocols for all research involving human beings before a clinical trial is permitted to commence. However, as a result of the publication of ResolutionNo205, the ResolutionNo9 requirement to include the EC (CEP) approval in the initial DDCM or in any protocol amendment submission has been revoked. Consequently, as explained in Additional Resource (B), the EC (CEP) and ANVISA review processes may now be conducted in parallel. ResolutionNo205 specifies that the new EC (CEP) requirement is pertinent to rare disease drug clinical trials; however, per ResolutionNo9 and Additional Resource (B), this requirement is now applicable to all drug trials.

ResolutionNo9 and the G-DDCM Manual further state that only the clinical trials listed in the approved DDCM may be initiated in Brazil once all of the ethical approvals have been obtained. As indicated in ResolutionNo9, and also noted in Additional Resource (B), the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP))’s approval is required for certain studies (as explained below, 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 Additional Resource (C). In these cases, only the EC (CEP) is required to approve the amended protocol prior to implementation and ANVISA should be notified. Together, the CEPs and CONEP represent the ethical review system in Brazil, known as the CEP/CONEP System as discussed in ResolutionNo466, OSNo001/2013, and G-ClinProtocol-FAQs. Refer to the Ethics Committee topic for additional information on the CEP/CONEP System.

In addition, applications with coordination and/or sponsorship originating outside of Brazil also require additional EC (CEP) review by CONEP, as delineated in ResolutionNo292, ResolutionNo446, and ResolutionNo466. Per ResolutionNo446, an exception to the required CONEP review is when studies have been fully carried out abroad and have been approved by an EC or equivalent body in the country of origin. ResolutionNo292 further explains that the scope of research from abroad or with foreign participation includes: collaboration of 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 ResolutionNo292, special attention should be given to ensuring the EC or equivalent institution within the originating country has issued an approval. If not, the Brazilian EC (CEP) followed by CONEP must approve the protocol. Additionally, per OSNo001/2013, the principal investigator (PI) is required to submit a list of the participating institutions and associated protocols in a multicenter study as part of the research protocol package sent to the CEP for review. Along with the protocol and previously described list, OSNo001/2013 states the PI should also submit an explanation detailing the co-sponsored research project through an official agreement issued by the federal manager of the Ministry of Health (MOH)’s Science, Technology and Strategic Health Inputs. Refer to the Ethics Committee topic, Scope of Review subtopic for additional multicenter study requirements.

Clinical Trial Review Process

As delineated in ResolutionNo61 and ResolutionNo176, ANVISA’s Office of 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). ResolutionNo9 and the G-DDCM Manual explain that following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all of the trials included in the DDCM that are permitted to initiate the clinical study. Additional Resource (A) further explains COPEC experts conduct a preliminary review that includes a benefit-risk assessment based on various criteria including 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 90- or 180-day expiration deadline date so that the applicant may proceed with conducting the trial, or request a meeting, or conduct a more detailed and complete dossier evaluation. See Clinical Trial Lifecycle topic, Submission Content and Submission Process subtopics for detailed DDCM submission requirements.

As specified in ResolutionNo9, upon receipt of the 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. ResolutionNo9 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.

In addition to the previously stated DDCM requirements, ResolutionNo204 establishes a priority category to register, amend previously registered, or request prior approval for drug submissions. ResolutionNo204 states that the priority submission may be submitted as a DDCM or as a Specific Clinical Trial Dossier (Dossiês Específico de Ensaio Clínico (DEEC)). A 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 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 (SUS). A 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 issue a first written opinion letter within 45 calendar days from the first working 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. Refer to ResolutionNo204 for detailed information on priority submissions. See also Additional Resources (B), (C), and (E) for additional information on priority submission.

ResolutionNo205 also 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 linked either 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.

Per ResolutionNo205, a sponsor (applicant) must request a pre-submission meeting with ANVISA to present the application (DDCM, secondary petition, or DEEC), and ANVISA should hold the meeting within 60 days following this request. Following the pre-submission meeting, the application should be submitted, and ANVISA, in turn, will evaluate the application within 30 days of receipt with either a notification of additional information requirements or a final decision. The sponsor (applicant) should respond to ANVISA’s notification request for further information within 30 days, and ANVISA should assess the submitted requirements within 30 days of receipt. Secondary petitions and DEECs for rare disease drugs should be handled in the same manner. Refer to ResolutionNo205 for additional submission documentation requirements. Additional Resource (B) also provides a helpful summary of ResolutionNo204 and ResolutionNo205.

As earlier noted, EC (CEP) approval is no longer required in order to submit the initial clinical trial application (DDCM) or in the submission of protocol amendments for any experimental drugs, including those targeting rare diseases, per ResolutionNo205.

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1, 3.5, and 3.10
Fagundes P, Dresel P and Miler E.; Regulatory Focus
Relevant Sections: Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Conducting a Clinical Trial in Brasil
(D) (Document) Enhanced Electronic Petition System (Portuguese) (Last Modified May 16, 2018)
ANVISA, Ministry of Health
(E) (Website) ANVISA - Protocol Filing FAQs (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(F) (Website) New Drug Registration (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(G) (Website) Unified Health System (SUS): Structure, Principles and How it Works (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(H) (Document) Guidance on Scheduling Meetings with COPEC (Version 1.1) (April 18, 2018)
ANVISA, Ministry of Health
Regulatory Authority > Regulatory Fees
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Article 38
(2) (Regulation) Resolution of the Board of Directors – RDC No. 222 of December 28, 2006 (ResolutionNo222 - Portuguese) (Last Amended July 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 2, 9, and 14-16
(3) (Regulation) Resolution of the Board of Directors – RDC No. 76 of October 23, 2008 (ResolutionNo76 - Portuguese) (Effective October 27, 2008)
ANVISA, Ministry of Health
Relevant Sections: Articles 2, 9, 14, and 16
(4) (Regulation) Interministerial Ordinance No. 45, of January 21, 2017 (OrdNo45 - Portuguese) (Effective Date: February 9, 2017)
Ministry of Finance
(5) (Regulation) Resolution of the Board of Directors – RDC No. 198 of December 26, 2017 (ResolutionNo198 – Portuguese) (Effective December 28, 2017)
ANVISA, Ministry of Health
Relevant Sections: Articles 6 and 7
Summary

Overview

As set forth in ResolutionNo9, ResolutionNo222, and ResolutionNo76, the sponsor is responsible for paying a Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) to submit a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clinico de Medicamento (DDCM))) to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). ResolutionNo222 and ResolutionNo76 explain that a document known as a Union Collection Guide (Guia de Recolhimento da União (GRU)) is generated by ANVISA’s Petitioning System (Sistema de Peticionamento) (see Additional Resource (A) for system access) once the sponsor has completed the process of submitting a DDCM request (“petition” in Portuguese). Per Additional Resources (B) and (C), the GRU is a document the Ministry of Finance created for payments made to federal public agencies. ANVISA uses the GRU as its primary method to generate TFVS fees. Refer to Additional Resource (D) for detailed information on the GRU.

ResolutionNo222 and ResolutionNo76 further state that ANVISA will only review the DDCM once the Regulatory Agent has paid the TFVS fee and the original electronic bank payment receipt is forwarded together with the original printed copy of the GRU, the petition (request), and all of the documentation required for protocol review. If a petition is filed without due payment of the TFVS fee, the request and the documentation will be returned to the sponsor. Additional Resource (C) specifies that in addition to the original GRU receipt and bank payment receipt, the sponsor should include the transaction number issued by ANVISA’s Electronic Petition and Collection System.

Instructions for Payment of GRU Fees

According to Additional Resource (B), ANVISA determines the TFVS fee based on the company’s size (referred to as the Generating Fact) and the Subject Code assigned to the application request (also referred to as a petition in Portuguese). Per the TFVS fee table provided in Additional Resource (E) that was implemented by OrdNo45 and ResolutionNo198, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain approval for the clinical research process.

As described in ResolutionNo222, the GRU contains a bar code that may be scanned for payment purposes at the Bank of Brazil or any participating financial institution participating in the bank clearing system. Additional Resource (C) adds that bank payments may be completed in person, or by using the bank’s website or self-service (ATM) terminals. In addition, per Additional Resource (C), payment must be made within 30 days after the GRU has been issued. Additional Resource (F) further notes that a fee payment is required by ANVISA for substantial amendments to the clinical protocol.

Additional Resources
(A) (Website) ANVISA - Petitioning (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(B) (Website) Petitioning - General Definitions (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
Relevant Sections: 2 and 6
(C) (Website) Rates - Collection of Fees (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
Relevant Sections: 1-4, and 10
(D) (Website) Union Collection Guide (Guia de Recolhimento da União - (GRU)) (Portuguese) (Current as of June 20, 2019)
National Treasury Secretariat, Ministry of Finance
ANVISA, Ministry of Health
Relevant Sections: Annex I (4.7)
(F) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.2
(G) (Document) Updated Sanitary Surveillance Inspection Fees (Portuguese) (Last Modified April 6, 2017)
ANVISA, Ministry of Health
ANVISA, Ministry of Health
Ethics Committee > Ethics Committee
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: Sections VI-X
(2) (Regulation) CNS Resolution No. 446 of August 11, 2011 (ResolutionNo446 - Portuguese) (Effective Date: August 29, 2011)
National Health Council, Ministry of Health
Relevant Sections: Preamble, Articles 1 and 16
(3) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 1 and 2
(4) (Legislation) Law No. 8.142, of December 28, 1990 (LawNo8.142 - Portuguese) (Effective Date: December 31, 1990)
Presidency of the Republic, Civil House Sub­Office for Legal Affairs, Federative Republic of Brazil
Relevant Sections: Article 1
(5) (Regulation) CNS Resolution No. 453, of May 10, 2012 (ResolutionNo453 - Portuguese) (May 10, 2012)
National Health Council, Ministry of Health
Relevant Sections: Of The Health Council Definition
(6) (Guidance) Guidance Manual: Frequent Pending Issues in Clinical Research Protocols (Version 1.0) (G-ClinProtocols-FAQs) (Portuguese) (2015)
Brazilian National Board of Health (CNS) and Brazilian National Research Ethics Committee (CONEP)
Relevant Sections: Introduction, 6, and Summary Chart: Frequent Pending Issues (6)
(7) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 3.2-3.5
(8) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: Sections 2, 3, and 18
(9) (Regulation) CNS Resolution No. 240 of June 5, 1997 (ResolutionNo240 – Portuguese) (June 5, 1997)
National Health Council, Ministry of Health
(10) (Regulation) CNS Resolution No. 370 of March 8, 2007 (ResolutionNo370 - Portuguese) (March 8, 2007)
National Health Council, Ministry of Health
Relevant Sections: Chapter I.4
Summary

Overview

As per ResolutionNo466, ResolutionNo446, and OSNo001/2013, Brazil has a centralized registration process for ethics committees (ECs) and requires institutional level EC approval for each trial site. The National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs, known as Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) in Brazil, and for registering and accrediting the ECs (CEPs). ResolutionNo466, ResolutionNo446, and OSNo001/2013 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 Unified Health System (SUS). Per LawNo8.142 and ResolutionNo453, the SUS is Brazil’s public health system and is part of the Ministry of Health (MOH)’s organizational structure.

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 ResolutionNo466, ResolutionNo446, and OSNo001/2013. ResolutionNo466 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 a researcher 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 ResolutionNo466, OSNo001/2013, and G-ClinProtocol-FAQs. See also Additional Resources (A), (B), and (C) for useful information on CONEP and the CNS.

ResolutionNo466 and OSNo001/2013 also indicate that the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur through the Plataforma Brasil. According to Additional Resource (D), Plataforma Brasil was created to provide a national and unified registry for research involving human participants. The platform represents the review and approval processes of both the EC (CEP) and CONEP. Research applications can be tracked from submission to final approval by the EC (CEP), and when necessary, by CONEP. Applications with coordination or sponsorship originating outside of Brazil require additional EC review by CONEP, unless the co-sponsor is the Brazilian Government.

CONEP Composition

Please refer to Ethics Committee topic, Authorizing Body subtopic.

EC (CEP) Composition

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 OSNo001/2013 and OMREC require the EC (CEP) to be composed of a minimum of seven (7) members having proven expertise in research. The OSNo001/2013 also requires at least 50% of the members to have this research experience. The PANDRH-GCPs, the OSNo001/2013, and OMREC 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 OSNo001/2013 and OMREC further state that not more than half of its members should belong to the same professional category. 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). ResolutionNo240 further establishes standards and mandatory requirements for all ECs (CEPs) in Brazil to include user representatives who either are research study participants or represent the collective interests of the local communities. Users participating in institutional research studies should belong to the target population group or to the patient organization that represents their rights.

Additional criteria for EC (CEP) membership is available in Section 3.2 of the PANDRH-GCPs, Section 2.2 of the OSNo001/2013, and Section 2 of OMREC.

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 followed 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.

Per the PANDRH-GCPs and OMREC, 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 ResolutionNo370, the registration and appointment terms of EC (CEP) members are valid for three (3) years, and may be renewed at the end of that period.

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.

