Clinical Research Regulation For 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
Consent for Specimen
Sources
Requirements
Additional Resources
Forms
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: May 12, 2022
Summary

National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))

As per ResNo9, ResNo61, and ResNo176, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspection of drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of ResNo9, ResNo61, and ResNo176.

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 ResNo61 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 ResNo61, ANVISA is headed by a Collegiate Board of Directors composed of up to five (5) members, one (1) of whom serves as the Chief Executive Officer. Among the Collegiate Board’s key responsibilities are its role in defining ANVISA’s strategic guidelines and proposing governmental policies and directives to the Minister in support of the agency’s sanitary surveillance objectives.

LawNo9.782 and ResNo61 further indicate that ANVISA has an Advisory Board and an Ombudsman. Per ResNo61 and BRA-36, the Advisory Board’s main objectives include requesting information and proposing guidelines and technical recommendations to the Collegiate Board to be addressed by ANVISA, and providing opinions on proposed governmental policies. The Ombudsman’s activities, as described in ResNo61, 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, ResNo61, BRA-36, and BRA-35 for detailed Collegiate Board, Advisory Board, and Ombudsman responsibilities.

As delineated in ResNo61, 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 ResNo61 and ResNo176, 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 ResNo61 and ResNo176 for detailed information on ANVISA’s organizational structure and administrative units.

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

Contact Information

Per BRA-35 and BRA-42, the following is ANVISA’s contact information:

ANVISA
Setor de Indústria e Abastecimento (SIA)
Trecho 5
Area Especial 57
CEP: 71205-050
Brasília (DF)

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

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

For medicines and biological products information:

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

For clinical research information:

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

Articles 3-4, 8-10, and 15
Articles 1-2, 4, and Annex III amending ResNo61
Chapter I (Articles 1 and 2)
Articles 1-3, 4-6, 60-61, 63, 88, 91, 97, 103, 208, and Annex III
Regulatory Authority > Scope of Assessment
Last content review/update: August 16, 2022
Summary

Overview

As delineated in ResNo9, ResNo61, and ResNo176, 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 ResNo9, the G-DDCMManual, and BRA-8, the clinical trial application (known as a Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the DDCM to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. Per ResNo9 and BRA-8, while the DDCM may be submitted at any stage of development, Phase IV post-marketing trials are only subject to Clinical Trial Notification by ANVISA after obtaining ethical approvals. See ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products in Brazil (i.e., medicines for human use that are based on genes, tissues, or cells).

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

Clinical Trial Review Process

As delineated in ResNo61 and ResNo176, 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). ResNo9 and the G-DDCMManual explain that following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all the trials included in the DDCM that are permitted to initiate the clinical study. BRA-8 further explains COPEC experts conduct a preliminary review that includes a benefit-risk assessment based on various criteria 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 expiration deadline date so that the sponsor (applicant) may proceed with conducting the trial, requesting a meeting, or conducting a more detailed and complete dossier evaluation. See the Timeline of Review section for additional ANVISA timeline information. Also, see BRA-79 for additional information on ANVISA’s clinical trial review and approval framework, and BRA-40 for information on ANVISA drug registration requirements.

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

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

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

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

See BRA-98 for a list of COPEC documents, regulations, and clinical research guidelines available on the ANVISA portal and their corresponding locations, and BRA-60 for COPEC’s 2020-2021 annual report.

Priority Submissions

In addition to the previously stated DDCM requirements, ResNo204 establishes a priority category to register, amend previously registered, or request prior approval for drug submissions. ResNo204 states that the priority submission may be submitted as a DDCM or as a Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)). A priority DDCM submission is required to meet one (1) or more of the following criteria: new drug trial in any phase to be carried out in Brazil, the drug is part of the Ministry of Health (MOH)’s National Immunization Program, or the product is determined to be of strategic public health interest and included under the MOH’s Unified Health System (SUS) (BRA-53). A priority DEEC submission is required to comply with the following: the drug is to be used for neglected, emerging or reemerging diseases, health emergencies, or serious debilitating conditions for which there is no alternative; the trial is to be conducted exclusively with the pediatric population; or the drug will be used in a Phase I trial only to be manufactured in Brazil. The sponsor should specify at the time of submission that the new or amended protocol is a priority category request. If not confirmed prior to the technical review phase, the request for approval may be denied. ANVISA is required to 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 ResNo204 and BRA-14 for detailed information on priority submissions. See also BRA-2, BRA-1, and BRA-42 for additional information on priority submission.

New Drugs for Rare Diseases

ResNo205 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 ResNo205, a sponsor (applicant) must request a pre-submission meeting with ANVISA to present the application to register a new drug for a rare disease (the DDCM, the amended DDCM or secondary petition, or the 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. Refer to ResNo205 for additional submission documentation requirements. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.

See also BRA-19, BRA-89, and BRA-90 for guidance on scheduling pre-submission meetings with COPEC to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted.

Special Reviews During COVID-19 Public Health Emergency

During the COVID-19 public health emergency as described in OrdNo188, ANVISA issued ResNo573 to implement an urgent and temporary amendment to ResNo9. Although OrdNo913 declared an end to the public health emergency as of May 22, 2022, ResNo683 has extended the validity of ResNo573 to May 21, 2023. The ResNo573 amendment specifically affects ANVISA’s technical reviews 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 as delineated in ResNo9 (see Art. 36). Per ResNo573, ANVISA is required to evaluate this category of applications within 120 calendar days, counting from the date of linking the first DEEC to the DDCM. The 120-day review deadline only amends the original ResNo9 180-day deadline specified in ResNo9 for these types of studies.

Pursuant to ResNo573, in the event that ANVISA fails to respond within the 120-day deadline, the agency will issue a Document for Importation of Product(s) under Investigation for a DDCM that has one (1) or more studies approved by at least one (1) regulatory authority of an ICH founding or standing member country or by the UK’s MHRA. The DDCM must also be identical to the one (1) approved by the ICH member country or the UK. An official document issued by the regulatory authority or a declaration of compliance with the criteria described in this document must be presented to prove the authorization or non-objection to carry out the clinical trial by the ICH member country or the UK. In the case of a DDCM that falls within the previously stated provisions, clinical development may begin after the relevant ethical approvals. However, this rule does not apply to DDCMs of vaccines, whose clinical development can only be started after analysis and consent by ANVISA and the relevant ethical approvals.

ResNo573 delineates that the provisions of this regulation apply to DDCMs received by ANVISA and whose analysis was not initiated by the technical area. See Submission Process section for details on complying with ResNo573.

Sections VI-XI
Chapters I (Articles 1, 2, and 4), II (Article 7), and III-IV
Articles 1-2 and Annex III amending ResNo61
Articles 1, 3-6, and 10-13
Articles 5-11 and 22-23
Chapters I (Articles 1-3, and 6), III (Articles 33-38), IV (Article 43), and X (Article 78)
Articles 91, 103, and Annex III
Introduction
5.1, 7, and 9
1, 2.1, 3.1, and 3.4
Conducting a Clinical Trial in Brasil
Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
4.2
Introduction and Regulatory Framework
3.1, 3.5, and 3.10
1, 2, and Annexes 1-2
Regulatory Authority > Regulatory Fees
Last content review/update: May 12, 2022
Summary

As set forth in ResNo9, ResNo222, and ResNo76, the sponsor is responsible for paying a Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) to submit a clinical trial application (known as a Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). As per ResNo222 and ResNo76, once the sponsor has completed the process of submitting a DDCM request (“petition” in Portuguese), ANVISA’s Electronic Petition Request System (BRA-38) generates a Union Collection Guide (Guia de Recolhimento da União (GRU)). According to BRA-41 and BRA-43, ANVISA uses the GRU as its primary method to generate TFVS fees. Refer to BRA-51 for detailed information on the GRU and BRA-69 for information on the TFVS fee. See also BRA-10 and BRA-12 for additional information on TFVS requirements.

Per BRA-41, ANVISA determines the TFVS fee based on the company’s size and the subject code assigned to the application request. Per the TFVS fee table provided in BRA-11 that was implemented by OrdNo45 and ResNo198, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval.

Payment Instructions

In accordance with ResNo222 and ResNo76, ANVISA will only review the DDCM once the sponsor (also referred to as 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. BRA-43 specifies that ANVISA will accept the following documents as proof of payment from the sponsor:

  • Presentation of the original GRU receipt collected electronically, which must be accompanied by the original electronic banking network payment receipt
  • Presentation of the original GRU receipt collected from the banking network, which must contain the original receipt stamp for authentication
  • The transaction number issued by ANVISA’s Electronic Petition Request System (BRA-38)

As described in ResNo222, 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. BRA-43 adds that bank payments may be completed in person, or by using the bank’s website or self-service (ATM) terminals. In addition, per BRA-43, payment must be made within 30 days after the GRU has been issued. BRA-8 further notes that ANVISA charges a fee for substantial amendments to the clinical protocol. See BRA-67 for further guidance on how to complete the electronic petition request process for fee payments.

Articles 6 and 7
Articles 2, 9, 14, and 16
Chapter III (Article 38)
Articles 2, 9, and 14-16
Annex I (4.7)
3.2
1-4, and 10
2 and 6
Ethics Committee > Ethics Committee
Last content review/update: May 12, 2022
Summary

Overview

As per ResNo466, ResNo446, and OSNo001, Brazil has a centralized registration process for ethics committees (ECs) and requires institutional level EC approval for each trial site. The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs, known as Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) in Brazil, and for registering and accrediting the ECs (CEPs). ResNo466, ResNo446, and OSNo001 state that CONEP is a collegiate advisory body directly linked to the National Health Council (Conselho Nacional de Saúde (CNS)), a permanent body within the Unified Health System (SUS) (BRA-53). Per LawNo8.142 and ResNo453, 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 ResNo466, ResNo446, and OSNo001. ResNo466 further notes that institutions conducting research involving human participants may establish one (1) or more ECs (CEPs) according to their particular requirements. For those institutions lacking an EC (CEP), or in the case of 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 ResNo466, OSNo001, and G-ClinProtocols-FAQs. See also BRA-50, BRA-16, and BRA-49 for useful information on CONEP and the CNS.

Ethics Committee Composition

CONEP Composition

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

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 OMREC requires the EC (CEP) to be composed of a minimum of seven (7) members having proven expertise in research. The PANDRH-GCPs, the OSNo001, 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 OMREC further states 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). ResNo647 further establishes standards and mandatory requirements for all ECs (CEPs) in Brazil to include Research Participant Representatives (RPPs) who represent the interests of research participants. RPPs must be at least 18 years old; have a history of participation in a social and/or community movement in which the participation is not limited to health areas and can cover all segments of social movement activity; and must be able to express the viewpoints and interests of individuals and/or groups of research participants in order to represent the collective interests of different audiences in the CEP/CONEP System. See ResNo647 for detailed information on RPPs.

Additional criteria for EC (CEP) membership is available in Section 3.2 of the PANDRH-GCPs 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 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 ResNo370, 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. Also, see CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up REC accreditation and renewal processes and maintain regular functioning of RECs.

Article 1
Chapter I.4
Preamble, Articles 1 and 16
Definition of Health Council
Sections VI-X
Preamble, Chapters I-III, and Chapter VII
3.2-3.5
Introduction, 6, and Summary Chart: Frequent Pending Issues (Item 6)
Sections 2, 3, and 18
1, 2.1, 2.3, and 3
Chapter I
Ethics Committee > Scope of Review
Last content review/update: May 12, 2022
Summary

Overview

As set forth in ResNo466, the PANDRH-GCPs, ResNo251, and the G-ClinProtocols-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 Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), jointly known as the CEP/CONEP System, relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial.

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

The CEP/CONEP System is also responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol as stated in ResNo466, the PANDRH-GCPs, and OSNo001. It must act in the interests of the potential research participants and the communities involved, evaluating the possible risks and expected benefits to participants, confirming the suitability of the investigator(s), facilities, and methods, and verifying the adequacy of confidentiality and privacy safeguards. See ResNo466, the PANDRH-GCPs, and OSNo001 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) (BRA-53), per ResNo580. ResNo580 recognizes strategic research protocols as those studies that may contribute to public health, justice, reduction of social inequalities and technological dependencies, and those that address public health emergencies. Refer to Authorizing Body section for additional information on CONEP’s review requirements for this type of protocol. A working group was also created to support the MOH’s assessment of research involving human beings when carried out in the SUS sphere, per OrdNo552. The interagency working group includes National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), CONEP, and the National Health Council (Conselho Nacional de Saúde (CNS)), and is coordinated by an MOH representative.

See also ResNo506 for information on the CEP/CONEP System’s role in reviewing protocols submitted for clinical trials with advanced therapy products in Brazil (i.e., medicines for human use based on genes, tissues, or cells).

In addition to conducting international project reviews, per ResNo466, ResNo446, and ResNo340, CONEP is required to review certain studies involving human genetics, human reproduction, invasive therapeutic procedures, indigenous populations, genetically modified organisms, embryonic stem cells, and the establishment and operation of biobanks for research. ResNo466, ResNo446, and ResNo340 may be referenced for specific details on CONEP protocol review requirements and CLNo51 for CONEP specimens consent instructions.

Role in Clinical Trial Approval Process

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

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

ResNo466 and OSNo001 specify that the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur through Plataforma Brasil (BRA-34). Per BRA-93, Plataforma Brasil is a national and unified database of human subjects research records that represents the entire CEP/CONEP system. The platform is also used to track research applications from submission to final approval by the EC (CEP), and when necessary, by CONEP. See BRA-33 for the most current Plataforma Brazil CEP and researcher manuals. Also see the Timeline of Review section for additional EC timeline information.

There is no stated expiration date for an EC (CEP) approval in ResNo466, the PANDRH-GCPs, ResNo9, or OSNo001. However, in the event that an EC (CEP) revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator and ANVISA.

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

  • EC (CEP) member profiles (names and addresses)
  • Documented approval of EC (CEP)’s favorable opinion
  • Copy of EC (CEP) recommendations in case it has based its approval on change(s) in any aspect of the study (e.g., protocol modifications, written informed consent form, 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 the Submission Content section for additional details on the EC review process).

In addition, CONEP has published a number of circular letters to clarify submission instructions related to the following: classifying thematic areas in the protocols, protocol amendments, providing correct protocol timelines, updating the informed consent form (ICF), obtaining consent for human specimens, electronic processing for biobank development protocols and associated CEP/CONEP communication and documentation, adverse event processing for Brazil and abroad, institutional registration responsibilities, and citing international clinical trials registries in research protocols (See CLNo172, CLNo038, CLNo061, CLNo17, CLNo51, CLNo041, CLNo046, CLNo3, CLNo13, and CLNo060 for specific submission instructions). (See the Documentation Requirements and Consent for Specimen sections for additional CONEP ICF and specimens consent instructions).

Foreign Research

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

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

Multicenter Research

ResNo346 establishes the submission process for multicenter research protocols and indicates that the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. Per OSNo001, the principal investigator is also required to submit a list of the participating institutions and associated protocols, the coordinating center, and the EC (CEP) designated to monitor the study’s progress as part of the research protocol package sent to the EC (CEP) for review. ResNo346 further notes that CONEP will only evaluate the first protocol submitted and then send its final opinion to the original EC (CEP) and the other participating institutions. See ResNo346 for additional multicenter protocol processing information and OSNo01 for detailed information on the coordinating center’s role in this process.

Preamble, I, and VII-VIII
III-VI
IV and VI
II
Preamble and Articles 1 and 16
III and VII-X
Articles 1 and 11-12
I and III-V
Articles 1-2
Chapter I (Articles 1, 2, and 4), II (Articles 7 and 15), III (Article 26)
Article 9
Chapter III (Articles 35-36, and 38) and Chapter V (Articles 46-47)
Chapters 2 (2.3), 3 (3.1 and 3.3-3.4), 4 (4.3), 5 (5.5-5.6), 6 (6.10-6.11 and 6.23), and 9
Introduction, 6, and Summary Chart: Frequent Pending Issues (6)
5
1, 2.1, and 3
Regulatory Submission Process and Conducting a Clinical Trial in Brasil
Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
Ethics Committee > Ethics Committee Fees
Last content review/update: May 12, 2022
Summary

According to ResNo466 and OMREC, the National Research Ethics Commission (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.

Section VII
2.5
Ethics Committee > Authorizing Body
Last content review/update: May 12, 2022
Summary

Overview

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

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

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

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

Registration, Auditing, and Accreditation

As per ResNo466, ResNo370, SP006REC, OSNo001, and ResNo446, all ECs (CEPs) must be registered and accredited by CONEP. CONEP’s Executive Secretariat who performs a documentation review to ensure compliance with the requirements delineated in ResNo446 carries out accreditation. ResNo370 and CNSResNo506 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 ResNo370, SP006REC, and CNSResNo506. See ResNo370, SP006REC, and CNSResNo506 for additional details on CONEP’s accreditation process. See CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up EC (CEP) accreditation and renewal processes and maintain regular functioning of RECs.

High-Risk Research Protocols

In addition to being accredited by CONEP per the earlier stated requirements, CNSResNo506 explains that ECs (CEPs) may also be certified for their role in the ethical analysis of high-risk research protocols. CONEP plans to publish a risk classification standard that will provide the criteria to assess the risk level of research protocols. Per CNSResNo506, until the standard is published, CONEP has determined that protocols falling within the special thematic areas listed in section IX.4 of ResNo466 must be considered high risk. As earlier mentioned in this section and in the Scope of Review section, these areas include human genetics, human reproduction, indigenous populations, genetically modified organisms, and the establishment and operation of biobanks. Refer to ResNo466, ResNo446, and ResNo340 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. BRA-2 also provides helpful information on this process.

IV and VI
I and II
Preamble and Sections I, V, and VII
Sections VII, IX, and XIII
Chapters I, II, IV, and VI-VIII
2.3
2
Local Accreditation
Clinical Trial Lifecycle > Submission Process
Last content review/update: May 12, 2022
Summary

Overview

As stated in ResNo9, the G-DDCMManual, and BRA-8, 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 Clínico de Medicamento (DDCM))) for a drug to be registered in Brazil that will have all or part of its development in Brazil. Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from 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 Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. ResNo205 repealed the ResNo9 requirement that EC (CEP) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel.