Additional Resources
(A) (Website) National Commission for Research Ethics (CONEP) (Portuguese) (Current as of June 20, 2019)
National Health Council, Ministry of Health
(B) (Document) Bylaws of CONEP/CNS (Portuguese) (June 6, 2001)
National Health Council, Ministry of Health
Relevant Sections: Chapter I
(C) (Website) National Health Council - About Us (Portuguese) (Current as of June 20, 2019)
National Health Council, Ministry of Health
Lopes, Aníbal Gil, European Group on Ethics in Science and New Technologies, Bureau of European Policy Advisers, European Commission
Relevant Sections: CEP/CONEP System Role and Responsibilities
(E) (Website) Plataforma Brazil (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(F) (Website) Unified Health System (SUS): Structure, Principles and How it Works (Portuguese) (Current as of June 20, 2019)
Ministry of Health
Ethics Committee > Scope of Review
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: III and VII-X
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.3, 3.1, 3.3-3.4, 4.3, 5.5-5.6, 6.10-6.11, 6.23, and Chapter 9
(3) (Regulation) CNS Resolution No. 251 of August 7, 1997 (ResolutionNo251 – Portuguese) (August 7, 1997)
National Health Council, Ministry of Health
Relevant Sections: I and III-V
(4) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 2 and 3
(5) (Regulation) CNS Resolution No. 304 of August 9, 2000 (ResolutionNo304) (Portuguese) (August 9, 2000)
National Health Council, Minister of Health
Relevant Sections: III-VI
(6) (6)(Regulation) CNS Resolution No. 580 of March 22, 2018 (ResolutionNo580 – Portuguese) (March 22, 2018)
National Health Council, Ministry of Health
Relevant Sections: Articles 1 and 11-12
(7) (Regulation) Ordinance No. 552 of March 9, 2007 (OrdNo552 - Portuguese) (March 9, 2007)
Minister’s Office, Ministry of Health
Relevant Sections: Articles 1-2
(8) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 35-36, 38, and 46-47
(9) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Article 9
(10) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5
(11) (Regulation) CNS Resolution No. 446 of August 11, 2011 (ResolutionNo446 - Portuguese) (Effective Date: August 29, 2011)
National Health Council, Ministry of Health
Relevant Sections: Preamble, and Articles 1 and 16
(12) (Regulation) CNS Resolution No. 292 of July 8, 1999 (ResolutionNo292 – Portuguese) (July 8, 1999)
National Health Council, Ministry of Health
Relevant Sections: Preamble, I, and VII-VIII
(13) (Regulation) CNS Resolution No. 346 of January 13, 2005 (ResolutionNo346 – Portuguese) (January 13, 2005)
National Health Council, Minister of Health
Relevant Sections: II
(14) (Guidance) Operational Standard No. 01/2012 of March 7, 2012 (OSNo01/2012 - Portuguese) (March 7, 2012)
National Health Council, Ministry of Health
(15) (Regulation) CNS Resolution No. 340 of July 8, 2004 (ResolutionNo340) (Portuguese) (July 8, 2004)
National Health Council, Ministry of Health
Relevant Sections: IV and VI
(16) (Regulation) Resolution RDC No. 260, of December 21, 2018 (ResolutionNo260 - Portuguese) (Effective February 26, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1, 2, 4, and 7
Summary

Overview

As set forth in ResolutionNo466, the PANDRH-GCPs, ResolutionNo251, and the G-ClinProtocol-FAQs, the primary scope of information assessed by institutional ethics committees (ECs) (Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) and the National Commission for Research Ethics (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 ResolutionNo466, the PANDRH-GCPs, ResolutionNo251, and OSNo001/2013, the CEP/CONEP System must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See Informed Consent topic, and the subtopics of Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired for additional information about these populations). ResolutionNo304 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 Informed Consent topic, Documentation Requirements and Vulnerable Populations subtopics and the Specimens topic, Consent for Specimen subtopic.

The CEP/CONEP System is also responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol as stated in ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013. 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. See ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013 for detailed ethical review guidelines.

In addition to the earlier described research protocol requirements, 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 (SUS), per ResolutionNo580. ResolutionNo580 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 Ethics Committee topic, Authorizing Body subtopic 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.

See also ResolutionNo260 for detailed information on the CEP/CONEP system’s role in reviewing protocols submitted for clinical trials with advanced research therapy products in Brazil. Advanced research therapy products include medicines for human use based on genes, tissues, or cells.

Role in Clinical Trial Approval Process

As delineated in ResolutionNo9, ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013, ANVISA and the EC (CEP) (and CONEP, if applicable) must approve a clinical trial application before a trial is permitted to commence. The PANDRH-GCPs, ResolutionNo9, and OSNo001/2013 further state that the EC (CEP) must review and approve any protocol amendments prior to those changes being implemented.

ResolutionNo466 and OSNo001/2013 specify that the principal investigator (PI) is responsible for submitting an application to the CEP/CONEP System via the online platform, Plataforma Brasil (Additional Resource (M)). Per OSNo001/2013, the EC (CEP) preliminary review to verify protocol documentation is complete must be conducted within 10 days following submission and the EC (CEP) is required to issue its initial opinion within 30 days from the date the protocol documents are fully accepted. If the opinion is pending, the researcher will have 30 days from the protocol’s original submission to respond, and the EC (CEP) will have 30 days, in turn, to issue its final approving or disapproving opinion. In addition, the EC (CEP) has a continuing responsibility to monitor the approved trial(s) to ensure ethical compliance throughout the study duration. Refer to OSNo001/2013 for detailed EC (CEP) review procedures.

As a result of the publication of ResolutionNo205, the ResolutionNo9 requirement to include the EC (CEP) approval in the initial clinical trial application (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) or in any protocol amendment submitted to ANVISA has been revoked. Consequently, as explained in Additional Resource (A), the EC (CEP) and ANVISA review processes may now be conducted in parallel. In addition, as indicated in ResolutionNo9, and also noted in Additional Resource (A), CONEP’s approval is not a requirement for ANVISA to approve the DDCM. Similarly, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory, but may be requested, according to Additional Resource (B). In these cases, only the EC (CEP) is required to approve the amended protocol prior to implementation and ANVISA should be notified.

Per ResolutionNo9, upon receipt of the 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. ResolutionNo9 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. ResolutionNo9 and the G-DDCM Manual further indicate that only the clinical trials listed in the approved DDCM may be initiated in Brazil once all of the ethical approvals have been obtained. (See the Clinical Trial Lifecycle topic, Submission Process subtopic for detailed submission requirements.)

In addition, applications with coordination and/or sponsorship originating outside of Brazil require additional EC review by CONEP, as delineated in ResolutionNo292, ResolutionNo446, and ResolutionNo466. Per ResolutionNo446, 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. ResolutionNo580 also amends the ResolutionNo466 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.

ResolutionNo292 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 ResolutionNo292, 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 ResolutionNo292 and the G-ClinProtocol-FAQs for additional guidance on research studies submitted from abroad.

ResolutionNo346 establishes the submission process for multicentric research protocols and indicates that the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. Per OSNo001/2013, the principal investigator (PI) 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. ResolutionNo346 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. See ResolutionNo346 for additional multicentric protocol processing information and OSNo01/2012 for detailed information on the coordinator center’s role in this process. In addition, per Additional Resources (C), (D), (E), (F), (G), (H), (I), (J), and (K), CONEP has published a number of circular letters to clarify submission instructions related to classifying thematic areas in the protocols, protocol amendments, providing correct protocol timelines, updating the informed consent form (ICF), obtaining consent for human specimens, institutional registration responsibilities, and the requirement to register clinical trials with the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)). (See the Informed Consent topic, Documentation Requirements subtopic and the Specimens topic, Consent for Specimen subtopic for additional CONEP ICF and specimens consent instructions).

In addition to conducting international project reviews, per ResolutionNo466, ResolutionNo446, and ResolutionNo340, 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. ResolutionNo466, ResolutionNo446, and ResolutionNo340 may be referenced for specific details on CONEP protocol review requirements and Additional Resource (G) for CONEP specimens consent instructions.

There is no stated expiration date for an EC (CEP) approval in ResolutionNo466, the PANDRH-GCPs, ResolutionNo9, or OSNo001/2013. 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.

Additional Resources
Fagundes P, Dresel P and Miler E.; Regulatory Focus
Relevant Sections: Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Regulatory Submission Process and Conducting a Clinical Trial in Brasil
National Commission for Research Ethics, National Health Council, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
National Health Council, National Commission on Ethics in Research, Ministry of Health
National Health Council, National Commission on Ethics in Research, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
(L) (Website) Brazilian Clinical Trials Registry (ReBEC) (Portuguese) (Current as of June 20, 2019)
Department of Science and Technology, Ministry of Health (DECIT/MS); Institute of Communication and Information Science and Technology in Health (Icict/Fiocruz); Pan American Health Organization (PAHO); Latin American and Caribbean Center on Health Sciences (Bireme)
(M) (Website) Plataforma Brazil (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(N) (Document) Plataforma Brasil Researcher's Manual Coparticipant Projects (Portuguese) (Version 3.1) (October 13, 2017)
Ministry of Health
National Health Council, Ministry of Health
(P) (Form) Cover Sheet for Research Involving Human Beings (Portuguese) (January 2013)
National Commission for Research Ethics, National Health Council, Ministry of Health
Ethics Committee > Ethics Committee Fees
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: Section VII
(2) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 2.5
Summary

Overview

According to ResolutionNo466 and OMREC, the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit ethics committees (ECs), known as Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) in Brazil, to charge a fee to review clinical trial protocols. CONEP states that financing to support ethical reviews should come from a specific scientific committee budget designated within each institution.

Additional Resources
No additional resources
Ethics Committee > Authorizing Body
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: Sections VII, IX, and XIII
(2) (Regulation) CNS Resolution No. 370 of March 8, 2007 (ResolutionNo370 - Portuguese) (March 8, 2007)
National Health Council, Ministry of Health
Relevant Sections: I and II
(3) (Guidance) Standard Procedures No. 006 – Evaluation of Research Ethics Committees (SP006REC - Portuguese) (January 10, 2009)
National Health Council, Ministry of Health
Relevant Sections: 2
(4) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 2.3
(5) (Regulation) CNS Resolution No. 446 of August 11, 2011 (ResolutionNo446 - Portuguese) (Effective Date: August 29, 2011)
National Health Council, Ministry of Health
Relevant Sections: Preamble and Sections I, V, and VII
(6) (Regulation) CNS Resolution No. 340 of July 8, 2004 (ResolutionNo340) (Portuguese) (July 8, 2004)
National Health Council, Ministry of Health
Relevant Sections: IV and VI
(7) (6)(Regulation) CNS Resolution No. 580 of March 22, 2018 (ResolutionNo580 – Portuguese) (March 22, 2018)
National Health Council, Ministry of Health
Relevant Sections: Articles 1 and 11-13
(8) (8)(Regulation) CNS Resolution No. 506 of February 3, 2016 (ResolutionNo506 - Portuguese) (Effective Date: March 23, 2016)
National Health Council, Ministry of Health
Relevant Sections: Chapters I, II, IV, and VI-VIII
Summary

Overview

The National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central statutory body responsible for the registration, audit, and accreditation of institutional ethics committees (ECs), known as Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) in Brazil. As per ResolutionNo466, OSNo001/2013, and ResolutionNo446, 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 ResolutionNo466, OSNo001/2013, and ResolutionNo446, 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 Ethics Committee topic, Scope of Review subtopic for detailed EC (CEP) and CONEP review requirements associated with protocols originating outside of Brazil.

CONEP Composition

As per OSNo001/2013 and ResolutionNo446, 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 MOH’s CNS. In addition, according to Additional Resource (A), 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. CONEP also has a coordinator and an Executive Secretariat selected by the CNS. See ResolutionNo466, OSNo001/2013, ResolutionNo446, and Additional Resources (A) and (B) for detailed information on CONEP composition and responsibilities.

Registration, Auditing, and Accreditation

As per ResolutionNo466, ResolutionNo370, SP006REC, OSNo001/2013, and ResolutionNo446, 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 ResolutionNo446 carries out accreditation. ResolutionNo370 and ResolutionNo506 state that accreditation is valid for three (3) years. In order to apply for renewal, an EC (CEP) must follow the same procedures as in its initial application. The renewal application must be submitted within the window of 60 days before to 60 days after the accreditation’s expiration date, as noted in ResolutionNo370, SP006REC, and ResolutionNo506. See ResolutionNo370, SP006REC, and ResolutionNo506 for additional details on CONEP’s accreditation process.

In addition to being accredited by CONEP per the earlier stated requirements, ResolutionNo506 explains that ECs (CEPs) may now also be certified for their role in the ethical analysis of high-risk research protocols. CONEP plans to publish a risk classification standard that will provide the criteria to assess the risk level of research protocols. Per ResolutionNo506, until the standard is published, CONEP has determined that protocols falling within the special thematic areas listed in section IX.4 of ResolutionNo466 shall be considered high risk. As earlier mentioned in this subtopic and in the Ethics Committee topic, Scope of Review subtopic, these areas include human genetics, human reproduction, indigenous populations, genetically modified organisms, and the establishment and operation of biobanks. Refer to ResolutionNo466, ResolutionNo446, and ResolutionNo340 for a complete listing.

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 EC (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. Additional Resource (C) also provides helpful information on this new process.