Regulatory Submission

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

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

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA, as stated in ResNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial DDCM submission. If the modification has occurred following ANVISA’s issuance of the authorizing document known as a Special Notice (Comunicado Especial (CE)), per BRA-8, ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version. While the sponsor is required to submit all amendments to ANVISA, per ResNo9 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 BRA-13 for updated ANVISA application forms.

See BRA-8, BRA-6, and BRA-7 for requirements associated with submitting specific clinical trial dossiers for comparative bioavailability studies and comparative pharmacokinetic studies for biosimilars.

As described in the G-DDCMManual and BRA-8, all DDCM petitions (both initial and secondary) should be submitted electronically to ANVISA via the Electronic Petition Request System (BRA-38). Per BRA-58, once the DDCM has been submitted, the sponsor (applicant) is then required to electronically file all the documents corresponding to the initial DDCM petition’s subject code checklist. As explained in BRA-75, the sponsor (applicant) must electronically attach all the documents required in the related DDCM checklist (accessed online via BRA-38) that corresponds to one (1) of the following related subject codes: 10748, 10749, 10750, 10751, 10752, 10753, 10754, and 10755.

BRA-59 provides detailed instructions for submitting the DDCM checklist documents via BRA-38. The instructions emphasize that the sponsor (applicant) must first submit the DDCM petition request along with payment of the Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) fee. Once the fee is paid, a reference (transaction) number is generated that will be required for the subsequent submission of the associated checklist documents. BRA-59 states that the processing of this request can take up to two (2) days, which is the time given to the banking network to clear the payment. Refer to BRA-59 for additional instructions. See also BRA-67 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition Request Form.

Per the G-DDCMManual, all of the other documentation associated with the original DDCM including the secondary petitions and the DEEC(s) should be submitted electronically via BRA-38. ResNo204 and BRA-14 further note that DEECs may be submitted as priority requests to ANVISA to register, amend previously registered, or request prior consent for drug submissions. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections. The G-DDCMManual also specifies that for the electronic submission of secondary petitions and DEECs, the sponsor should append at least one (1) PDF file for each item contained in the petition checklist to enable text searching. It is possible to attach up to five (5) files of 750 kb each. BRA-8 also provides an example of an electronic submission in Annex 1.

In addition, BRA-92 provides detailed instructions for companies to comply with ANVISA’s requirement to submit an official document issued by an International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) member country regulatory authority or by the United Kingdom’s (UK’s) Medicines and Healthcare Products Regulatory Agency (MHRA), or a declaration of compliance with the criteria described in ResNo573. (Refer to the Scope of Assessment section for detailed information on ResNo573 requirements). Per BRA-92, if the company has already submitted a DDCM, the official document or declaration may be submitted as an attachment via email with the corresponding DDCM file number to: Pesquisaclinica@anvisa.gov.br, using the following subject line: RDC 573/2021 - Amendment - File XXXXXXX/XX-X. This will ensure that the request is reviewed in the shortest time possible. However, this additional submission is unnecessary for those cases in which the official document or declaration has already been attached to the DDCM by subject code 11634 - CLINICAL TRIALS - Simplified Analysis of the Quality Dossier per ServBltnNo104. Refer to BRA-92 for additional information.

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

See also BRA-19, BRA-89, and BRA-90 for guidance on scheduling pre-submission meetings with ANVISA’s Office of Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted. Refer to BRA-98 for a list of COPEC documents, regulations and clinical research guidelines available on the ANVISA portal and their corresponding locations.

Ethics Review Submission

Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the PI must also obtain approval from his/her EC (CEP). The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional EC review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil CEP and researcher manuals. Please refer to Scope of Review and Authorizing Body sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval.

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

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

VI, VIII, IX-XI
Articles 1, 3-6, and 10-13
Articles 5-11 and 22-23
Chapters I (Articles 1-3, and 6), II (Article 8), III (Articles 32-39), IV-V, and X (Article 78)
2.3, 3.1, 3.3, 4.3, 5.5-5.6, 6.10-6.11, and 6.23
5 and 7-9
5-6, 10 (Annexes), and 11
2.1 and 3
Regulatory Submission Process and Conducting a Clinical Trial in Brasil
Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
3.1-3.2, 4, and 7.1 (Annex 1)
1, 2, and Annexes 1-2
Annexes I and II
Clinical Trial Lifecycle > Submission Content
Last content review/update: May 12, 2022
Summary

Regulatory Authority Requirements

As delineated in ResNo9 and the G-DDCMManual, to complete the clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), the sponsor, the designated contract research organization (CRO), or the sponsor-investigator is required to submit ANVISA’s DDCM Petition Request Form (BRA-21) along with the following documentation (Note: The regulatory sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

  • Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResNo222 and ResNo76 (tax payment imposed on individuals and companies engaged in clinical research)
  • Drug development plan (known as experimental drug dossier (See the G-BioIProdManual for instructions on completing a biological products dossier and the G-SynthDrugProdManual for completing a synthetic/semi-synthetic products dossier)
  • Certified copy of the clinical agreement (contract or statement) that has been written, dated, and signed by the sponsor or his/her CRO
  • Clinical research protocol
  • Investigator’s Brochure (IB)
  • Summary of the investigational product (IP)’s safety aspects based on previous research in humans
  • Information on any discontinued development or withdrawal of IP
  • IP dossier
  • Specific dossier for each clinical trial to be conducted in Brazil
  • Proof of clinical trial registration in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE) (Note: the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.) Per ResNo449, which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25). Note that per ResNo205, the ResNo9 requirement to include the institutional ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP)) approval in the initial DDCM or in any protocol amendment submission has been revoked.

Substantial Protocol Modifications

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

While the sponsor is required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, 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 ResNo9 and the G-DDCMManual for detailed ANVISA application submission requirements, BRA-22 for the clinical trial submission form, and BRA-13 for updated ANVISA application forms. See also BRA-95 for instructions on providing expiration date information for imported IPs to be used during the trial and which the applicant must include in its submission in BRA-22.

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

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

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

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

Ethics Committee Requirements

As per OMREC and OSNo001, the CONEP requires applicants to submit the following documentation online via BRA-34 (Note: The regulatory sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each source.):

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

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

Clinical Protocol

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

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

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

Articles 5-11
Article 1
Articles 9, 14, and 16
Chapters I (Articles 1-2 and 6), III (Articles 33-38), and IV (Article 43)
Articles 9, 14, and 16
Chapters 2 (2.3), 3 (3.1 and 3.3), 4 (4.3), 5 (5.5-5.6), 6 (6.10-6.11, and 6.23), and 8
5-6
5-6, 10 (Annexes), and 11
9.1 and Annex C
2.1 and 3
2
2
3.1-3.2
Annexes I and II
Clinical Trial Lifecycle > Timeline of Review
Last content review/update: August 16, 2022
Summary

Overview

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

Regulatory Authority Approval

As specified in ResNo9, upon receipt of the clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), ANVISA has 90 calendar days to evaluate the application. If the agency fails to issue a response within 90 days of receipt, clinical development can begin as long as all of the ethical approvals have been obtained.

During the COVID-19 public health emergency as described in OrdNo188, ANVISA issued ResNo573 to implement an urgent and temporary amendment to the original ResNo9 180-day review timeline for 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 as delineated in ResNo9. Although OrdNo913 declared an end to the public health emergency as of May 22, 2022, ResNo683 has extended the validity of ResNo573 to May 21, 2023. The ResNo573 amendment requires ANVISA to evaluate these application categories within 120 calendar days, counting from the date of linking the first Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínicos (DEEC)) to the DDCM.

Pursuant to ResNo573, in the event that ANVISA fails to respond within the 120-day deadline, the agency will issue a Document for Importation of Product(s) under Investigation for a DDCM that has one (1) or more studies approved by at least one (1) regulatory authority of an International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) founding or standing member country or by the United Kingdom’s (UK’s) Medicines and Healthcare Products Regulatory Agency (MHRA). The DDCM must also be identical to the one (1) approved by the ICH member country or the MHRA. An official document issued by the regulatory authority or a declaration of compliance with the criteria described in this document must be presented to prove the authorization or non-objection to carry out the clinical trial by the ICH member country or the MHRA. In the case of a DDCM that falls within the previously stated provisions, clinical development may begin after the relevant ethical approvals. However, this rule does not apply to DDCMs of vaccines, whose clinical development can only be started after analysis and consent by ANVISA and the relevant ethical approvals.

ResNo573 delineates that the provisions of this regulation apply to DDCMs received by ANVISA and whose analysis was not initiated by the technical area. See Submission Process section for details on complying with ResNo573.

According to BRA-60, DDCM petitions that require a longer review period (up to 120 days per ResNo573) are described as “exceptions” requiring technical analysis whereas the 90-day review period for typical petitions are referred to as “no exceptions” and do not require technical analysis. BRA-60 further notes that the deadline for analyzing initial DEEC petitions may be relatively longer when dealing with processes considered to be complex, such as with biological products, including the development of vaccines, which are also referred to as “exceptions.”

BRA-60 further states that the median deadline required by ANVISA to complete an analysis of a DDCM petition with technical requirements by the companies was 30 days, with 2 days being the shortest time observed and 197 days being the longest, in cases where there was more than one (1) technical requirement and times for meeting more than one (1) requirement added up. Refer to BRA-60 for detailed petition review timelines. Currently, companies have up to 120 days to respond to any type of agency-issued process and/or petition requirements. Typically, submissions with more complicated DDCM processes require companies to spend more time fulfilling ANVISA’s requirements.