Additional Resources
(A) (Document) Bylaws of CONEP/CNS (Portuguese) (June 6, 2001)
National Health Council, Ministry of Health
Relevant Sections: Chapters I and II (I and II)
Lopes, Aníbal Gil, European Group on Ethics in Science and New Technologies, Bureau of European Policy Advisers, European Commission
Relevant Sections: CEP/CONEP System Role and Responsibilities
Fagundes P, Dresel P and Miler E.; Regulatory Focus
Relevant Sections: Local Accreditation
(D) (Website) National Commission for Research Ethics (CONEP) (Portuguese) (Current as of June 20, 2019)
National Health Council, Ministry of Health
(E) (Website) National Health Council (Portuguese) (Current as June 20, 2019)
National Health Council, Ministry of Health
Clinical Trial Lifecycle > Submission Process
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-3, 6, 8, 32-35, 37-39, Chapters IV-V, and 78
(2) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5 and 8-9
(3) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: VI, VIII, IX-XI
(4) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.3, 3.1, 3.3, 4.3, 5.5-5.6, 6.10-6.11, and 6.23
(5) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 2-3
(6) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 5-11
(7) (Guidance) Manual for Submission of Modifications, Amendments, Suspensions and Cancellations (G-DDCMAmdmts - Portuguese) (Version 1.9) (4th Edition) (2018)
General Management of Medicines (GGMED), Coordination of Clinical Research in Medicines and Biological Products (COPEC), ANVISA, Ministry of Health
Relevant Sections: 5-6 and 10 (Annexes)
(8) (Regulation) Resolution of the Board of Directors – RDC No. 102 of August 24, 2016 (ResolutionNo102 – English, unofficial translation) (Portuguese) (Effective Date: December 22, 2016)
ANVISA, Ministry of Health
Relevant Sections: Article 1, Chapters II- IV, and Annex I
(9) (9)(Regulation) Resolution of the Board of Directors – RDC No. 86 of June 27, 2016 (ResolutionNo86 – Portuguese) (Effective Date: July 28, 2016)
ANVISA, Ministry of Health
Relevant Sections: Articles 1 and 3-10
(10) (Guidance) Procedures Manual for Standardization of Electronically Formatted Documents (G-ElecDocFormat – Portuguese) (2016)
Management of Documentary and Corporate Memory (GEDOC), ANVISA, Ministry of Health
Relevant Sections: 3-6
(11) (Regulation) Resolution of the Board of Directors – RDC No. 222 of December 28, 2006 (ResolutionNo222 - Portuguese) (Last Amended July 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 9, 14, and 16
(12) (Regulation) Resolution of the Board of Directors – RDC No. 76 of October 23, 2008 (ResolutionNo76 - Portuguese) (Effective October 27, 2008)
ANVISA, Ministry of Health
Relevant Sections: Articles 9, 14, and 16
(13) (Regulation) Resolution of the Board of Directors – RDC No. 204 of December 27, 2017 (ResolutionNo204 – English, unofficial translation) (Portuguese) (Effective Date: February 25, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1, 3-6, and 10-13
Summary

Overview

As delineated in ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) requires the sponsor, his/her designated contract research organization (CRO), or the sponsor-investigator to obtain application approval for a clinical trial that will have all or part of its development in Brazil for drug registration purposes. In addition, per ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the clinical trial application (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) must contain at least one (1) Specific Clinical Trial Dossier in order for the DDCM to be approved. ResolutionNo9 and the G-DDCM Manual define a Specific Clinical Trial Dossier as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCM Manual, the Specific Clinical Trial Dossier may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. ResolutionNo9 further notes that DDCM submissions to ANVISA can only be made by a CRO when the sponsor has no headquarters or subsidiary in Brazil.

Per ResolutionNo9, ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013, the principal investigator (PI) must also obtain approval from his/her institutional ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)). The PI is responsible for submitting the EC (CEP) application via the online Plataforma Brasil, and if applicable, also submitting the application to the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) for review and approval. Applications with coordination or sponsorship originating outside of Brazil require additional EC review by CONEP, unless the co-sponsor is the Brazilian Government. Please refer to Ethics Committee topic, Scope of Review and Authorizing Body subtopics for detailed information on CONEP responsibilities and other studies requiring CONEP approval.

Although the EC (CEP) must review and approve all clinical research protocols before a trial is permitted to commence, as a result of the publication of ResolutionNo205, the ResolutionNo9 requirement to include the EC (CEP) approval in the initial clinical trial application or in any protocol amendment submission has been revoked. ResolutionNo205 specifies that the new EC requirement is pertinent to rare disease drug clinical trials; however, per ResolutionNo9 and Additional Resource (B), this requirement is now applicable to all drug trials. Consequently, as explained in Additional Resource (B), the EC (CEP) and ANVISA review processes may now be conducted in parallel. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all of the trials included in the DDCM that are permitted to initiate the clinical study.

As indicated in ResolutionNo9, and also noted in Additional Resource (B), 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, but may be requested, according to Additional Resource (C). Refer to the Regulatory Authority topic, Scope of Assessment subtopic for additional information on applications with coordination and/or sponsorship originating outside of Brazil.

As per OSNo001/2013, 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.

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA, as stated in ResolutionNo9 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 CE, per Additional Resource (A), 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 ResolutionNo9 and the G-DDCMAmdmts, he/she is 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 also Additional Resources (A), (E), and (F) for requirements associated with submitting specific clinical trial dossiers for comparative bioavailability studies and comparative pharmacokinetic studies for biosimilars.

In addition, per ResolutionNo102, in the case of a company requesting a global transfer of ownership for product registration or updating its operation and certification data as a result of corporate transactions or business operations, the company is also required to request a global transfer of responsibility for a clinical trial. ANVISA will issue a Special Notice (CE), a Specific Special Notice (Comunicado Especial Específico (CEE)), or a Document for Importation of Product(s) under Investigation (Documento para Importação de Produto(s) sob Investigação) in the name of the new company responsible for the project. This transfer also includes projects under the responsibility of a CRO. Per ResolutionNo9, a CEE is issued for import/export purposes while an applicant is awaiting for ANVISA to review his/her DDCM, or a CEE is issued for Phase IV trials that are only subject to ANVISA’s Clinical Trial Notification requirement. A Document for Importation of Product(s) under Investigation is issued in the case of non-manifestation of the DDCM.

ResolutionNo102 states that the new company is required to update company operation and certification data in the DDCM through a global transfer of responsibility application that should be accompanied by the following documents:

  • Duly completed and signed application form
  • Statement of corporate or commercial transaction practiced, as provided in Annex I

Refer to ResolutionNo102 for additional information.

Delivery Address for Clinical Trial Application (DDCM)

ANVISA
Setor de Indústria e Abastecimento (SIA)
Bloco 5, Area Especial 57, Lote 200, Bloco A, Uniap
Brasília (DF)
CEP: 71205-050

Phone: (61) 3462 6700
Email: protocol@anvisa.gov.br

Assembly and Number of Copies

As per ResolutionNo9, the sponsor (applicant) must submit one (1) hard copy of the DDCM and one (1) electronic copy on CD-ROM in Adobe Acrobat PDF or Microsoft Word file format. The electronic documents should also have text searching capability. Per ResolutionNo9, the electronic media will apply until ANVISA adopts information technology tools that allow for the electronic submission of all requested documentation.

As described in the G-DDCM Manual and Additional Resource (A), all requests for clinical trial approval, also known as petitions (both initial and secondary) should be submitted electronically to ANVISA via the Petitioning System (Sistema de Peticionamento) (see Additional Resource (I)) for system access). However, the associated protocol for the initial petition should be submitted manually along with the DDCM request form (Additional Resource (D)). ResolutionNo86 and the G-ElecDocFormat document requirements should be followed to comply with the manual protocol submission requirements indicated in ResolutionNo9.

Per ResolutionNo86 and the G-ElecDocFormat, the following documents must also be included in print and electronic format when filing an electronic dossier:

  • Cover sheet with document identification
  • Application form
  • Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResolutionNo222 and ResolutionNo76 (tax payment imposed on individuals and companies engaged in clinical research)
  • Media (CD-ROM or DVD-ROM) and corresponding labeling information (including company name, active substance trade name/product, when applicable, process number (for secondary petitions), number of media in relation to the set, when applicable (e.g., 1/3, 2/3, 3/3))

See ResolutionNo86 and the G-ElecDocFormat for detailed instructions on required criteria for CD-ROM or DVD-ROM media, and how to create a digital file as well as digital signature requirements.

All other documentation associated with the original DDCM including the secondary petitions and Specific Clinical Trial Dossier(s) should be submitted electronically via ANVISA’s Petitioning System (Additional Resource (G)). ResolutionNo204 and Additional Resource (H) also describe how Specific Clinical Trial Dossiers (referred to as (Dossiês Específico de Ensaio Clínicos (DEECs) in ResolutionNo204) 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 Regulatory Authority topic, Scope of Assessment subtopic and the Clinical Trial Lifecycle topic, Timeline of Review subtopic.

The G-DDCM Manual further 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. Additional Resource (A) also provides an example of an electronic submission in Annex 1.

Clinical Trial Application Language Requirements

As indicated in OSNo001/2013, the G-DDCM Manual, and Additional Resource (A), ANVISA recommends that the DDCM and associated documents (including the protocol, investigator brochure, informed consent form, and sponsor and institutional declarations), as well as all documentation provided to the CONEP/CEP System 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 (applicant) to provide free translation of the submitted documentation, according to G-DDCM Manual and Additional Resource (A).

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1-3.2, 4, and 7.1 (Annex 1)
Fagundes P, Dresel P and Miler E.; Regulatory Focus
Relevant Sections: Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Regulatory Submission Process and Conducting a Clinical Trial in Brasil
(D) (Form) Request for Consent Form for Clinical Drug Development (DDCM) Dossier (Portuguese) (Version 1.2) (Date Unavailable)
ANVISA, Ministry of Health
Coordination of Therapeutic Equivalence (CETER), Coordination of Clinical Research in Drugs and Biological Products (COPEC), General Management of Drugs (GGMED), Superintendence of Drugs and Biological Products (SUMED), and Brazilian Health Surveillance Agency (ANVISA)
Coordination of Therapeutic Equivalence (CETER), Coordination of Clinical Research in Drugs and Biological Products (COPEC), General Management of Drugs (GGMED), and Brazilian Health Surveillance Agency (ANVISA)
(G) (Website) ANVISA - Petitioning (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(H) (Document) Enhanced Electronic Petition System (Portuguese) (Last Modified May 16, 2018)
ANVISA, Ministry of Health
(I) (Website) ANVISA - Protocol Filing FAQs (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(J) (Website) Plataforma Brazil (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(K) (Document) Guidance on Scheduling Meetings with COPEC (Version 1.1) (April 18, 2018)
ANVISA, Ministry of Health
(L) (Form) Clinical Trial Application Submission Form (FAEC) (Portuguese) (Version 4.0) (Commented Version 1.0) (Last Updated August 16, 2018)
ANVISA, Ministry of Health
ANVISA, Ministry of Health
Clinical Trial Lifecycle > Submission Content
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-2, 6, 33-35, 36-38
(2) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5-6
(3) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: VI and VIII-XI
(4) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.3, 3.1, 3.3, 4.3, 5.5-5.6, 6.10-6.11, and 6.23, and Chapter VIII
(5) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 2-3
(6) (Regulation) Resolution of the Board of Directors – RDC No. 222 of December 28, 2006 (ResolutionNo222 - Portuguese) (Last Amended July 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 9, 14, and 16
(7) (Regulation) Resolution of the Board of Directors – RDC No. 76 of October 23, 2008 (ResolutionNo76 - Portuguese) (Effective October 27, 2008)
ANVISA, Ministry of Health
Relevant Sections: Articles 9, 14, and 16
(8) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Biological Products (G-BioIProdManual - Portuguese) (2nd Edition) (Version 1.2) (2017)
ANVISA, Ministry of Health
Relevant Sections: 2
(9) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Synthetic and Semisynthetic Medicines (G-SyntheticDrugProdManual - Portuguese) (2nd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 2
(10) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 5-11
(11) (Guidance) Manual for Submission of Modifications, Amendments, Suspensions and Cancellations (G-DDCMAmdmts - Portuguese) (Version 1.9) (4th Edition) (2018)
General Management of Medicines (GGMED), Coordination of Clinical Research in Medicines and Biological Products (COPEC), ANVISA, Ministry of Health
Relevant Sections: 5-6 and 10 (Annexes)
(12) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 9.1
Summary

Overview

As set forth in ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) requires the sponsor, his/her designated contract research organization (CRO), or the sponsor-investigator to obtain approval for a clinical trial application that will have all or part of its development in Brazil for a drug to be registered in Brazil. In addition, per ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the clinical trial application (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) must contain at least one (1) Specific Clinical Trial Dossier in order for the DDCM to be approved. ResolutionNo9, the G-DDCM Manual define a Specific Clinical Trial Dossier as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCM Manual, the Specific Clinical Trial Dossier may be linked as a new process to the DDCM being submitted, or as a process that modifies a previously submitted DDCM.

Per ResolutionNo9, ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013, the principal investigator (PI) must also obtain approval from his/her institutional ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)). The PI is responsible for submitting the EC (CEP) application via the online Plataforma Brasil, and if applicable, also submitting the application to the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa) (CONEP)) for review and approval. Applications with coordination or sponsorship originating outside of Brazil require additional EC review by CONEP, unless the co-sponsor is the Brazilian Government. Please refer to Ethics Committee topic, Scope of Review and Authorizing Body subtopics for detailed information on CONEP responsibilities and other studies requiring CONEP approval.

According to Additional Resource (B), the DDCM is organized into two (2) main sections: an administrative section consisting of a compilation of all the administrative data, including specific requirements for imported products, and a technical section comprised of quality, nonclinical, and clinical reports. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that lists all of the trials included in the DDCM permitted to initiate the clinical study.

ANVISA Requirements

As delineated in ResolutionNo9 and the G-DDCM Manual, to complete the DDCM, the sponsor, the designated CRO, or the sponsor-investigator is required to submit ANVISA’s DDCM Request Form (see Additional Resource (C)) along with the following documentation:

Note that per ResolutionNo205, the ResolutionNo9 requirement to include the CEP approval in the initial DDCM or in any protocol amendment submission has been revoked.

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA using the DDCM request form (Additional Resource (C)), as stated in ResolutionNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial submission of the DDCM. If the modification has occurred following ANVISA’s issuance of the CE, per Additional Resource (A), 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 ResolutionNo9 and the G-DDCMAmdmts, he/she is 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 ResolutionNo9 and the G-DDCM Manual for detailed ANVISA application submission requirements.

EC Requirements

As per OMREC and OSNo001/2013, the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) requires applicants to submit the following documentation online via Plataforma Brasil:

  • Cover Sheet for Research Involving Human Beings (see Additional Resource (D))
  • Clinical research protocol
  • Statement of Commitment from Principal Investigator (PI)
  • Informed Consent Form (ICF) (See Informed Consent topic for additional information)
  • Research budget
  • PI and other investigator(s) Curriculum Vitaes (CVs)
  • Research project schedule

See OMREC and OSNo001/2013 for detailed CEP/CONEP system submission requirements.