Timeline information for ANVISA’s simplified analysis of DDCMs that meet the criteria for ServBltnNo104 is not available. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.)

Priority Submissions

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. See also BRA-40 for additional information on ANVISA drug registration requirements.

In addition, per ResNo204, 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 ResNo204 for detailed information on DEEC submissions. See also BRA-8 and BRA-14 for additional information on priority petitions.

See the Scope of Assessment section for further information on priority submissions.

New Drugs for Rare Diseases

ResNo205 sets forth specific approval procedures for clinical trials to be conducted to register new drugs to treat, diagnose or prevent rare diseases. 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 ResNo205, a sponsor (applicant) must request a pre-submission meeting with ANVISA to present the application to register a new drug for a rare disease (the DDCM, the amended DDCM or secondary petition, or the 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. Refer to ResNo205 for additional submission documentation requirements. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.

See also BRA-19, BRA-89, and BRA-90 for guidelines on scheduling a pre-submission meetings with ANVISA’s Office of Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted. Also, see BRA-98 for a list of COPEC documents, regulations and clinical research guidelines available on the ANVISA portal and their corresponding locations.

Ethics Committee Approval

As delineated in OSNo001 and BRA-91, the institutional EC (CEP) is required to issue an initial report in 30 days from the date the principal investigator (PI) submits an application for review. The CEP’s review of the protocol documentation for completeness should be accomplished within 10 days following submission. Per BRA-91, the review period must be counted from the date the project entered “Ethical Assessment” (i.e., after going through the validation of documents which takes around 10 days and when the Certificate of Presentation for Ethical Assessment (CAAE) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment.

ATTENTION: If these deadlines have expired, we suggest that the researcher responsible for the research project, contact the CEP to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation.

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

No timeline of review is currently available for CONEP’s review. (See the Submission Process section for additional submission requirements.)

Articles 1, 3-6, and 10-13
Articles 5-11
Chapters I (Articles 1-3, and 6), 3 (Articles 33-36, and 38), and X (Article 78)
2.1 and 3
Regulatory Submission Process and Conducting a Clinical Trial in Brasil
Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
2.1 and 4.2
Process of Processing Projects in the CEP
3.1 and 3.5
1, 2, and Annexes 1-2
Clinical Trial Lifecycle > Trial Initiation
Last content review/update: May 12, 2022
Summary

Overview

In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, a clinical trial can only commence after the sponsor, his/her designated contract research organization (CRO), or the sponsor-investigator receives clinical trial application (known as Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from 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 Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. Please refer to Scope of Review and Authorizing Body sections 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 ResNo9, 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 Manufacturing & Import section for additional information). As stated in the PANDRH-GCPs and ResNo9, all investigators must possess appropriate qualifications, training, and experience. The trials should be conducted in compliance with the PANDRH-GCPs, ResNo466, and ResNo9. Clinical trials must also be conducted in a laboratory complying with the Organisation for Economic Co-operation and Development (OECD)’s Good Laboratory Practices (GLP) (BRA-15) as mandated by Brazil’s National Institute of Metrology, Quality and Technology (INMETRO). Refer to BRA-15 and BRA-48 for additional information on GLP requirements.

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

Clinical Trial Agreement

As delineated in the PANDRH-GCPs, the sponsor or 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 ResNo9.

Clinical Trial Registration

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

VI and VIII-XI
Article 1
Chapter I (Articles 1-3, and 6) and Chapter III (Articles 33, 35-36, 38, and 40)
2.3, 3.1, 4.3, 5.1, 5.5-5.6, 6.2, and 6.10-6.11
5.1
2.1 and 3
Clinical Trial Lifecycle > Safety Reporting
Last content review/update: August 16, 2022
Summary

Safety Reporting Definitions

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

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

Safety Reporting Requirements

Investigator Responsibilities

As specified in ResNo9 and the AESafetyManual, the investigator must inform the sponsor within 24 hours of all SAEs/SADRs occurring during the study. The PANDRH-GCPs also states that the immediate reports should be followed promptly by detailed, written reports in which the participants are identified by unique code numbers. AEs/ADRs identified in the protocol as critical to safety evaluations should also be reported to the sponsor. Per the AESafetyManual, the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the 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

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

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

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

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

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

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

Ethics Committee Responsibilities

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

Per CLNo13, CEPs must present SAE notifications about a participant’s SAE index (initial SAE) and subsequent events in a single document, in tabular format, and submit it online to the CEP/CONEP System via Plataforma Brasil (BRA-34) using the “notification” function. This document must also be updated with each occurrence of a subsequent SAE. The document must contain the study identification research title and Certificate of Presentation of Ethical Appreciation (Certificado de Apresentação de Apreciação Ética) (CAAE)) number, name of the research center, name of the responsible researcher, coded identification of the participant and description of the index and subsequent events. Per BRA-70, the CAAE is the number generated by Plataforma Brasil (BRA-34) to identify the research project when it is received by CEP for ethical review.

Each SAE must be characterized according to the following:

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

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

Refer to CLNo13 for detailed instructions on submitting completed SAE reports to the CEP/CONEP System for review.

Form Completion & Delivery Requirements

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

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

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

Other Safety Reports

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

IX.4
Chapter V
Chapters I (Article 6), VI (Article 52), and VII
Chapters 5 (5.11), 6 (6.5 and 6.16-6.17), and 9
7
3.7
Introduction, VigiMed-Clinical Research, and Registration in VigiMed-Clinical Research
Clinical Trial Lifecycle > Progress Reporting
Last content review/update: May 12, 2022
Summary

Interim and Annual Progress Reports

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

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

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

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

Final Report

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

  • Trial title
  • Protocol code
  • Breakdown of the number of participants recruited or removed from the trial
  • Description of participants included in each statistical analysis and those who were excluded from the efficacy analysis
  • Participant demographics and statistics
  • Number/description of protocol deviations and violations
  • 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 ResNo9, or they may be submitted using the ICH E3 format (BRA-27). See BRA-23 for the annual/final report form.

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

Other Reporting Requirements

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

Articles 40, 68, and 69
5.10 and 5.13
3 and 5-7
3.6
Sponsorship > Definition of Sponsor
Last content review/update: May 12, 2022
Summary

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

ResNo9 states that a sponsor can authorize a contract research organization (CRO) to carry out certain work and obligations regarding the trial. As delineated in ResNo9, any trial-related responsibilities to be transferred and assumed by a CRO should be specified in a written agreement or contract. In addition, a CRO can only submit a clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

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

For the purposes of data protection requirements, LawNo13.709 delineates that the sponsor acts as the “controller” who is responsible for decisions regarding the processing of personal or sensitive personal research data. Within this context, the sponsor (controller) may carry out studies as a research body, guaranteeing, whenever possible, the anonymization of personal data. For more information on the sponsor’s role in data protection, see the Quality, Data & Records Management section.

Chapter I (Article 6) and Chapter VI (Articles 37 and 39)
II (11)
Articles 6, 20, and 27
Chapter 9
Sponsor and Contract Research Organizations
Sponsorship > Trial Authorization
Last content review/update: May 12, 2022
Summary

In accordance with ResNo9, the PANDRH-GCPs, the G-DDCMManual, and BRA-8, 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 ResNo9, the G-DDCMManual, and BRA-8, the clinical trial application (known as the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the DDCM to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents to be submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted, or as a process that modifies a previously submitted DDCM. 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 ResNo9, DDCM submissions to ANVISA can only be made by a CRO when the sponsor has no headquarters or subsidiary in Brazil.

As described in ResNo9 and the G-DDCMManual, to complete the DDCM, the sponsor, the designated CRO, or the sponsor-investigator is required to submit ANVISA’s DDCM Petition Request Form (see BRA-21) along with the following documentation:

  • Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResNo222 and ResNo76 (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 (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)) (BRA-45). Per ResNo449 which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25)

See the Submission Content section for detailed documentation submission requirements.

Substantial Protocol Modifications

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA electronically as stated in ResNo9 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 BRA-8, ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version. While the sponsor is required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, 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. See BRA-22 for the clinical trial submission form, BRA-13 for updated ANVISA application forms, BRA-1 for detailed documentation requirements, and BRA-42 for protocol filing requirements.

See BRA-19, BRA-89, and BRA-90 for guidance on scheduling pre-submission meetings with ANVISA’s Office of Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted. Refer to BRA-95 for instructions on providing expiration date information for imported IPs to be used during the trial and which the applicant must include in its submission in BRA-22. Also, see the Scope of Assessment section for information on submission requirements for new drugs for rare diseases.

Global Transfer of Ownership/Trial Responsibility

Per ResNo102, 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 CE, a Specific Special Notice (Comunicado Especial Específico (CEE)), or a Document for Importation of Product(s) under Investigation in the name of the new company responsible for the project. This transfer also includes projects under the responsibility of a CRO. Per ResNo9, 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.

ResNo102 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

Please refer to ResNo102 for detailed instructions on submitting appropriate documentation for these updates. See also the Submission Process section for detailed information on documentation to be submitted.