Clinical Protocol

As delineated in the PANDRH-GCPs, OMREC, and OSNo001/2013, 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 Clinical Trial Lifecycle topic, Safety Reporting subtopic 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 OSNo001/2013.

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1- 3.2
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Regulatory Submission Process and Documentation Required
(C) (Form) Request for Consent Form for Clinical Drug Development (DDCM) Dossier (Portuguese) (Version 1.2) (Date Unavailable)
ANVISA, Ministry of Health
(D) (Form) Cover Sheet for Research Involving Human Beings (Portuguese) (January 2013)
National Commission for Research Ethics, National Health Council, Ministry of Health
(E) (Website) Brazilian Clinical Trials Registry (ReBEC) (Portuguese) (Current as of June 20, 2019)
Department of Science and Technology, Ministry of Health (DECIT/MS); Institute of Communication and Information Science and Technology in Health (Icict/Fiocruz); Pan American Health Organization (PAHO); Latin American and Caribbean Center on Health Sciences (Bireme)
International Clinical Trials Registry Platform (ICTRP), World Health Organization
(G) (Article) Launch of the Brazilian Registry of Clinical Trials - REBEC - During DECIT 10 Years (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(H) (Article) Brazil Wins International Clinical Trials Registry (Portuguese) (March 30, 2017)
Institute of Communication and Scientific and Technological Information in Health
(I) (Website) ANVISA - Protocol Filing FAQs (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(J) (Website) Plataforma Brazil (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(K) (Form) Clinical Trial Application Submission Form (FAEC) (Portuguese) (Version 4.0) (Commented Version 1.0) (Last Updated August 16, 2018)
ANVISA, Ministry of Health
ANVISA, Ministry of Health
Clinical Trial Lifecycle > Timeline of Review
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-3, 6, 33-36, 38, and 78
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.3, 3.1, 4.3, 5.5- 5.6, and 6.10-6.11
(3) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5-6
(4) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: VI and VIII-XI
(5) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 2-3
(6) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 5-11
(7) (Regulation) Resolution of the Board of Directors – RDC No. 204 of December 27, 2017 (ResolutionNo204 – English, unofficial translation) (Portuguese) (Effective Date: February 25, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1, 3-6, and 10-13
Summary

Overview

As stated in ResolutionNo9, the PANDRH-GCPs, the G-DDCM Manual, and Additional Resource (A), the sponsor, his/her 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 (known as a Clinical Drug Development Dossier (Dossier de Desenvolvimento Clinico de Medicamento (DDCM)) that will have all or part of its development in Brazil for a drug to be registered in Brazil. In addition, per ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the clinical trial application (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) must contain at least one (1) Specific Clinical Trial Dossier in order for the DDCM to be approved. ResolutionNo9 and the G-DDCM Manual define a Specific Clinical Trial Dossier as a collection of documents to be submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCM Manual, the Specific Clinical Trial Dossier may be linked as a new process to the DDCM being submitted, or as a process that modifies a previously submitted DDCM. ResolutionNo9 and the G-DDCM Manual explain that following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all of the trials included in the DDCM that are permitted to initiate the clinical study.

Per ResolutionNo9, ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013, the principal investigator (PI) must also obtain approval from his/her institutional ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside of Brazil require additional EC review by the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. Please refer to Ethics Committee topic, Scope of Review and Authorizing Body subtopics for detailed information on CONEP responsibilities and other studies requiring CONEP approval.

As a result of the publication of ResolutionNo205, the ResolutionNo9 requirement to include the EC (CEP) approval in the initial clinical trial application or in any protocol amendment submission has been revoked. Consequently, as explained in Additional Resource (C), the EC (CEP) and ANVISA review processes may now be conducted in parallel.

ANVISA Approval

As specified in ResolutionNo9, upon receipt of the 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. ResolutionNo9 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.

In addition to the previously stated DDCM requirements, ResolutionNo204 establishes a priority category to register, amend previously registered, or request prior consent for drug submissions. ResolutionNo204 states that priority submission may be submitted as a DDCM, or, as a Specific Clinical Trial Dossier (Dossiês Específico de Ensaio Clínico (DEEC)). A 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 (SUS). A 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 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 protocol priority petition submission, and any requests for clarification or additional technical requirements will result in suspending the counting of deadlines until the requests have been met.

In addition, per ResolutionNo204, ANVISA must first issue a written opinion letter for priority petitions for prior consent in the clinical development dossier process and prior consent in the drug research process, as well as secondary petitions referring to the prioritized primary process, 45 calendar days from the first working day following protocol submission. Refer to ResolutionNo204 for detailed information on DEEC submissions. See also Additional Resources (A) and (D) for additional information on priority petitions.

ResolutionNo205 also 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.

Per ResolutionNo205, a sponsor (applicant) must request a pre-submission meeting with ANVISA to present the application (DDCM, secondary petition, or DEEC), and ANVISA should hold the meeting within 60 days following this request. Following the pre-submission meeting, the application should be submitted, and ANVISA, in turn, will evaluate the application within 30 days of receipt with either a notification of additional information requirements or a final decision. The sponsor (applicant) should respond to ANVISA’s notification request for further information within 30 days, and ANVISA should assess the submitted requirements within 30 days of receipt. Secondary petitions and DEECs for rare disease drugs should be handled in the same manner.

Refer to ResolutionNo205 for additional submission documentation requirements. Additional Resource (B) also provides a helpful summary of ResolutionNo204 and ResolutionNo205.

EC Approval

As delineated in OSNo001/2013, the institutional EC (CEP) is required to issue an initial report 30 days from the date the protocol documents are fully accepted for review. The CEP’s review of the protocol documentation for completeness should be accomplished within 10 days following submission.

No timeline of review is currently available for CONEP’s review. (See the Clinical Trial Lifecycle topic, Submission Process subtopic for additional submission requirements.)

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1 and 3.5
Fagundes P, Dresel P and Miler E.; Regulatory Focus
Relevant Sections: Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Regulatory Submission Process and Conducting a Clinical Trial in Brasil
(D) (Document) Enhanced Electronic Petition System (Portuguese) (Last Modified May 16, 2018)
ANVISA, Ministry of Health
(E) (Website) New Drug Registration (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
Clinical Trial Lifecycle > Trial Initiation
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-3, 6, 33, 35-36, 38, and 40
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.3, 3.1, 4.3, 5.1, 5.5-5.6, and 6.2, 6.10-6.11
(3) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5.1
(4) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: VI and VIII-XI
(5) (Guidance) Operational Standard No. 001/2013 (OSNo001/2013) (Portuguese(September 30, 2013)
National Health Council, Ministry of Health
Relevant Sections: 2-3
Summary

Overview

In accordance with ResolutionNo9, the PANDRH-GCPs, and the G-DDCM Manual, a clinical trial can only commence after the sponsor, his/her designated contract research organization (CRO), or the sponsor-investigator receives clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clinico de Medicamento (DDCM)) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Per ResolutionNo9, ResolutionNo466, the PANDRH-GCPs, and OSNo001/2013, the principal investigator (PI) must also obtain approval from his/her institutional ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside Brazil require an additional review and approval by the National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa) (CONEP), unless the co-sponsor is the Brazilian Government. Please refer to Ethics Committee topic, Scope of Review and Authorizing Body subtopics for detailed information on CONEP responsibilities and other studies requiring CONEP approval. No waiting period is required following the applicant’s receipt of these approvals.

In addition, per ResolutionNo9, the sponsor or his/her 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 Investigational Products topic, Manufacturing & Import subtopic for additional information). As stated in the PANDRH-GCPs and ResolutionNo9, all investigators must possess appropriate qualifications, training, and experience. The trials should be conducted in compliance with the PANDRH-GCPs, ResolutionNo466, and ResolutionNo9. Clinical trials must also be conducted in a laboratory complying with the Organisation for Economic Co-operation and Development’s Good Laboratory Practices (GLP) as mandated by Brazil’s National Institute of Metrology, Quality and Technology (INMETRO). Refer to Additional Resources (A), (B), and (C) for additional information on GLP requirements.

ResolutionNo9 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 Additional Resource (D) for DDCM request form).

Clinical Trial Agreement

As delineated in the PANDRH-GCPs, the sponsor or his/her 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 ResolutionNo9.

EC Confirmation of Review and Approval

ResolutionNo466, the PANDRH-GCPs, and ResolutionNo9 mandate that the sponsor obtain confirmation of EC (CEP) review and approval from the investigator(s) or institution(s) prior to the trial’s commencement. The PANDRH-GCPs also state 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, or any other written information or other procedures)

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 Ethics Committee topic, Scope of Review subtopic and Clinical Trial Lifecycle topic, Submission Content subtopic for additional details on the EC review process).

Clinical Trials Registry

As delineated in ResolutionNo9, it is mandatory for the sponsor to register the clinical trial with the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)). According to Additional Resource (E), ReBEC is a primary registry in the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) network. See also Additional Resources (F), (G), and (H) for further information about ReBEC.

Data Safety and Monitoring Board

According to ResolutionNo9, an Independent Safety Monitoring Committee should be established to systematically evaluate aggregate adverse event/adverse drug reaction data.

Additional Resources
Environment Directorate, Organisation for Economic Co-operation and Development
National Institute of Metrology, Quality and Technology (INMETRO), Ministry of Development, Industry and Foreign Trade
(C) (Website) Recognition of Compliance with GLP Principles (Portuguese) (Current as of June 20, 2019)
National Institute of Metrology, Quality and Technology (INMETRO), Ministry of Development, Industry and Foreign Trade
(D) (Form) Request for Consent Form for Clinical Drug Development (DDCM) Dossier (Portuguese) (Version 1.2) (Date Unavailable)
ANVISA, Ministry of Health
International Clinical Trials Registry Platform (ICTRP), World Health Organization
(F) (Website) Brazilian Clinical Trials Registry (ReBEC) (Portuguese) (Current as of June 20, 2019)
Department of Science and Technology, Ministry of Health (DECIT/MS); Institute of Communication and Information Science and Technology in Health (Icict/Fiocruz); Pan American Health Organization (PAHO); Latin American and Caribbean Center on Health Sciences (Bireme)
(G) (Article) Launch of the Brazilian Registry of Clinical Trials - REBEC - During DECIT 10 Years (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(H) (Article) Brazil Wins International Clinical Trials Registry (Portuguese) (March 30, 2017)
Institute of Communication and Scientific and Technological Information in Health
(I) (Form) Clinical Trial Application Submission Form (FAEC) (Portuguese) (Version 4.0) (Commented Version 1.0) (Last Updated August 16, 2018)
ANVISA, Ministry of Health
ANVISA, Ministry of Health
Clinical Trial Lifecycle > Safety Reporting
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 5.11, 6.5, 6.16-6.17, and Chapter 9
(2) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Article 6 and Chapter VII
(3) (Guidance) Manual for Notification of Adverse Events and Safety Monitoring in Clinical Trials (AE&SafetyManual - Portuguese) (1st Edition) (Version 1.1) (2016)
General Management of Medicines, Coordination of Clinical Research in Medications and Biological Products, ANVISA, Ministry of Health
Summary

Overview

In accordance with the PANDRH-GCPs, ResolutionNo9, and the AE&SafetyManual, the following definitions provide a basis for a common understanding of Brazil’s safety reporting requirements:

  • 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 is a birth defect or congenital anomaly
  • 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)

Reporting Requirements for AEs/ADRs

Investigator Responsibilities

As specified in ResolutionNo9 and the AE&SafetyManual, 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 AE&SafetyManual, 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 ethics committee (EC) (known as a Comitê de Ética em Pesquisa) (CEP)) with any additional requested information (e.g., autopsy reports and terminal medical reports).

Sponsor Responsibilities

As per ResolutionNo9 and the AE&SafetyManual, the sponsor should ensure all relevant information pertaining to fatal or life-threatening SAEs/SADRs 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. The AE&SafetyManual also 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 (see Additional Resource (D)). The recommended criterion to categorize each event is as follows: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and Unassessable/Unclassifiable.

ResolutionNo9 also indicates that any additional information should be included in the assessment up to eight (8) calendar days from the notification date. Additionally, per ResolutionNo9 and the AE&SafetyManual, all other AEs/ADRs 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.

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’s (CEP’s) approval of the trial. In addition, ResolutionNo9 specifies that the sponsor must submit to ANVISA annual safety update reports on the development of the investigational product (IP). The annual report must be filed within a maximum of 60 calendar days starting from the date that ANVISA approves the clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clinico de Medicamento (DDCM)).

Form Completion & Delivery Requirements

According to Additional Resource (A), notifications of expected or unexpected SAEs/SADRs should be submitted via ANVISA’s Notification of SAEs in Clinical Trials with Medications or Biological Products – NotivisaEC (Notificação de EAGs em Ensaios Clínicos com Medicamentos ou Produtos biológicos – NotivisaEC).

Data Safety and Monitoring Board

According to ResolutionNo9, an Independent Safety Monitoring Committee (ISMC) should be established to systematically evaluate and aggregate AE/ADR data.

In addition, per the AE&SafetyManual, in the case of a Phase III clinical trial, an ISMC should monitor the trial and the sponsor must report the committee’s recommendations to ANVISA. If an ISMC is not established, it must be justified in accordance with ResolutionNo9.

Additional Resources
(A) (Website) Notification of Serious Adverse Events in Clinical Trials (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
Relevant Sections: Notification of Serious Adverse Events in Clinical Trials - NotivisaEC Form link
(B) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.7
The Uppsala Monitoring Centre (UMC), World Health Organization (WHO)
Clinical Trial Lifecycle > Progress Reporting
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 5.10 and 5.13
(2) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 40, 68, and 69
(3) (Guidance) Manual for Submission of Monitoring Reports and Forms for Beginning and End of Clinical Trial (G-CTReptsManual - Portuguese) (1st Edition) (2016)
ANVISA, Ministry of Health
Relevant Sections: 3, 5-7
Summary

Overview

In accordance with the PANDRH-GCPs, ResolutionNo9, and the G-CTReptsManual, the investigator and the sponsor share responsibility for submitting progress and final reports on the status of a clinical trial. Per ResolutionNo9 and the G-CTReptsManual, clinical trial progress reports are referred to as annual clinical trial protocol monitoring reports in Brazil. According to Additional Resource (A), progress reports submitted annually refer to clinical trial data compiled from the national clinical study centers and the final reports refer to data collected at the end of the study from all of the participating centers.

As stated in ResolutionNo9 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 Clinico de Medicamento (DDCM)) request form (Additional Resource (B)). See Additional Resource (C) for the petitioning system website that allows users to submit these forms electronically, and Additional Resources (D) and (E) for links to the notification forms.

Progress Reports/Annual Clinical Trial Monitoring Reports

As per ResolutionNo9 and the G-CTReptsManual, the sponsor must file a progress report (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. ResolutionNo9 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. Additional Resource (A) 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 (see Additional Resource (F)). See Additional Resource (G) for the annual/final report form that may be used.

The PANDRH-GCPs also provides a separate a separate ethics committee (EC) (known as the Comitê de Ética em Pesquisa (CEP) in Brazil) submission requirement in which the investigator or institution is required to submit written summaries on the status of the trial to the EC (CEP) annually, or more frequently, if requested by the EC (CEP). According to Additional Resource (H), progress and annual reports are prepared and submitted following local requirements, and the clinical study staff must submit an interim report to its EC (CEP) every six (6) months.

Final Reports

ResolutionNo9 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 ResolutionNo9 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
  • Relating of 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 ResolutionNo9, or they may be submitted using the ICH E3 format (see Additional Resource (F)). See Additional Resource (G) 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.

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.6
(B) (Form) Request for Consent Form for Clinical Drug Development (DDCM) Dossier (Portuguese) (Version 1.2) (Date Unavailable)
ANVISA, Ministry of Health
(C) (Website) ANVISA - Petitioning (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(D) (Form) Notification Form for Starting the Clinical Trial in Brazil (Portuguese) (Version 2.0) (August 30, 2016)
ANVISA, Ministry of Health
(E) (Form) End of Clinical Trial Notification Form in Brazil (Portuguese) (Version 2.0) (August 30, 2016)
ANVISA, Ministry of Health
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(G) (Form) Clinical Trial Report – Annual or Final (Portuguese) (Date Unavailable)
ANVISA, Ministry of Health
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Regulatory Submission Process and Conducting a Clinical Trial in Brasil
Sponsorship > Definition of Sponsor
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: II (11)
(2) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 6, 20, and 27
(3) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: Chapter 9
Summary

Overview

As per ResolutionNo466, ResolutionNo9, 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.

ResolutionNo9 states that a sponsor can authorize a contract research organization (CRO) to carry out certain work and obligations regarding the trial. As delineated in ResolutionNo9, any trial-related responsibilities to be transferred and assumed by a CRO should be specified in a written agreement or contract. In addition, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

As delineated in ResolutionNo9, 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 researcher, who will be responsible for conducting the clinical trial at the institution, and the sponsor-investigator will serve as the secondary sponsor.

Additional Resources
No additional resources
Sponsorship > Trial Authorization
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-3, 6, 8, 32-35, 37-39, Chapter IV, and 78
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 6.10
(3) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 5-6
(4) (Regulation) Resolution of the Board of Directors – RDC No. 222 of December 28, 2006 (ResolutionNo222 - Portuguese) (Last Amended July 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 9, 14, and 16
(5) (Regulation) Resolution of the Board of Directors – RDC No. 76 of October 23, 2008 (ResolutionNo76 - Portuguese) (Effective October 27, 2008)
ANVISA, Ministry of Health
Relevant Sections: Articles 9, 14, and 16
(6) (Guidance) Manual for Submission of Modifications, Amendments, Suspensions and Cancellations (G-DDCMAmdmts - Portuguese) (Version 1.9) (4th Edition) (2018)
General Management of Medicines (GGMED), Coordination of Clinical Research in Medicines and Biological Products (COPEC), ANVISA, Ministry of Health
Relevant Sections: 5-6
(7) (Regulation) Resolution of the Board of Directors – RDC No. 102 of August 24, 2016 (ResolutionNo102 – English, unofficial translation) (Portuguese) (Effective Date: December 22, 2016)
ANVISA, Ministry of Health
Relevant Sections: Article 1, Chapters II-IV, and Annex I
(8) (Regulation) Resolution of the Board of Directors – RDC No. 204 of December 27, 2017 (ResolutionNo204 – English, unofficial translation) (Portuguese) (Effective Date: February 25, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1, 3-6, and 10-13
(9) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 5-9
Summary

Overview

In accordance with ResolutionNo9, the PANDRH-GCPs, the G-DDCM Manual, and Additional Resource (A), the sponsor, his/her 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 that will have all or part of its development in Brazil for a drug to be registered in Brazil. In addition, per ResolutionNo9, the G-DDCM Manual, and Additional Resource (A), the clinical trial application (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) must contain at least one (1) Specific Clinical Trial Dossier in order for the DDCM to be approved. ResolutionNo9 and the G-DDCM Manual define a Specific Clinical Trial Dossier as a collection of documents to be submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCM Manual, the Specific Clinical Trial Dossier may be linked as a new process to the DDCM being submitted, or as a process that modifies a previously submitted DDCM. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that lists all of the trials included in the DDCM permitted to initiate the clinical study. Per ResolutionNo9, DDCM submissions to ANVISA can only be made by a CRO when the sponsor has no headquarters or subsidiary in Brazil.

As described in ResolutionNo9 and the G-DDCM Manual, to complete the DDCM, the sponsor, the designated CRO, or the sponsor-investigator is required to submit ANVISA’s DDCM Request Form (see Additional Resource (B)) along with the following documentation:

  • Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResolutionNo222 and ResolutionNo76 (tax payment imposed on individuals and companies engaged in clinical research)
  • Drug development plan
  • Certified copy of the clinical agreement (contract or statement) that has been written, dated, and signed by the sponsor or his/her CRO
  • Clinical research protocol Investigator’s Brochure (IB)
  • Summary of investigational product’s (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 the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)) (Additional Resource (D))

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA electronically as stated in ResolutionNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial submission of the DDCM. If the modification has occurred following ANVISA’s issuance of the CE, per Additional Resource (A), 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 ResolutionNo9 and the G-DDCMAmdmts, he/she is only required to submit substantial protocol amendments via a secondary electronic 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.

Per ResolutionNo102, in the case of a company requesting a global transfer of ownership for product registration or the updating of company operation and certification data as a result of corporate transactions or business operations, ANVISA will issue a CE, a Specific Special Notice (Comunicado Especial Específico (CEE)), or a Document for Importation of Product(s) under Investigation (Documento para Importação de Produto(s) sob Investigação) in the name of the new company responsible for the project. This transfer also includes projects under the responsibility of a CRO. Refer to ResolutionNo102 for detailed instructions on submitting appropriate documentation for this update.

In addition to the previously stated DDCM requirements, ResolutionNo204 establishes a priority category to register, amend previously registered, or request prior consent for drug submissions. ResolutionNo204 states that priority submission may be submitted as a DDCM, or as a Specific Clinical Trial Dossier (Dossiês Específico de Ensaio Clínico (DEEC)). A DDCM submission is required to meet one 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 (SUS). A 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. See the Regulatory Authority topic, Scope of Assessment subtopic, and the Clinical Trial Lifecycle topic, Timeline of Review subtopic for further information on these types of submissions.

ResolutionNo205 also 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 linked either 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.

Per ResolutionNo205, a sponsor (applicant) must request a pre-submission meeting with ANVISA to present the application (DDCM, secondary petition, or DEEC), and ANVISA should hold the meeting within 60 days following this request. Following the pre-submission meeting, the application should be submitted, and ANVISA in turn, will evaluate the application within 30 days of receipt with either a notification of additional information requirements or a final decision. The sponsor (applicant) should respond to ANVISA’s notification request for further information within 30 days, and ANVISA should assess the submitted requirements within 30 days of receipt. Secondary petitions and DEECs for rare disease drugs should be handled in the same manner.

Refer to ResolutionNo205 for additional submission documentation requirements. Additional Resource (C) also provides a helpful summary of ResolutionNo204 and ResolutionNo205.

See the Clinical Trial Lifecycle topic, Submission Content subtopic for detailed documentation submission requirements.

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1 and 3.2
(B) (Form) Request for Consent Form for Clinical Drug Development (DDCM) Dossier (Portuguese) (Version 1.2) (Date Unavailable)
ANVISA, Ministry of Health
Fagundes P, Dresel P and Miler E.; Regulatory Focus
Relevant Sections: Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
(D) (Website) Brazilian Clinical Trials Registry (ReBEC) (Portuguese) (Current as of June 20, 2019)
Department of Science and Technology, Ministry of Health (DECIT/MS); Institute of Communication and Information Science and Technology in Health (Icict/Fiocruz); Pan American Health Organization (PAHO); Latin American and Caribbean Center on Health Sciences (Bireme)
(E) (Article) Launch of the Brazilian Registry of Clinical Trials - REBEC - During DECIT 10 Years (Portuguese) (Current as of June 20, 2019)
Ministry of Health
(F) (Article) Brazil Wins International Clinical Trials Registry (Portuguese) (March 30, 2017)
Institute of Communication and Scientific and Technological Information in Health
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Documentation Required
(H) (Website) ANVISA - Protocol Filing FAQs (Portuguese) (Current as of June 20, 2019)
ANVISA, Ministry of Health
(I) (Form) Clinical Trial Application Submission Form (FAEC) (Portuguese) (Version 4.0) (Commented Version 1.0) (Last Updated August 16, 2018)
ANVISA, Ministry of Health
ANVISA, Ministry of Health
Sponsorship > Insurance
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 6.8
Summary

Overview

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 Additional Resource (A), in the event that 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.

Additional Resources
Huynh-Ba and Beumer Sassi, AAPS Open
Relevant Sections: Documentation Required
Sponsorship > Compensation
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 6.8
(2) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: Sections II (7 and 18) and V (7)
(3) (Regulation) CNS Resolution No. 563 of November 10, 2017 (ResolutionNo563 – English, unofficial translation) (Portuguese) (November 10, 2017)
National Health Council, Ministry of Health
Relevant Sections: Articles 1, 3, and 4
(4) (Regulation) Resolution of the Board of Directors – RDC No. 38 of August 12, 2013 (ResolutionNo38 - Portuguese) (Effective Date: August 13, 2013)
ANVISA, Ministry of Health
Relevant Sections: 4, 10, 15, 18, and Annexes
Summary

Overview

As specified in the PANDRH-GCPs and ResolutionNo466, 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.

As per ResolutionNo466, participants may also be compensated for travel expenses incurred while participating in the trial. In addition, per ResolutionNo563, 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. ResolutionNo38 further states that the sponsor or his/her contract research organization (CRO) may request consent from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to obtain access to a post-study drug supply program for research participants enrolled in a specific clinical study. Once this access is approved, the sponsor will provide a free supply of medicines to the participants as long as the benefit is based on a physician’s medical evaluation. The free supply of medicines should also be available to participants when the study is terminated early.

Additional Resources
ABRACRO
Sponsorship > Quality, Data & Records Management
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Article 6, 9-11, 18-20, 27, and 71
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 5.12, 6.1, 6.5-6.6, 6.19, and 6.23
(3) (Regulation) Normative Instruction No. 20 of October 2, 2017 – Provides Inspection Procedures in Good Clinical Practice for Clinical Drug Trials (NormNo20 - English, unofficial translation) (Portuguese) (Effective Date: October 3, 2017)
ANVISA, Ministry of Health
Relevant Sections: Articles 1-2
Summary

Overview

As stated in ResolutionNo9 and the PANDRH-GCPs, the sponsor or his/her contract research organization (CRO) is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol, the PANDRH-GCPs, the International Conference on Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R1) (ICH-GCPs), and other applicable requirements. According to Additional Resource (B), Brazil will require clinical drug research studies to comply with the ICH’s Guideline for Good Clinical Practice E6(R2) (ICH-GCPs-Addendum) in December 2019.

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.

The sponsor must also obtain the investigator(s) and the institution(s) agreement to:

  • Conduct the trial in compliance with the PANDRH-GCPs, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the institutional ethics committee (EC) (known as a 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

Electronic Data Processing System

When using electronic trial data processing systems, the sponsor or his/her CRO must ensure that the system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance, and that he/she maintains SOPs for using these systems. Refer to the PANDRH-GCPs for detailed information on electronic trial data systems.

Record Management

As set forth in ResolutionNo9, the sponsor or his/her 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. ResolutionNo9 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. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

Audit Requirements

As part of its QA system, ResolutionNo9 and the PANDRH-GCPs note that the sponsor or his/her CRO should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. 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 his/her 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.

In addition, NormNo20 provides guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with Good Clinical Practices (GCPs) delineated in ResolutionNo9, the PANDRH-GCPs, and the ICH-GCPs. ­In the event of a routine inspection, NormNo20 states that ANVISA will notify the institution at least 15 calendar days in advance of the visit. Both the sponsor and/or his/her 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 Official of Notification of Inspection in GCPs. For more detailed information on ANVISA’s inspection process, refer to NormNo20.

Premature Study Termination/Suspension

The PANDRH-GCPs explain that if the sponsor or his/her CRO chooses, or is required to terminate a study, the investigator(s) should promptly inform the institution. The investigator or institution should also immediately inform the EC (CEP) and provide a detailed explanation of the termination or suspension.