Per BRA-96, ANVISA has also modified the request process for the global transfer of responsibility of a clinical trial for medicines and biological products. The requests must be carried out electronically by the company that has requested the transfer via the Electronic Petition Request System (BRA-38) using the DDCM petition’s subject code 12130 for medicines and 11795 for advanced therapy products. See BRA-96 for additional information.

Per BRA-96, ANVISA has also modified the global transfer of responsibility request process for a clinical trial or assistance program for medicines and biological products. The requests must be carried out electronically by the company that has requested the transfer via the Electronic Petition Request System (BRA-38). using the DDCM petition’s subject code 12130 for medicines and 11795 for advanced therapy products. See BRA-96 for additional information.

Priority Submissions

In addition to the previously stated DDCM requirements, ResNo204 establishes a priority category to register, amend previously registered, or request prior consent for drug submissions. ResNo204 states that priority submission may be submitted as a DDCM or as a 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) (BRA-53). 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 Scope of Assessment and Timeline of Review sections for further information on these types of submissions.

New Drugs for Rare Diseases

ResNo205 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 ResNo205, a sponsor (applicant) must request a pre-submission meeting with ANVISA to present the application to register a new drug for a rare disease (the DDCM, the amended DDCM or secondary petition, or the 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. Refer to ResNo205 for additional submission documentation requirements. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.

See also BRA-19, BRA-89, and BRA-90 for guidelines on scheduling pre-submission meetings with COPEC to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to COPEC. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted.

Chapter I (Article 1), Chapters II-IV, and Annex I
Articles 1, 3-6, and 10-13
Articles 5-9
Article 1
Articles 9, 14, and 16
Chapters I (Articles 1-3, and 6), II (Article 8), III (Articles 32-35 and 37-39), IV, and X (Article 78)
Articles 9, 14, and 16
6.10
5-6, 10 (Annexes), and 11
7 and 11
Documentation Required
Priority Review, Rare Diseases, and ANVISA Review in Parallel with Ethics Process
3.1 and 3.2
1, 2, and Annexes 1-2
Annexes I and II
Sponsorship > Insurance
Last content review/update: May 12, 2022
Summary

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

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

6.8
Documentation Required
Financing the Clinical Trial and Supply of Products to the Research Participants
Sponsorship > Compensation
Last content review/update: May 12, 2022
Summary

Injury or Death

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

Trial Participation

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

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

According to ResNo563, for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) registration.

Furthermore, ResNo311, which amends ResNo38, states that the sponsor or his/her contract research organization (CRO) should guarantee access to the post-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (CNS)). The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Study Medicine Supply Programs (see Annex VI of ResNo38). See also BRA-17 and for additional information on post-study access to investigational products and BRA-79 for additional information on sponsor/CRO insurance coverage.

Sections II-V
Articles 1, 3, and 4
4, 10, 15, 18, and Annex VI
6.8
Financing the Clinical Trial and Supply of Products to the Research Participants
Sponsorship > Quality, Data & Records Management
Last content review/update: May 12, 2022
Summary

Quality Assurance/Quality Control

As stated in ResNo9 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(R2) (BRA-28), and other applicable requirements.

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

Data Protection

As set forth in C-AmndtNo115, the protection of personal data is a guaranteed fundamental right in Brazil. LawNo13.709 further delineates data protection principles (e.g., purpose, adequacy, necessity, free access, data quality, transparency, security, prevention, non-discrimination, and accountability) with which the sponsor (known as the “controller” in data protection legislation) must comply.

Per LawNo13.709, the data quality principle is fulfilled when the sponsor can guarantee to the data subjects that their personal data is processed with accuracy, clarity, and relevance, and is updated as required to meet the compliance requirements for the stated purpose. LawNo13.709 further explains that the sponsor must keep a record of the personal data processing operations he/she carries out, especially when the processing operation is for an official purpose. The sponsor must also provide instructions to the operator, the person responsible for processing the personal data on the sponsor (controller)’s behalf, to check compliance with the specified instructions and rules.

Pursuant to LawNo13.709, the sponsor may implement a privacy governance program that, at a minimum:

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

See LawNo13.709 and BRA-76 for detailed information on data protection requirements in Brazil.

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (CEPs) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment.

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.

Records Management

As set forth in ResNo9, 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. ResNo9 and the PANDRH-GCPs also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, a marketing application receives the last approval, or there are no pending or contemplated marketing applications. 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, ResNo9 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, per ResNo449, which amends ResNo9, ANVISA is allowed to use remote Good Clinical Practice (GCP) inspection mechanisms for temporary and emergency use in lieu of in-person inspections. Remote inspections are carried out by means of videoconferencing and data transmission technologies for GCP verification. Remote inspections replace the need for in-person inspectors in the establishment. Establishments under inspection may be inspected remotely at any time by ANVISA.

NormNo122 provides further guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with GCPs delineated in ResNo9, the PANDRH-GCPs, and the BRA-28. Per BRA-30, ANVISA’s administrative unit, the Coordination of Clinical Research on Medicines and Biological Products (COPEC), requires all clinical trial inspections to be conducted in accordance with the BRA-28.

In the event of a routine inspection, NormNo122 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 a GCP Inspection Notification Letter. For more detailed information on ANVISA’s inspection process, refer to NormNo122.

ANVISA has also published GuideNo35-2020 and GuideNo36-2020 to provide guidance on the procedures for conducting GCP inspections in clinical trial centers, and provide guidance for sponsors and clinical research organization representatives respectively for clinical trials involving medicines and biological products. Both guides describe ANVISA’s compliance with the GCP inspection requirements set forth in NormNo122 with the goal of guiding those involved in the inspection procedures to ensure a unified standard and the safety of all involved parties.

GuideNo35-2020 and GuideNo36-2020 explain that GCP inspections of sponsors and clinical research organization representatives and in clinical trial centers may be carried out before, during, or after a clinical trial has been conducted and will be classified as either a routine inspection or complaint/suspected irregularity, per NormNo122. In addition, per GuideNo35-2020 and GuideNo36-2020, the inspections will involve at least two (2) ANVISA inspectors, one (1) of whom will be the lead inspector and the focal point for communication with either the clinical trial center or the sponsor/clinical research organization representative(s). The inspections for both entities will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.

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

Premature Study Termination/Suspension

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

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

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

In addition, ResNo9 states that ANVISA may, at any time, cancel or suspend a DDCM or any related clinical trial if it believes that the approval conditions have not been met or if there are safety or efficacy reports that significantly affect either the trial participants or scientific validity. In this case, ANVISA will inform the sponsor of the reasons for this cancellation or suspension. Per ResNo9, the sponsor must immediately inform those involved in a clinical trial when it is prematurely cancelled or suspended for any reason. The PANDRH-GCPs also explains 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 cancellation or suspension.

Article 1
Chapters I (Article 5), II (Articles 7 and 11), and VII (Article 50)
Articles 1-2, and 12
Article 1
Chapters I (Article 6), II (Articles 9-11, 18-20, and 27), VI, and VIII (Article 71)
5.12, 6.1, 6.5-6.6, and 6.19
1, 2, 4, and 5
1, 2, 4, and 5
8
7 and 11
5
Sponsorship > Site/Investigator Selection
Last content review/update: May 12, 2022
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 Submission Content section for additional information on clinical trial application requirements.

Foreign Sponsor Responsibilities

As specified in the PANDRH-GCPs and ResNo9, 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 ResNo9, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

Data Safety and Monitoring Board

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

Multicenter Studies

Per the PANDRH-GCPs, in the event of a multicenter clinical trial, the sponsor or his/her CRO should ensure that all investigators conduct the trial in strict compliance with the protocol as well as National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s and the institutional ethics committee (EC) (known as a Comitê de Ética em Pesquisa (CEP))’s requirements.

Articles 6, 20, 37, and 56
5.6, 6.2, 6.5-6.6, and 6.23
Informed Consent > Documentation Requirements
Last content review/update: May 12, 2022
Summary

Obtaining Consent

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

As per the PANDRH-GCPs, ResNo466, the G-ClinResSubjectRts, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by an 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 (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). CLNo17 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 CLNo17 also apply to assent forms. CLNo51 further clarifies that the ICF should be written as an invitation rather than as a statement as this may reduce the participant’s autonomy. Refer to CLNo51 for detailed information. See the Required Elements section for details on contents to be included in the form.

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the investigator, or 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 ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, OMREC, and the G-ClinProtocols-FAQs, the ICF content should be presented in a clearly organized format using practical and non-technical language commensurate with the participant’s level of understanding. Per the PANDRH-GCPs and the G-ClinResSubjectRts, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. The PANDRH-GCPs further explains that none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or 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. ResNo466 and the G-ClinResSubjectRts further note that the investigator must bear in mind that the prospective participant's ability to understand the information required to give consent depends on 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 CLNo17, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by the EC (CEP) and submitted to ANVISA before such changes are implemented. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and CLNo51, the 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. CLNo17 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.

Documenting Consent

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. ResNo466 and the G-ClinProtocols-FAQs specify that two (2) original copies of the ICF should be prepared with all pages initialed and signed by the participant and/or the participant’s legal representative(s) or guardian(s), and the investigator(s) or person(s) overseeing the consent process.

Consent for Processing Personal Data

LawNo13.709 provides a definition for sensitive personal data or information that encompasses health related considerations. Sensitive personal data refers to personal data about racial or ethnic origin; religious belief; political opinion; union membership or organization of a religious, philosophical or political nature; data relating to health or sexual life; and genetic or biometric data, when linked to a natural person.