Multicenter Studies

Per the PANDRH-GCPs, in the event of a multicenter clinical trial, the sponsor or his/her CRO should ensure that all investigators conduct the trial in strict compliance with the protocol as well as ANVISA’s and the EC (CEP)’s requirements.

Additional Resources
(A) (ICH Guidance) Guideline for Good Clinical Practice E6(R1) (ICH-GCPs) (Step 4 Version) (June 10, 1996)
International Conference on Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(B) (Document) Addendum to ICH Guide E6 Should be Implemented in 2 Years (Portuguese) (Last Modified March 2, 2018)
ANVISA, Ministry of Health
Sponsorship > Site/Investigator Selection
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 5.6, 6.2, 6.5, and 6.6
(2) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 6, 20, 37, and 56
Summary

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 training and experience. 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. The sponsor must also sign an agreement or contract with the participating institution(s). If a multicenter trial is going to be conducted, the sponsor must organize a coordinating committee or select coordinating investigators.

(See the Clinical Trial Lifecycle topic, Submission Content subtopic for additional information on clinical trial application requirements).

Data Safety and Monitoring Board

According to ResolutionNo9, an Independent Safety Monitoring Committee (ISMC) should be established to systematically evaluate aggregate adverse event/adverse drug reaction data.

Foreign Sponsor Responsibilities

As specified in the PANDRH-GCPs and ResolutionNo9, the sponsor may transfer his/her study related duties and functions to a contract research organization (CRO). However, he/she 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 ResolutionNo9, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

Additional Resources
No additional resources
Informed Consent > Documentation Requirements
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.6, 3.1, 4.1-4.3, 5.5, and Annex 3
(2) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: II-IV
(3) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(4) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 9 and Annexes C-D
(5) (Guidance) Guidance Manual: Frequent Pending Issues in Clinical Research Protocols (Version 1.0) (G-ClinProtocols-FAQs) (Portuguese) (2015)
Brazilian National Board of Health (CNS) and Brazilian National Research Ethics Committee (CONEP)
Relevant Sections: Introduction (Chart 1), 1.1, 1.19-1.20, and Summary Chart: Frequent Pending Issues (1)
Summary

Overview

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, ResolutionNo466, 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, ResolutionNo466, the G-ClinResSubjectRts, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a 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. Additional Resource (A) also notes that the ICF must consist of a single and complete document, free of addenda and/or other documents associated with it. The clarifications delineated in Additional Resource (A) also apply to assent forms. Additional Resource (B) 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 Additional Resource (B) for detailed information. (See the Informed Consent topic, Required Elements subtopic for details on contents to be included in the form.)

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, state that the investigator, or his/her designated representative, must provide detailed research study information to the participant and/or his/her legal representative(s) or guardian(s). As delineated in ResolutionNo466, 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. ResolutionNo466 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 his/her 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 his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

Re-Consent

According to the PANDRH-GCPs and Additional Resource (A), 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 and submitted to ANVISA before such changes are implemented. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and Additional Resource (B), the researcher must ensure that the participant and/or his/her legal representative(s) or guardian(s) sign the revised ICF and any other updated information. Additional Resource (A) further notes that changes made to the ICF through separate documents are not considered acceptable. The update requires the investigator to generate a new version of the document. The investigator or his/her delegated representative should also emphasize the changes contained in the updated ICF.

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 he/she does 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.

Documentation Copies

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, state that the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. In addition, the PANDRH-GCPs explains that if the participant and/or his/her legal representative(s) or guardian(s) is illiterate, an impartial witness should be present throughout the consent process. At this time, the participant and/or his/her legal representative(s) or guardian(s) 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. ResolutionNo466 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 and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) or person(s) overseeing the consent process.

Additional Resources
National Commission for Research Ethics, National Health Council, Ministry of Health
National Commission for Research Ethics, National Health Council, Ministry of Health
Informed Consent > Required Elements
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 2.6, 3.1.8, 4.3, 5.5, and Annex 3
(2) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 9 and Annex C
(3) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(4) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: III-IV
(5) (Guidance) Guidance Manual: Frequent Pending Issues in Clinical Research Protocols (Version 1.0) (G-ClinProtocols-FAQs) (Portuguese) (2015)
Brazilian National Board of Health (CNS) and Brazilian National Research Ethics Committee (CONEP)
Relevant Sections: Introduction (Chart 1)
Summary

Overview

As delineated in the PANDRH-GCPs and OMREC, prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)) approval for the written informed consent form (ICF), and any other information being provided to the research participant and/or his/her legal representative(s) or guardian(s).

The PANDRH-GCPs, the G-ClinResSubjectRts, OMREC, ResolutionNo466, and the G-ClinProtocols-FAQs state that information about the research study should be presented in easily understandable and unambiguous language in both written and oral form. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and the G-ClinProtocols-FAQs, the potential research participant or his/her legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.

No Coercion

As 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 his/her legal representative(s) and/or guardian(s) to waive or to appear to waive his/her 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.

ICF Required Elements

Based on the PANDRH-GCPs, ResolutionNo466, and OMREC, the ICF should include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):

  • 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 EC, 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 his/her consent
  • The consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
  • That the participant and/or his/her legal representative(s) or guardian(s) 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 Informed Consent topic, Compensation Disclosure and the Vulnerable Populations subtopics and the Specimens topic, Consent for Specimen subtopic for further information.

Additional Resources
No additional resources
Informed Consent > Compensation Disclosure
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: II and IV-V
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 4.4
(3) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(4) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: II, V, and Annex C
Summary

Overview

In accordance with ResolutionNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, the informed consent form (ICF) should contain a statement describing the compensation or medical treatment a participant can receive for participating in a clinical trial.

Compensation for Participation in Research

As specified in ResolutionNo466, the G-ClinResSubjectRts, and Additional Resource (A), compensation to participants is prohibited other than to provide transportation costs and meals to the participants and/or their legal representative(s) or guardian(s) during the trial.

Compensation for Injury

As per ResolutionNo466, the G-ClinResSubjectRts, the PANDRH-GCPs, and OMREC, the ICF should include a statement advising the participant that compensation and medical treatment is available in the event of any trial-related injuries. The G-ClinResSubjectRts and OMREC also specify that research participants who suffer trial-related injuries should be entitled to compensation regardless of provisions included or not included in the study protocol or consent form. OMREC further notes that an ICF shall not contain any stipulation that prevents a research participant from receiving compensation or implies that a participant waives his/her legal rights, including the right to seek damages for any injuries.

Additional Resources
ABRACRO
Informed Consent > Participant Rights
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: III-IV
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: Chapters 2 and 4
(3) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 9 and Annex C
(4) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(5) (Regulation) CNS Resolution No. 563 of November 10, 2017 (ResolutionNo563 – English, unofficial translation) (Portuguese) (November 10, 2017)
National Health Council, Ministry of Health
Relevant Sections: Articles 1, 3, and 4
Summary

Overview

In accordance with ResolutionNo466, the PANDRH-GCPs, and OMREC, Brazil’s ethical standards promote respect for all human beings and safeguard the rights of research participants, including the right of 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 Informed Consent topic, and the subtopics of Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired for additional information regarding requirements for participant rights.)

The Right to Participate, Abstain, or Withdraw

As set forth in the ResolutionNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, the participant, or his/her legal representative(s) or guardian(s), should be informed that participation is voluntary, that he/she 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 ResolutionNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, a potential research participant, and/or his/her legal representative(s) or guardian(s), 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 ResolutionNo466, 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, and/or his/her legal representative(s) or guardian(s), 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 his/her rights.

The Right to Safety and Welfare

ResolutionNo466 and PANDRH-GCPs clearly state that a research participant’s right to safety and the protection of his/her health and welfare must take precedence over the interests of science and society.

In addition, per ResolutionNo563, 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 National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) registration.

Additional Resources
(A) (Website) Document Guides Clinical Trial Participants (Portuguese) (Last Updated March 20, 2017)
ANVISA, Ministry of Health
ABRACRO
Informed Consent > Special Circumstances/Emergencies
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 4.3.19
(2) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 9
(3) (Regulation) CNS Resolution No. 251 of August 7, 1997 (ResolutionNo251 – Portuguese) (August 7, 1997)
National Health Council, Ministry of Health
Relevant Sections: V
Summary

Overview

The PANDRH-GCPs makes provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by special circumstances, including medical emergencies.

Medical Emergencies

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 his/her legal representative(s) or guardian(s) should be obtained. If the prior consent of the participant or his/her legal representative(s) or guardian(s) cannot be obtained, the ethics committee (EC) (known as the 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 his/her legal representative(s) or guardian(s) should provide consent as soon as possible. OMREC and ResolutionNo251 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 of his/her participation in the study.

Additional Resources
No additional resources
Informed Consent > Vulnerable Populations
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 3.1-3.2, and Chapter 9
(2) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(3) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: II-III(2), and IV (6(a))
(4) (Regulation) CNS Resolution No. 304 of August 9, 2000 (ResolutionNo304) (Portuguese) (August 9, 2000)
National Health Council, Minister of Health
Relevant Sections: III and V
Summary

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, ResolutionNo466, 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 ResolutionNo466 and PANDRH-GCPs specify that ethics committees (ECs) (known as 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. ResolutionNo466 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.

Indigenous Peoples

As delineated in ResolutionNo304, 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 ResolutionNo304 for detailed information on research and protection requirements when conducting a study with this population.

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

Additional Resources
No additional resources
Informed Consent > Children/Minors
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 4.3
(2) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: II and IV
(3) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: 9
(4) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
Summary

Overview

The applicable regulatory requirements do not specify the age of minors.

As per PANDRH-GCPs, ResolutionNo466, and OMREC, when the research participant is a child, the child’s legal representative(s) and/or guardian(s) must sign the informed consent form. However, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand.

As stated in the G-ClinResSubjectRts, children should only participate in clinical studies when their participation is necessary to promote the health of the population represented.

ResolutionNo466 also indicates that an assent form should be used to obtain informed consent from children. The form should be prepared in a language that is accessible to minors or those legally incapable of giving their own consent. After the form is explained and the research study is clarified, the child participants shall provide their consent to participate in the study, without the influence of their legal representative(s) or guardian(s).

Additional Resources
No additional resources
Informed Consent > Pregnant Women, Fetuses & Neonates
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: III
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: Annex 3
(3) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
Summary

Overview

As per ResolutionNo466, the PANDRH-GCPs, and the G-ClinResSubjectRts, any Brazilian clinical studies involving women of childbearing age or who are pregnant, require additional safeguards to ensure that the participants are fully aware of the risks and that the research assesses the risks and benefits as well as any potential impact on fertility, pregnancy, the embryo or fetus, labor, lactation, and the newborn. ResolutionNo466 further states that research on pregnant women should be preceded by research on women outside the gestational period, except when pregnancy is the fundamental purpose of the study. The investigator(s) should also ensure that female participants have the right to participate in the research without the use of compulsory contraceptives—if they have expressly indicated that they are free from the risk of pregnancy and sexual practices, or they are sexually active in a non-reproductive way.

Additional Resources
No additional resources
Informed Consent > Prisoners
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: Chapter 9
(2) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: IV
Summary

Overview

According to the PANDRH-GCPs, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. ResolutionNo466 also states that freedom of consent must be guaranteed to those research participants who are fully competent, but are exposed to specific constraints or have restricted autonomy. These participants must have the freedom to decide whether or not to participate without any fear of reprisal.

Additional Resources
No additional resources
Informed Consent > Mentally Impaired
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: IV
(2) (Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(3) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 4.3
Summary

Overview

According to ResolutionNo466 and the G-ClinResSubjectRts, the ethics committee (known as a Comitê de Ética em Pesquisa (CEP)) must approve the participation of research participants who are mentally or physically incapable of giving consent, and sufficient justification must be provided for involving this population in a study. As delineated in the PANDRH-GCPs, consent should only be provided once the participant is informed about the study, to the extent that he/she is able to understand it, and if able, should sign and date the written informed consent in person. The participant’s legal representative(s) or guardian(s) must also be present during the informed consent process and sign and date the informed consent form.

Additional Resources
No additional resources
Investigational Products > Definition of Investigational Product
Last content review/update: June 21, 2019
Requirements
(1) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: Chapter 9
(2) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Article 6
(3) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Biological Products (G-BioIProdManual - Portuguese) (2nd Edition) (Version 1.2) (2017)
ANVISA, Ministry of Health
Relevant Sections: 9
(4) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Synthetic and Semisynthetic Medicines (G-SyntheticDrugProdManual - Portuguese) (2nd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 9
Summary

Overview

As delineated in the PANDRH-GCPs, an investigational product (IP) is defined as a dosage form of an active ingredient or placebo that is being tested or used as a reference in a clinical trial. ResolutionNo9, the G-BioIProdManual and the G-SyntheticDrugProdManual add that the IP may also be referred to as an experimental drug, comparator, or any other product to be used in a trial. According to Additional Resource (A), the definition of an IP in ResolutionNo9 differs from that of the PANDRH-GCPs because when ResolutionNo9 was adopted, an IP was mainly thought of in relation to the imports required to carry out each clinical trial. For this reason, the definition of "product under investigation" encompasses all products to be used in a trial, including medicine comparators, equipment, and laboratory kits. In addition, the PANDRH-GCPs definition further states that an IP may include a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form, or when it is used to gain further information about an approved use. Note: The terms experimental drug and IP are used interchangeably throughout the profile.