As set forth in LawNo13.709, the processing of sensitive personal data may only be carried out when the holder or his/her legal guardian consents, in a specific and obvious way, for the purpose of processing sensitive personal data. The holder is defined as the person whose personal data are being processed per LawNo13.709. The consent must be provided in writing or by another means that demonstrates the holder’s intention. If the consent is provided in writing, it must be included in a separate clause of the other contractual clauses. The sponsor (known as the “controller” in LawNo13.709) bears the burden of proving that the consent was obtained in accordance with the provisions of this law. The processing of personal data is prohibited by the absence of consent. The consent must refer to specific purposes, and generic authorizations for the processing of personal data will be void. The consent can be revoked at any time by express statement of the holder, by a free and facilitated procedure. In case of alteration of the information, the sponsor must inform the holder, with emphasis on the content of the changes, and the holder, in cases where his/her consent is required, can revoke this consent if he/she disagrees with the change.

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (CEPs) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment.

Chapter I (Article 5) and Chapter II (Articles 7, 8, and 11)
II-IV
2.6, 3.1, 4.1-4.3, 5.5, and Annex 3
Introduction (Chart 1), 1.1, 1.19-1.20, and Summary Chart: Frequent Pending Issues (1)
9 and Annexes C-D
Informed Consent > Required Elements
Last content review/update: May 12, 2022
Summary

Based on the PANDRH-GCPs, ResNo466, and OMREC, the informed consent form (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 ethics committee(s), and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to access the participant’s medical records to verify the procedures or trial data without violating the participant’s confidentiality, insofar as the applicable laws and regulations permit
  • That participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
  • Contact information for the sponsor and investigator in the event of participant problems or trial-related injuries
  • Foreseeable circumstances under which the investigator(s) may remove the participant without 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 Compensation Disclosure, Vulnerable Populations, and Consent for Specimen sections for further information.

III-IV
2.6, 3.1.8, 4.3, 5.5, and Annex 3
9 and Annex C
Informed Consent > Compensation Disclosure
Last content review/update: May 12, 2022
Summary

Overview

In accordance with ResNo466, 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 ResNo466, the G-ClinResSubjectRts, and BRA-17, 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 ResNo466, 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. See also BRA-79 for additional information on sponsor/contract research organization insurance coverage.

II and IV-V
4.4
II, V, and Annex C
Financing the Clinical Trial and Supply of Products to the Research Participants
Informed Consent > Participant Rights
Last content review/update: May 12, 2022
Summary

Overview

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

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ethics committees (ECs) (known as a Comitê de Ética em Pesquisas (CEPs)) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment.

The Right to Participate, Abstain, or Withdraw

As set forth in the ResNo466, 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 ResNo466, 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.

In addition, per LawNo13.709, in the context of complying with data protection requirements, data holders (clinical trial participants) have the right to be informed about the collection and use of their personal data. LawNo13.709 further states that the data holder is entitled to obtain from the sponsor (known as the “controller in LawNo13.709) access to his/her treated data at any time and upon request. Treatment is defined by LawNo13.709 as any operation performed with personal data. See Chapter III of LawNo13.709 for additional information on the rights of data holders.

The Right to Privacy and Confidentiality

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

As delineated in the LawNo13.709, the sponsor (controller) is required to protect the confidentiality of the holder of the personal data and his/her background. For more information about the sponsor’s role in data protection, see the Quality, Data & Records Management section.

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

ResNo466 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 ResNo563, for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) registration. See also BRA-17 for additional information on post-study access to investigational products.

Chapter I (Articles 1, 2, and 5) and Chapter III (Articles 17 and 18)
III-IV
Articles 1, 3, and 4
Chapters 2 and 4
9 and Annex C
Informed Consent > Special Circumstances/Emergencies
Last content review/update: May 12, 2022
Summary

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 ResNo251 similarly state that the EC (CEP) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner of his/her participation in the study.

V
4.3.19
9
Informed Consent > Vulnerable Populations
Last content review/update: May 12, 2022
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, ResNo466, and the G-ClinResSubjectRts characterize vulnerable populations as those who are relatively (or absolutely) incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes. These participants may include those with incurable diseases, people in convalescent homes, the unemployed or indigent, patients in emergency situations, ethnic minorities, homeless people, seasonal workers, refugees, minors, and those who cannot give their consent.

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

The ResNo466 and PANDRH-GCPs specify that 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. ResNo466 and the G-ClinResSubjectRts also state that vulnerable groups should not be included unless the research is necessary to promote the health of the population represented, and this research cannot instead be performed on legally competent participants.

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (CEPs) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment.

Indigenous Peoples

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

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

III and V
II-III (2), and IV (6(a))
Chapter 3 (3.1-3.2) and Chapter 9
Informed Consent > Children/Minors
Last content review/update: May 12, 2022
Summary

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

As per PANDRH-GCPs, ResNo466, 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.

Assent Requirements

ResNo466 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).

Consent for Processing Personal Data

Per LawNo13.709, in the context of complying with data protection requirements, the processing of personal data of children and adolescents must be carried out in their best interest with specific and highlighted consent given by at least one (1) of the parents or the legal guardian. However, the sponsors (known as “controllers” in LawNo13.709) are permitted to collect personal data from children without the consent of a parent or legal guardian when collection is necessary to contact the parent or legal guardian, used only once and without storage, or for their protection, and in no case may be passed on to a third party without the consent of at least one (1) parent or the legal guardian.

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

Chapter II (Article 14)
II and IV
4.3
9
Informed Consent > Pregnant Women, Fetuses & Neonates
Last content review/update: May 12, 2022
Summary

As per ResNo466, 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. ResNo466 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.

III
Annex 3
Informed Consent > Prisoners
Last content review/update: May 12, 2022
Summary

According to the PANDRH-GCPs, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. ResNo466 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.

IV
Chapter 9
Informed Consent > Mentally Impaired
Last content review/update: May 12, 2022
Summary

According to ResNo466 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.

IV
4.3
Investigational Products > Definition of Investigational Product
Last content review/update: May 12, 2022
Summary

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. ResNo9, the G-BioIProdManual, and the G-SynthDrugProdManual 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 BRA-8, the definition of an IP in ResNo9 differs from that of the PANDRH-GCPs because when ResNo9 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.

Article 6
Chapter 9
11
9
3.10
Investigational Products > Manufacturing & Import
Last content review/update: May 12, 2022
Summary

Manufacturing

As stated in ResNo9, 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 (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))).

ANVISA has also released ServBltnNo104 to expedite the evaluation of clinical drug research development in Brazil without compromising the quality of the technical analysis. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.) According to ServBltnNo104, the IP manufacturing process must meet the criteria and recommendations described in the current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s guidelines, as applicable, according to the phase of clinical development. In addition, the technical experts in ANVISA’s Office of Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) require DDCM petitions and substantial quality modifications to meet ServBltnNo104 criteria and be accompanied by the documentation required in ResNo9. COPEC will then analyze the following:

  • The results of stability studies under accelerated and long-term conditions that support the proposed expiration date for the IP and, where applicable, for the modified placebo and comparator, when the storage recommendation is at room temperature (between 15 and 30oC); and
  • The sample IP label for DDCM petitions

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

Import

Per ResNo9 and the G-DDCMManual, 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 DDCM to ANVISA as indicated in ResNo9. 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 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 Submission Process and Submission Content sections for additional application requirements). See also BRA-103 for detailed instructions on obtaining a drug import license authorization and BRA-102 to check on the status of a petition submission.

BRA-95 provides instructions to sponsors and/or their legal representatives in Brazil on completing the expiration date information for imported IPs in the clinical trial submission form (BRA-22). The expiration date is frequently updated, and is, therefore, often linked to inconsistencies and requests for clarification of requirements by those responsible for importing drugs and products for clinical trials. See BRA-95 for detailed information on stability requirements and instructions on completing the form.

ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. Pursuant to ResNo74, the process involves electronically submitting ANVISA’s Industry Petition Form (BRA-71) to the Integrated Foreign Trade System (SISCOMEX)’s Single Portal (BRA-80). ResNo81 explains that the following documentation must be included with the petition:

  • Copy of the CE (Note: per ResNo9, 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 carrier/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 ResNo81 for detailed import documentation requirements and the G-ElecImprtPetition for step-by-step instructions on how to electronically submit import documents to ANVISA via using BRA-80. See also BRA-8 for frequently asked questions on importation requirements and BRA-87 for additional information on BRA-80.

Per BRA-86 and BRA-94, ANVISA has also initiated a project for applicants to request an import license for advanced therapy products to be used for clinical research or commercial/industrial purposes. The process involves registering an import license through the Licenses, Permissions, Certificates and Other Documents (LPCO) module of BRA-80, and attaching the ANVISA import license petition to this application—which is obtained using ANVISA’s Electronic Petition Request System (BRA-38). See G-LPCOImprtPetition for additional information on filing an import license petition for an advanced therapy product with ANVISA. Per ResNo506, advanced therapy products refer to medicines for human use that are based on genes, tissues, or cells. Refer to ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products. See also BRA-104 for detailed instructions on submitting an import license petition to ANVISA through LPCO.