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.10
Investigational Products > Manufacturing & Import
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 6 and 34-36, and Chapter IX
(2) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 7
(3) (Regulation) Resolution of the Board of Directors – RDC No. 81 of November 5, 2008 (ResolutionNo81 – Portuguese) (Effective Date: November 5, 2008)
ANVISA, Ministry of Health
Relevant Sections: Chapters I (1.9), II (1.2), III (Sections I-IV), XXII, XXVI (Sections I and V), XXVII, and XXXI
(4) (Regulation) Resolution of the Board of Directors – RDC No. 208 of January 5, 2018 (ResolutionNo208 – Portuguese) (Effective Date: January 8, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 3-4, and 16
(5) (Regulation) Resolution of the Board of Directors – RDC No. 172 of September 8, 2017 (ResolutionNo172 – English, unofficial translation) (Portuguese) (Effective Date: October 12, 2017)
ANVISA, Ministry of Health
Relevant Sections: Chapters I, II (Sections II and III), and IV, and Annex I
(6) (7)(Legislation) Law No. 10.742 of October 6, 2003 (LawNo10.742 – Portuguese) (Effective Date: October 6, 2003)
Presidency of the Federative Republic of Brazil, House Civil Cabinet Subcommittee for Legal Affairs
Relevant Sections: Article 24
(7) (Legislation) Law No. 6.360 of September 23, 1976 (LawNo6.360 Portuguese) (Effective Date: December 27, 1976)
Presidency of the Federative Republic of Brazil, House Civil Cabinet Subcommittee for Legal Affairs
Relevant Sections: Article 24
(8) (Regulation) Resolution of the Board of Directors – RDC No. 102 of August 24, 2016 (ResolutionNo102 – English, unofficial translation) (Portuguese) (Effective Date: December 22, 2016)
ANVISA, Ministry of Health
Relevant Sections: Article 1, Chapters II, III (Section III), and V, and Annex I
Summary

Overview

As stated in ResolutionNo9, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the manufacture of investigational products (IPs) in Brazil. ANVISA approves the manufacture of an IP as part of its review and approval of the clinical trial application.

Per ResolutionNo9 and the G-DDCM Manual, ANVISA is also responsible for authorizing the import of IPs. The sponsor may request approval to import/export IPs for study purposes at the same time that he/she submits a clinical trial application (referred to as a Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) to ANVISA as indicated in ResolutionNo9. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while his/her DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation (Documento para Importação de Produto(s) sob Investigação) in the case of non-manifestation of the DDCM. The sponsor is required to present one (1) of these ANVISA documents at the location where IPs for import/export are unloaded. (See Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics for detailed application requirements).

ResolutionNo81, ResolutionNo208 (amending ResolutionNo81), and ResolutionNo172 delineate the procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. The process involves manually or electronically submitting ANVISA’s Petition for Inspection and Sanitary Release of Imported Goods (see Additional Resource (A)) to the Integrated Foreign Trade System (SISCOMEX). ResolutionNo81 explains that the following documentation must be included with the petition:

  • Copy of CE (Note: per ResolutionNo9, other ANVISA authorizations may need to be included as well—i.e., CEE and Document for Importation of Product(s) under Investigation)
  • Shipment document (Includes shipment date, proof of IP deposit to the importer, and carrrier/transportation type: Airborne Cargo - Air Waybill (AWB), Aquatic Cargo - Bill Landing (BL), and Land Cargo – Knowledge of International Transport by Highway (CTR)
  • Access inspection authorization
  • Commercial invoice
  • Finished product analysis certificate or copy of IP purchase invoice, specifying all lots; and statement signed by technical manager containing number of lots, IP active ingredient name and trade name if IP is produced by a manufacturer other than the importer/clinical study sponsor

See ResolutionNo81 for detailed documentation requirements.

Per ResolutionNo172, ANVISA will analyze and release imported goods and products intended for use in human subject research within 48 hours after arrival in Brazil, provided that the legal requirements are met and that the purpose of the research is not to register or change the registration of a product. Also specified in ResolutionNo81, ResolutionNo208, and ResolutionNo172 is the requirement that the researcher and institution submit the imported products through one (1) of the following methods: express shipping, international air shipping, or the Simplified Import Declaration (Declaração de Importação Simplificada (DSI)). While each import option has different documentation requirements, they all require a Petition for Inspection and Sanitary Release of Imported Goods, commercial invoice, signed statement of responsibility (see ResolutionNo81 (Chapter XXVII) and ResolutionNo172 (Annex I)), institutional ethics committee approval, and where applicable National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) approval. Refer to ResolutionNo81 for additional required items depending on the import method used. With the DSI, the Brazilian Federal Revenue offers a simplified import procedure. Generally, the DSI is used for samples with no commercial value. See also Additional Resource (B) for more information on submitting documentation through the DSI.

Per ResolutionNo172, researchers accredited by the Brazilian Council for Scientific and Technological Development (CNPq) and whose tax regime is exempt, will be automatically granted an import license via SISCOMEX for imported goods and products intended for use in human subject research.

The import requirements described in the previous paragraphs do not apply to research involving human beings whose purpose is to register or change the registration of the product under research. ResolutionNo172 specifies that imports intended for clinical trials whose objective is registration or alteration of product registration will be analyzed within five (5) days after protocol approval and compliance with legal requirements.

Other requirements delineated in ResolutionNo81 and ResolutionNo172 include, but are not limited to, a prohibition on imports with accompanied and unaccompanied baggage; compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; and a mandate that once research is completed, the researcher or institution authorize final destination of the materials in accordance with the legal provisions of environmental control.

LawNo10.742 (amending LawNo6.360) also notes that new drugs, intended exclusively for experimental use and under medical supervision, may be imported with the express authorization of the Ministry of Health (MOH) and are exempted from registration. This exemption will only be valid for up to three (3) years. Following this period, the product must be registered or be subject to a penalty of seizure to be determined by the MOH.

In addition, per ResolutionNo102, in the case of a company requesting a global transfer of ownership for product registration or the updating of company operation and certification data as a result of corporate transactions or business operations, the CE, CEE, or Document for Importation of Product(s) under Investigation will be issued in the name of the new company. Company registration updates should include any changes to the company operating authorization, Good Manufacturing Practices Certificate (CBPF), or Good Distribution and Storage Practices Certificate (CBPDA). Please refer to ResolutionNo102 for detailed instructions on submitting appropriate documentation for these updates.

Additional Resources
ANVISA, Ministry of Health
(B) (Website) Simplified Import Declaration (DSI) (Portuguese) (Last Updated June 18, 2015)
Internal Revenue Service, Ministry of Finance
Ribeiro, Anderson and Calabria, Lucas Fenili; Kasznar Leonardos
ANVISA, Ministry of Health
(E) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.4
Investigational Products > IMP/IND Quality Requirements
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 14, 38, and 72
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 6.6.3, 6.12.2, 6.13-6.14, and Annex 5 (1)
(3) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 6.2-6.3
(4) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Biological Products (G-BioIProdManual - Portuguese) (2nd Edition) (Version 1.2) (2017)
ANVISA, Ministry of Health
Relevant Sections: 2 and 5.2
(5) (Regulation) Resolution of the Board of Directors - RDC No. 17 of April 16, 2010 (ResolutionNo17 - Portuguese) (April 16, 2010)
ANVISA, Ministry of Health
Relevant Sections: Chapter II
(6) (Regulation) Resolution of the Board of Directors – RDC No. 205 of December 28, 2017 (ResolutionNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 1 and 12-13
(7) (Regulation) Resolution of the Board of Directors – RDC No. 39 of August 14, 2013 (ResolutionNo39 - Portuguese) (August 14, 2013)
ANVISA, Ministry of Health
Relevant Sections: Chapters I-II, III (Section I), and V
Summary

Overview

In accordance with ResolutionNo9, the PANDRH-GCPs, and the G-DDCM Manual, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB) as part of the clinical trial application submission (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). The IB must contain all of the relevant information on the investigational product(s) (IPs) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor should also update the IB as significant new information becomes available.

The G-DDCM Manual, the G-BiolProdManual, and Additional Resource (A) further explain that the sponsor must include manufacturing process information in the Experimental Drug Dossier as part of the DDCM submission as described in ResolutionNo9. Please refer to ResolutionNo9, the G-DDCM Manual, and the G-BiolProdManual for additional experimental drug dossier requirements. Note: The terms experimental drug and IP are used interchangeably throughout the profile.

IB Content Requirements

ResolutionNo9 and the G-DDCM Manual state that the IB must provide coverage for the following areas:

  • Experimental drug
  • Formulation
  • Pharmacological and toxicological effects of the experimental drug in animals and in humans, where applicable
  • Information on safety and efficacy in humans obtained from clinical trials that have already been carried out
  • Possible risks and adverse events related to experimental medications, based on past experience, as well as precautions or special procedures to be followed during development

The sponsor is also accountable for supplying the IP, including the comparator(s) and placebo, if applicable. As specified in ResolutionNo9 and the PANDRH-GCPs, he/she must ensure that the products are manufactured in accordance with the Good Manufacturing Practices (GMPs) as laid down in ResolutionNo17. In addition, per ResolutionNo205, the DDCM submitted to National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to conduct a clinical trial using IPs for rare diseases should also be accompanied by a request for GMPs certification. See ResolutionNo205 for detailed submission information. ResolutionNo39 may also be referred to for instructions on how to obtain ANVISA certifications for GMPs and Good Distribution and/or Storage Practices.

(See Investigational Products topic, Product Management subtopic for additional information on IP supply, storage, and handling requirements)

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1 and 3.3
ANVISA, Ministry of Health
ANVISA, Ministry of Health
Investigational Products > Labeling & Packaging
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 6, 14, 38, and 75
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: 6.13 and Annex 5 (1)
(3) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Biological Products (G-BioIProdManual - Portuguese) (2nd Edition) (Version 1.2) (2017)
ANVISA, Ministry of Health
Relevant Sections: 6.3 and 8
Summary

Overview

Investigational product (IP) labeling in Brazil must comply with the requirements set forth in ResolutionNo9, the PANDRH-GCPs, and the G-BiolProdManual. As described in the G-BiolProdManual, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:

  • Sponsor name
  • Pharmaceutical form, route of administration, quantity of dosage units, and the drug name and concentration in the case of open studies
  • Batch or product identification code
  • Clinical trial reference code
  • Clinical trial participant identification code
  • Instructions for use (reference may be made to an explanatory pamphlet or other document that guides the trial participants or person administering the IP
  • Storage conditions
  • Expiration date
  • Warning phrases in capital letters such as: “EXCLUSIVE USE IN CLINICAL TRIALS” and “KEEP OUT OF REACH OF CHILDREN”

In addition, per the G-BiolProdManual, all of the text labeling must be written in Portuguese. Symbols, pictograms, and warnings may also be included on both the primary and outer packaging. The G-BiolProdManual further notes it is not necessary to include the primary contact’s address and telephone number on the label to obtain IP or clinical trial information, or to break the blinding code. The trial participant receives a leaflet or card containing contact information in the case of trial-related concerns or adverse events. If the expiration date changes, additional labeling may be superimposed on the previous label to update the shelf life so that the new information does not conflict with the original batch number. The G-BiolProdManual mentions that the labeling of the other study IPs should also follow the same model as the experimental product, and when any field(s) is not applicable, justification should be provided.

The PANDRH-GCPs further indicates that the IP should be coded and labeled in a manner that protects the blinding, if applicable, and be suitably packaged to prevent contamination and unacceptable deterioration during transport and storage. Additional Resource (A) adds that while a label template is requested for each clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) submission, if the label template differs between studies in a multicenter clinical trial, a note should be included in the DDCM to explain that separate templates will be provided for the specific dossiers.

As described in ResolutionNo9, the following external packaging information must also be provided with the IP to be imported into Brazil:

  • Special Notice (CE), Specific Special Notice (CEE), or Document for Importation of Product(s) under Investigation
  • IP quantity
  • Special storage precautions (e.g., temperature, humidity, and brightness)
  • IP physical/pharmaceutical form
  • Period of validity of the IP, and
  • Batch number or serial number

The following IP packaging requirements are also delineated in the G-BiolProdManual:

  • Provide technical specifications for primary, and where applicable, outer packaging
  • Include an assessment of possible interaction between the active substance and primary packaging, if applicable
  • Describe how the tamper resistance of the packaging will be guaranteed until the time of IP use
Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.3.2
Investigational Products > Product Management
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors - RDC No. 9 of February 20, 2015 (ResolutionNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
Relevant Sections: Articles 14-17, and 38
(2) (Guidance) Good Clinical Practices – Document of the Americas (PANDRH-GCPs) (Portuguese) (March 2005)
IV Pan American Conference on Drug Regulatory Harmonization, Pan American Health Organization, Dominican Republic
Relevant Sections: Chapter 6.12.2, 6.13-6.14, and Annex 5 (1)
(3) (Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCM Manual – English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
Relevant Sections: 6.2-6.3
(4) (Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Biological Products (G-BioIProdManual - Portuguese) (2nd Edition) (Version 1.2) (2017)
ANVISA, Ministry of Health
Relevant Sections: 2 and 5.2
(5) (Regulation) Resolution of the Board of Directors – RDC No. 17 of April 16, 2010 (ResolutionNo17 - Portuguese) (April 16, 2010)
ANVISA, Ministry of Health
Relevant Sections: Chapter II
(6) (Regulation) Resolution of the Board of Directors – RDC No. 39 of August 14, 2013 (ResolutionNo39 - Portuguese) (August 14, 2013)
ANVISA, Ministry of Health
Relevant Sections: Chapters I-II, III (Section I), and V
Summary

Overview

In accordance with ResolutionNo9, the PANDRH-GCPs, and the G-DDCM Manual, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB), which must be included as part of the clinical trial application submission (referred to as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). The IB must contain all of the relevant information on the investigational product(s) (IPs) obtained through the earlier research phases, including preclinical, toxicological, safety, efficacy, and adverse events data. The sponsor should also update the IB as significant new information becomes available.

The G-DDCM Manual, the G-BiolProdManual, and Additional Resource (A) further explain that the sponsor must include manufacturing process information in the Experimental Drug Dossier as part of the DDCM submission as described in ResolutionNo9. Please refer to ResolutionNo9, the G-DDCM Manual, and the G-BiolProdManual for additional experimental drug dossier requirements.