Per ResNo172, ANVISA will analyze and release imported goods and products intended for use in human subjects 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 ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172), is the requirement that the researcher and institution submit the imported products through one (1) of the following methods: BRA-80 or Express Shipping. While each import option has different documentation requirements, they all require the submission of an Industry Petition Form (BRA-71), a commercial invoice, a signed statement of responsibility (see ResNo81 (Chapter XXVII) and ResNo172 (Annex I)), institutional ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) approval. Refer to ResNo81 for additional required items based on the import method used.

Per ResNo172, researchers accredited by the National Council for Scientific and Technological Development (CNPq) and whose tax regime is exempt, will be automatically granted an import license via BRA-80.

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. ResNo172 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 ResNo81 and ResNo172 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 ResNo102, 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 ResNo102 for detailed instructions on submitting appropriate documentation for these updates. See also the Submission Process section for detailed information on documentation to be submitted.

Per BRA-96, ANVISA has also modified the global transfer of responsibility request process for a clinical trial or assistance program for medicines and biological products. The requests must be carried out electronically by the company that has requested the transfer via BRA-38 using the DDCM petition’s subject code 12130 for medicines and 11795 for advanced therapy products. See BRA-96 for additional information.

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

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

Article 24
Article 24
Chapter I (Articles 1, 2, and 4), II (Articles 7 and 15), and III-IV
Chapters I (Article 1), II, III (Section III), and V, and Annex I
Articles 3-4 and 16
Chapters I (1.9), II (1.2), III (Sections I-IV), XXII, XXVI (Sections I and V), XXVII, and XXXI
Chapters I (Article 6), III (Articles 34-36, and 38), IV (Article 43), and IX
Chapters I, II (Sections II and III), and IV, and Annex I
7
1 and 6
What is PIC/S?
3.4
Investigational Products > IMP/IND Quality Requirements
Last content review/update: May 12, 2022
Summary

Investigator's Brochure

In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). ResNo9 and the G-DDCMManual 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 should also update the IB as significant new information becomes available.

Quality Documentation

The G-DDCMManual, the G-BiolProdManual, and BRA-8 further explain that the sponsor must include manufacturing process information in the Experimental Drug Dossier as part of the clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) submission as described in ResNo9. Please refer to ResNo9, the G-DDCMManual, and the G-BiolProdManual for additional experimental drug dossier requirements.

As specified in ResNo9 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 ResNo301. In addition, per ResNo205, the DDCM submitted to National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to conduct a clinical trial using investigational products for rare diseases should also be accompanied by a request for GMPs certification. See ResNo205 for detailed submission information.

Articles 1 and 12-13
Chapter II
Articles 14, 38, 43, and 72
Chapter 6 (6.6.3, 6.12.2, 6.13-6.14) and Annex 5 (1)
6.2-6.3
2 and 5.3
3.1 and 3.3
Investigational Products > Labeling & Packaging
Last content review/update: May 12, 2022
Summary

Investigational product (IP) labeling in Brazil must comply with the requirements set forth in ResNo9, 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. BRA-8 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 ResNo9, 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
Articles 6, 14, 38, and 75
Chapter 6 (6.13) and Annex 5 (1)
6.3 and 10
3.3.2
Investigational Products > Product Management
Last content review/update: May 12, 2022
Summary

Supply, Storage, and Handling Requirements

As delineated in ResNo9 and the PANDRH-GCPs, the sponsor must also supply the investigator(s)/institution(s) with the investigational product(s) (IP), 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 clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (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 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 the Submission Process and Submission Content sections for detailed application requirements).

Per ResNo9 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 ResNo9 and ResNo301
  • 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 ResNo9 and PANDRH-GCPs for detailed sponsor-related IP requirements.

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

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.

Chapter II
Articles 14-17 and 38
Chapter 6 (6.12.2 and 6.13-6.14) and Annex 5 (1)
What is PIC/S?
3.1 and 3.3
Specimens > Definition of Specimen
Last content review/update: May 12, 2022
Summary

As per OrdNo2201, ResNo504, ResNo441, and the G-BiolMatTransprt, a specimen is defined as any human biological material such as organs, tissues, cells, body fluids, excreta, and other fluids of human origin obtained from a single participant at a particular time. ResNo508 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.

Article 1 (1)
Article 3
Chapter I (Article 3)
Chapter I (Article 7)
2
Specimens > Specimen Import & Export
Last content review/update: May 12, 2022
Summary

ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing human biological materials for clinical research purposes. Pursuant to ResNo74, the process involves electronically submitting National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s Industry Petition Form (BRA-71) to the Integrated Foreign Trade System (SISCOMEX)’s Single Portal (BRA-80). To obtain an import license through BRA-80, ResNo208 (amending ResNo81), and ResNo613 (amending ResNo172) specify that the researcher and institution should submit the imported human biological materials through one (1) of the following methods: BRA-80 or Express Shipping. ResNo81 and ResNo172 explain that the following documentation must be included with the petition form:

  • Shipment document (Includes shipment date, proof of investigational product (IP) deposit to the importer, and carrier/transportation type: Airborne Cargo - Air Waybill (AWB), Aquatic Cargo - Bill Landing (BL), or Land Cargo - Knowledge of International Transport by Highway (CTR))
  • Inspection authorization
  • Commercial invoice
  • Bill of lading
  • Signed statement of responsibility (see ResNo81 (Chapter XXVII) and ResNo172 (Annex I))
  • Institutional ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) approval

For step-by-step instructions on how to electronically submit import documents to ANVISA using BRA-80, please refer to the G-ElecImprtPetition.

ResNo172 further notes that an import license may be automatically granted via BRA-80 to researchers accredited by the National Council for Scientific and Technological Development (CNPq) and whose tax regime is exempt.

ResNo172 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 ResNo81 and ResNo172 for additional required items depending on the import method used.

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

As explained in ResNo504 and the G-BiolMatTransprt, 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 ResNo504, human biological material is classified as Category A or B infectious biological material, or Category Risk Minimum. Category A includes materials where exposure can cause permanent disability or fatal disease to humans and animals. Category B includes those materials not listed in Category A such as samples suspected or known to contain infectious agents causing diseases in humans. Category Risk Minimum or “exempt human specimens” include biological materials from healthy individuals. Human biological materials must also be classified according to the World Health Organization (WHO)’s risk classification diagram available in the WHO’s Guidance on Regulations for the Transport of Infectious Substances (BRA-54). Labeling should conform to 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 ResNo504 and the G-BiolMatTransprt, human biological material transport should be conducted in accordance with legislation from applicable regulatory bodies including the Ministry of Infrastructure, the National Land Transportation Agency, the National Civil Aviation Agency, and the National Agency for Waterway Transport. Refer to the G-BiolMatTransprt for detailed import and export transport requirements.

Refer to ResNo504 and the G-BiolMatTransprt for detailed instructions on shipping biological materials within these categories. See also ResNo508 for detailed transport requirements relating to human cells and advanced therapy products, and BRA-97 for preparing reports on biobanking for research purposes.

Chapter I (Sections I and II) and II-VI
Chapter I (Articles 3 and 6-7) and Chapter III (Section VIII)
7.3
Articles 1 and 2
Chapters I (1.9), II (1.2), III (Sections I-III), XXIII-XXVI (Sections IV and V), and XXVII
Chapters I (Article 1), II (Sections III and VI), and IV (Articles 20-21, and 23), and Annex I
4-8
1 and 6
Specimens > Consent for Specimen
Last content review/update: May 12, 2022
Summary

In accordance with OrdNo2201, ResNo441, ResNo466, and ResNo340, prior to collecting, storing, or using a research participant’s human biological material, consent must be obtained from the participant or his/her legal representative in writing. Per OrdNo2201, ResNo340, OMREC, and CLNo041, 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 OrdNo2201, ResNo441, and ResNo340, investigator(s) must also obtain institutional ethics committee (EC) (known as Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) approval of a new research project involving human biological materials. Per ResNo340, if it is not possible to obtain the participant’s consent, a formal justification shall be presented to the EC (CEP) for evaluation.

In addition, per ResNo441 and ResNo340, investigators should explain the possibility of 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. OrdNo2201 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 ResNo340, the G-ClinProtocols-FAQs, and CLNo041, the ICF for genetic research projects must communicate the following information to the participant:

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

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

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

  • A reference to the data types that may be obtained from the participant’s stored biological material for future research
  • An express guarantee of the participant’s right to access 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 OrdNo2201 and ResNo441, 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 ResNo441.

Please refer to OrdNo2201, ResNo441, and the G-ClinProtocols-FAQs, for detailed requirements and issues associated with storing human biological materials in a biorepository or a biobank. See also ResNo508 for informed consent requirements pertaining to human cell collection and other procedures conducted by cell processing centers.