Investigational Product Supply, Storage, and Handling Requirements

As delineated in ResolutionNo9 and the PANDRH-GCPs, the sponsor must also supply the investigator(s)/institution(s) with the IP(s), including the comparator(s) and placebo, if applicable. The sponsor is responsible for importing the necessary IP amount to conduct the study, but he/she should only distribute the IP to institutions that are listed in the approved DDCM as authorized by the ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)) and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while his/her DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation (Documento para Importação de Produto(s) sob Investigação) in the case of non-manifestation of the DDCM. The sponsor is required to present one (1) of these ANVISA documents at the location where IPs for import or export are unloaded. (See Clinical Trial Lifecycle topic, Submission Process and Submission Content subtopics for detailed application requirements).

Per ResolutionNo9 and the PANDRH-GCPs, the sponsor must ensure that the qualitative information and specifications include the following:

  • IP product quality and stability over the period of use
  • IP manufactured according to good manufacturing practices (GMPs) as per ResolutionNo9 and ResolutionNo17
  • Proper coding, packaging, and labeling of the IP(s)
  • IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP
  • Acceptable storage temperatures, conditions, and times for the IP
  • Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
  • Timely delivery of the IP(s)
  • Establishment of management and filing systems for the IPs

See ResolutionNo9 and PANDRH-GCPs for detailed sponsor-related IP requirements. ResolutionNo39 may also be referred to for instructions on how to obtain ANVISA certifications for GMPs and Good Distribution and/or Storage Practices.

Record Requirements

Per the PANDRH-GCPs, the sponsor is required to maintain records that document shipment, receipt, disposition, return, and destruction of the IPs. He/she must also maintain a system for retrieving IPs and documenting this retrieval, and maintain a system for the disposition of unused IPs. Finally, the sponsor should maintain sufficient samples from each batch and keep a record of their analyses and characteristics for reference so that, if necessary, an independent laboratory could reconfirm the same data. The sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related records are no longer needed.

As set forth in the PANDRH-GCPs, sponsor-specific essential documents should also be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development.

Additional Resources
(A) (Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
Relevant Sections: 3.1 and 3.3
ANVISA, Ministry of Health
ABRACRO
Specimens > Definition of Specimen
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Ordinance No. 2201 of September 14, 2011 (OrdinanceNo2201 - Portuguese) (September 14, 2011)
Ministry of Health
Relevant Sections: Article 3
(2) (Regulation) Resolution of the Board of Directors – RDC No. 20 of April 10, 2014 (ResolutionNo20 - Portuguese) (April 10, 2014)
ANVISA, Ministry of Health
Relevant Sections: Article 3
(3) (Regulation) CNS Resolution No. 441 of May 12, 2011 (ResolutionNo441 - Portuguese) (May 12, 2011)
National Health Council, Ministry of Health
Relevant Sections: Article 1 (1)
(4) (Guidance) Sanitary Surveillance Manual on the Transport of Human Biological Material for Clinical Diagnostic Purposes (G-BiolMatTransprt - Portuguese) (2015)
ANVISA, Ministry of Health
Relevant Sections: 2
(5) (5)(Regulation) Resolution of the Board of Directors – RDC No. 214 of February 7, 2018 (ResolutionNo214 - Portuguese) (Effective April 23, 2018)
ANVISA, Ministry of Health
Relevant Sections: Article 7
Summary

Overview

As per OrdinanceNo2201, ResolutionNo20, ResolutionNo441, and the G-BiolMatTransprt, a specimen is defined as any human biological material such as organs, tissues, cells, body fluids, excreta, and other fluids of human origin obtained from a single participant at a particular time. ResolutionNo214 adds that these biological samples are intended to be used for laboratory or quality control tests.

In addition, the G-BiolMatTransprt states that these materials are not considered hazardous if they are unlikely to cause disease in humans or animals. However, they are considered infectious substances, therefore dangerous materials, if through exposure to them, these substances are capable of spreading diseases.

Additional Resources
No additional resources
Specimens > Specimen Import & Export
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Resolution of the Board of Directors – RDC No. 81 of November 5, 2008 (ResolutionNo81 – Portuguese) (Effective Date: November 5, 2008)
ANVISA, Ministry of Health
Relevant Sections: Chapters I (1.9), II (1.2), III (Sections I-III), XXIII- XXVI (Sections IV and V), and XXVII
(2) (Regulation) Resolution of the Board of Directors – RDC No. 172 of September 8, 2017 (ResolutionNo172 – English, unofficial translation) (Portuguese) (Effective Date: October 12, 2017)
ANVISA, Ministry of Health
Relevant Sections: Article 1, Chapter II (Sections III and VI), Articles 20-21, 23, and Annex I
(3) (Regulation) Resolution of the Board of Directors – RDC No. 20 of April 10, 2014 (ResolutionNo20 - Portuguese) (April 10, 2014)
ANVISA, Ministry of Health
Relevant Sections: Chapter I (Sections II and III) and II-VI
(4) (Guidance) Sanitary Surveillance Manual on the Transport of Human Biological Material for Clinical Diagnostic Purposes (G-BiolMatTransprt - Portuguese) (2015)
ANVISA, Ministry of Health
Relevant Sections: 4-8
(5) (5)(Regulation) Resolution of the Board of Directors – RDC No. 214 of February 7, 2018 (ResolutionNo214 - Portuguese) (Effective April 23, 2018)
ANVISA, Ministry of Health
Relevant Sections: Articles 3, 6-7, and Chapter III (Section VIII)
Summary

Overview

ResolutionNo81 and ResolutionNo172 delineate the procedures associated with importing human biological materials for clinical research purposes. The process involves manually or electronically submitting National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s Petition for Inspection and Sanitary Release of Imported Goods (see Additional Resource (A)) to the Integrated Foreign Trade System (SISCOMEX). To obtain an import license through SISCOMEX’s non-automatic licensing procedure, ResolutionNo81 and ResolutionNo172 specify that the researcher and institution should submit the imported human biological materials through one (1) of the following methods: express shipping, international air shipping, or the Simplified Import Declaration (Declaração de Importação Simplificada (DSI)). ResolutionNo81 and ResolutionNo172 explain that the following documentation must be included with the petition form:

ResolutionNo172 further notes that an import license may be automatically granted via SISCOMEX to researchers accredited by the Brazilian Council for Scientific and Technological Development (CNPq) and whose tax regime is exempt.

ResolutionNo172 also states that ANVISA will analyze and release human biological samples intended for use in clinical research within 48 hours after arrival in Brazil, provided that the legal requirements are met. Refer to ResolutionNo81 and ResolutionNo172 for additional required items depending on the import method used. With the DSI, the Brazilian Federal Revenue offers a simplified import procedure. Generally, DSI is used for samples with no commercial value. See also Additional Resource (B) for more information on submitting documentation through the DSI.

Other requirements described in ResolutionNo81 and ResolutionNo172 include, but are not limited to, compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; a mandate that the researcher or institution give final destination to the materials in accordance with the legal provisions of environmental control; and, in ResolutionNo172, a prohibition on imports with accompanied and unaccompanied baggage.

As explained in ResolutionNo20 and the G-BiolMatTransprt, the procedures for the import and export of human biological material should be determined by the biological material type and the mode of transport. Regardless of the mode of transport or material type, transport operations are required to be recorded and standardized through regularly updated written instructions. All documents and records of activities relating to human biological material transport equipment should be readily available to the health authorities, upon request. The biological material must be packed in a form that will preserve its integrity and stability, and must be validated and approved by the supervisory technician.

According to ResolutionNo20, human biological material is classified as Category A or B infectious biological material, or Category Risk Minimum. Category A includes materials where exposure can cause permanent disability or fatal disease to humans and animals. Category B includes those materials not listed in Category A such as samples suspected or known to contain infectious agents causing diseases in humans. Category Risk Minimum or “exempt human specimens” include biological materials from healthy individuals. Human biological materials must also be classified according to the World Health Organization’s (WHO) risk classification diagram available in the WHO’s Guidance on Regulations for the Transport of Infectious Substances (Additional Resource (C)). Labeling should conform with the material type, risk classification, and specific requirements of the biological materials to be transported. The label for imported materials must be legible, understandable, and in English and Portuguese.

In addition to complying with ResolutionNo20 and the G-BiolMatTransprt, human biological material transport should be conducted in accordance with legislation from applicable regulatory bodies including the Ministry of Transport, the National Land Transportation Agency, the National Civil Aviation Agency, and the National Agency of Waterway Transportation. Refer to ResolutionNo20 and the G-BiolMatTransprt for detailed import and export transport requirements.

Refer to ResolutionNo20 and the G-BiolMatTransprt for detailed instructions on shipping biological materials within these categories. See also ResolutionNo214 for detailed transport requirements relating to human cells and advanced research therapy products.

Additional Resources
ANVISA, Ministry of Health
(B) (Website) Simplified Import Declaration (DSI) (Portuguese) (Last Updated June 18, 2015)
Internal Revenue Service, Ministry of Finance
Ribeiro, Anderson and Calabria, Lucas Fenili; Kasznar Leonardos
Specimens > Consent for Specimen
Last content review/update: June 21, 2019
Requirements
(1) (Regulation) Ordinance No. 2201 of September 14, 2011 (OrdinanceNo2201 - Portuguese) (September 14, 2011)
Ministry of Health
Relevant Sections: Chapter I (Article 3 (VI)), Chapter II, Chapter III, and Chapter IV (Articles 15, 17-18, and 24-25)
(2) (Regulation) CNS Resolution No. 441 of May 12, 2011 (ResolutionNo441 - Portuguese) (May 12, 2011)
National Health Council, Ministry of Health
Relevant Sections: Article 1 (2-10 and 15)
(3) (Regulation) CNS Resolution No. 466 of December 12, 2012 (ResolutionNo466 - Portuguese) (Effective Date: June 13, 2013)
National Health Council, Ministry of Health
Relevant Sections: Chapter III (3)
(4) (Regulation) CNS Resolution No. 340 of July 8, 2004 (ResolutionNo340) (Portuguese) (July 8, 2004)
National Health Council, Ministry of Health
Relevant Sections: Sections III, IV, and V
(5) (Guidance) Operating Manual for Research Ethics Committees (4th Edition revised and updated) (OMREC - Portuguese) (2008)
National Commission for Ethics in Research, National Health Council, Ministry of Health
Relevant Sections: Section 9 and Annex C
(6) (Guidance) Guidance Manual: Frequent Pending Issues in Clinical Research Protocols (Version 1.0) (G-ClinProtocols-FAQs) (Portuguese) (2015)
Brazilian National Board of Health (CNS) and Brazilian National Research Ethics Committee (CONEP)
Relevant Sections: Chart 1, 1.14, and 1.21-1.22
(7) (5)(Regulation) Resolution of the Board of Directors – RDC No. 214 of February 7, 2018 (ResolutionNo214 - Portuguese) (Effective April 23, 2018)
ANVISA, Ministry of Health
Relevant Sections: Article 109
Summary

Overview

In accordance with OrdinanceNo2201, ResolutionNo441, ResolutionNo466, and ResolutionNo340, prior to collecting, storing, or using a research participant’s human biological material, consent must be obtained from the participant or his/her legal representative in writing. Per OrdinanceNo2201, ResolutionNo340, OMREC, and Additional Resource (A), 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 delineated in OrdinanceNo2201, ResolutionNo441, and ResolutionNo340, investigator(s) must also obtain institutional ethics committee (EC) (known as Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Commission for Research Ethics (Comissão Nacional de Ética em Pesquisa (CONEP)) approval of a new research project involving human biological materials. Per ResolutionNo340, if it is not possible to obtain the participant’s consent, a formal justification shall be presented to the EC (CEP) for evaluation.

In addition, per ResolutionNo441 and ResolutionNo340, investigators should explain the possibility of the participant’s stored genetic materials being used in a new research project in the ICF. In this case, the participant will be contacted for further authorization or his/her waiver. If it is impossible to obtain either one (1) of these documents, this fact shall be justified to the EC (CEP). The investigator(s) is also required to explain to the participant that the material will only be used upon approval of a new project by the EC (CEP) and, when necessary, CONEP. OrdinanceNo2201 also states that when it is not possible to contact the research participant, the EC (CEP) must authorize use of the biological material stored in a biobank.

As described in ResolutionNo340, the G-ClinProtocols-FAQs, and Additional Resource (A), the ICF for genetic research projects must communicate the following information to the participant:

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

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

ResolutionNo441 and the G-ClinProtocols-FAQs, in turn, state that the ICF for the collection, deposit, storage, and use of human biological materials in biobanks must include the following:

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

As delineated in OrdinanceNo2201 and ResolutionNo441, the participant or his/her legal representative may withdraw consent at any time for care and use of biological material stored in a biorepository or biobank without any negative consequences. The G-ClinProtocols-FAQs further indicates that the participant or his/her legal representative may also withdraw consent specifically for genetic data stored in a storage bank without any negative impact. The withdrawal is valid from the date that the decision is communicated. The withdrawal must also be formalized in a document signed by the participant or his/her legal representative. In addition, the transfer of human biological material to be stored at a biorepository or a biobank, or another institution, must be communicated to the participant. If it is not possible to communicate with the participant or his/her legal representatives, a justification must be submitted to the CEP/CONEP System, per ResolutionNo441.

Please refer to OrdinanceNo2201, ResolutionNo441, and the G-ClinProtocols-FAQs, for detailed requirements and issues associated with storing human biological materials in a biorepository or a biobank. See also ResolutionNo214 for informed consent requirements pertaining to human cell collection and other procedures conducted by cell processing centers.

(See the Informed Consent topic, Required Elements and Participant Rights subtopics for additional information on informed consent).

Additional Resources
National Health Council, National Commission on Ethics in Research, Ministry of Health
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