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

Sections III, IV, and V
Article 1 (2-10 and 15)
Chapter III (3)
Chapters I (Article 3 (VI)), II, III, and IV (Articles 15, 17-18, and 24-25)
Chapter I (Article 7) and Chapter III (Article 109)
Chart 1, 1.14, and 1.21-1.22
Section 9 and Annex C
Sources > Requirements
(Legislation) Constitutional Amendment No. 115 of February 10, 2022 (C-AmndtNo115 - Portuguese) (February 10, 2022)
National Congress
(Legislation) Law No. 10.742 of October 6, 2003 (LawNo10.742 - Portuguese) (GoogleTranslate-LawNo10.742) (Effective October 6, 2003)
Federative Republic of Brazil
(Legislation) Law No. 13.709 of August 14, 2018 (LawNo13.709 - Portuguese) (GoogleTranslate-LawNo13.709) (Effective August 14, 2020)
Federative Republic of Brazil
(Legislation) Law No. 6.360 of September 23, 1976 (LawNo6.360 - Portuguese) (GoogleTranslate-LawNo6.360) (Effective December 27, 1976)
Federative Republic of Brazil
(Legislation) Law No. 8.142 of December 28, 1990 (LawNo8.142 - Portuguese) (GoogleTranslate-LawNo8.142) (Effective December 28, 1990)
Federative Republic of Brazil
(Legislation) Law No. 9.782 of January 26, 1999 (LawNo9.782 - Portuguese) (Effective January 26, 1999)
Federative Republic of Brazil
(Regulation) CNS Resolution No. 292 of July 8, 1999 (ResNo292 - Portuguese) (GoogleTranslate-ResNo292) (July 8, 1999)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 304 of August 9, 2000 (ResNo304) (Portuguese) (August 9, 2000)
National Health Council, Minister of Health
(Regulation) CNS Resolution No. 340 of July 8, 2004 (ResNo340) (Portuguese) (July 8, 2004)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 346 of January 13, 2005 (ResNo346 - Portuguese) (GoogleTranslate-ResNo346) (January 13, 2005)
National Health Council, Minister of Health
(Regulation) CNS Resolution No. 370 of March 8, 2007 (ResNo370 - Portuguese) (GoogleTranslate-ResNo370) (March 8, 2007)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 441 of May 12, 2011 (ResNo441 - Portuguese) (May 12, 2011)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 446 of August 11, 2011 (ResNo446 - Portuguese) (GoogleTranslate-ResNo446) (Effective August 29, 2011)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 453, of May 10, 2012 (ResNo453 - Portuguese) (GoogleTranslate-ResNo453) (May 10, 2012)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 466 of December 12, 2012 (ResNo466 - Portuguese) (Effective June 13, 2013)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 506 of February 3, 2016 (CNSResNo506 - Portuguese) (Effective March 23, 2016)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 563 of November 10, 2017 (ResNo563 - English, unofficial translation) (Portuguese) (November 10, 2017)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 580 of March 22, 2018 (ResNo580 - Portuguese) (March 22, 2018)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 251 of August 7, 1997 (ResNo251 - Portuguese) (GoogleTranslate-ResNo251) (August 7, 1997)
National Health Council, Ministry of Health
(Regulation) CNS Resolution No. 647 of October 12, 2020 (ResNo647 - Portuguese) (GoogleTranslate-ResNo647) (October 12, 2020)
National Health Council, Ministry of Health
(Regulation) Interministerial Ordinance No. 45, of January 27, 2017 (OrdNo45 - Portuguese) (GoogleTranslate-OrdNo45) (Effective February 9, 2017)
Ministry of Economy
(Regulation) Normative Instruction No. 122 of March 9, 2022 – Provides Good Clinical Practice Inspection Procedures for Clinical Drug Trials (NormNo122 - Portuguese) (Effective April 1, 2022)
ANVISA, Ministry of Health
(Regulation) Ordinance GM/MS No. 913 of April 22, 2022 (OrdNo913 - Portuguese) (Effective May 22, 2022)
Ministry of Health
(Regulation) Ordinance No. 188 of February 3, 2020 (OrdNo188 - Portuguese) (GoogleTranslate-OrdNo188) (February 3, 2020)
Ministry of Health
(Regulation) Ordinance No. 2201 of September 14, 2011 (OrdNo2201 - Portuguese) (GoogleTranslate-OrdNo2201) (September 14, 2011)
Ministry of Health
(Regulation) Ordinance No. 552 of March 9, 2007 (OrdNo552 - Portuguese) (GoogleTranslate-OrdNo552) (March 9, 2007)
Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 504 of May 27, 2021 (ResNo504 - Portuguese) (Effective July 1, 2021)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 506 of May 27, 2021 (ResNo506 - Portuguese) (Effective July 1, 2021)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 508 of May 27, 2021 (ResNo508 - Portuguese) (Effective July 1, 2021)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 573 of October 29, 2021 (ResNo573 - Portuguese) (GoogleTranslate-ResNo573) (Effective October 29, 2021)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 683 of May 12, 2022 (ResNo683 - Portuguese) (Effective May 22, 2022)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board of Directors - RDC No. 620 of March 9, 2022 (ResNo620 - Portuguese) (Effective April 1, 2022)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board – RDC No. 613 of March 9, 2022 (ResNo613 - Portuguese) (Effective April 1, 2022)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 102 of August 24, 2016 (ResNo102 - English, unofficial translation) (Portuguese) (Effective December 22, 2016)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 176 of September 15, 2017 (ResNo176 - Portuguese) (GoogleTranslate-ResNo176) (Effective September 19, 2017)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 198 of December 26, 2017 (ResNo198 - Portuguese) (Effective December 28, 2017)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 204 of December 27, 2017 (ResNo204 - English, unofficial translation) (Portuguese) (Effective February 25, 2018)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 205 of December 28, 2017 (ResNo205 - English, unofficial translation) (Portuguese) (Effective February 27, 2018)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 208 of January 5, 2018 (ResNo208 - Portuguese) (GoogleTranslate-ResNo208) (Effective January 8, 2018)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 301 of August 21, 2019 (ResNo301 - Portuguese) (GoogleTranslate-ResNo301) (Effective June 8, 2020)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 38 of August 12, 2013 (ResNo38 - Portuguese) (GoogleTranslate-ResNo38) (Effective August 13, 2013)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 449 of December 15, 2020 (ResNo449 - Portuguese) (Effective December 17, 2020)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 74 of May 2, 2016 (ResNo74 - Portuguese) (GoogleTranslate-ResNo74) (Effective May 3, 2016)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 76 of October 23, 2008 (ResNo76 - Portuguese) (GoogleTranslate-ResNo76) (Effective October 27, 2008)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 81 of November 5, 2008 (ResNo81 - Portuguese) (Effective November 5, 2008)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 9 of February 20, 2015 (ResNo9 - Portuguese) (Effective March 3, 2015)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board – RDC No. 172 of September 8, 2017 (ResNo172 - Portuguese) (Effective October 12, 2017)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board – RDC No. 222 of December 28, 2006 (ResNo222 - Portuguese) (GoogleTranslate-ResNo222) (Last Amended December 26, 2017)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board – RDC No. 61 of February 3, 2016 (ResNo61 - Portuguese) (GoogleTranslate-ResNo61) (Effective February 5, 2016)
ANVISA, Ministry of Health
(Regulation) Resolution of the Collegiate Board - RDC No. 311 of October 10, 2019 (ResNo311 - Portuguese) (Effective October 16, 2019)
ANVISA, Ministry of Health
(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
(Guidance) Guidance Manual: Frequent Pending Issues in Clinical Research Protocols (Version 1.0) (G-ClinProtocols-FAQs - English, unofficial translation) (Portuguese) (2015)
Brazilian National Board of Health (CNS) and Brazilian National Research Ethics Commission (CONEP)
(Guidance) Guidance on the Rights of Research Subjects (G-ClinResSubjectRts - Portuguese) (Version 1.2) (March 24, 2016)
ANVISA, Ministry of Health
(Guidance) Health Surveillance Manual on the Transport of Human Biological Material for Clinical Diagnostic Purposes (G-BiolMatTransprt - Portuguese) (2015)
ANVISA, Ministry of Health
(Guidance) Inspection Guide on Good Clinical Practice (GCP) for Clinical Trials with Drugs and Biological Products - Inspection in Clinical Trial Centers (GuideNo35-2020 - Portuguese) (Version 2) (Effective January 27, 2022)
ANVISA, Ministry of Health
(Guidance) Inspection Guide on Good Clinical Practice (GCP) for Clinical Trials with Drugs and Biological Products - Inspection of Sponsors and Clinical Research Organization Representatives (ORPC) (GuideNo36-2020 - Portuguese) (Version 2) (Effective January 27, 2022)
ANVISA, Ministry of Health
(Guidance) Manual for Notification of Adverse Events and Safety Monitoring in Clinical Trials (AESafetyManual - Portuguese) (1st Edition) (Version 1.1) (2016)
General Management of Medicines, Coordination of Clinical Research in Medications and Biological Products, ANVISA
(Guidance) Manual for Submission of Drug Clinical Development Dossier (DDCM) and Specific Dossier for Clinical Trial (G-DDCMManual - English, unofficial translation) (Portuguese) (3rd Edition) (2017)
ANVISA, Ministry of Health
(Guidance) Manual for Submission of Modifications, Amendments, Suspensions and Cancellations (G-DDCMAmdmts - Portuguese) (5th Edition) (April 26, 2021)
General Management of Medicines (GGMED), Coordination of Clinical Research in Medicines and Biological Products (COPEC), ANVISA
(Guidance) Manual for Submission of Monitoring Reports and Forms for Beginning and End of Clinical Trial (G-CTReptsManual - English, unofficial translation) (Portuguese) (1st Edition) (2016)
ANVISA, Ministry of Health
(Guidance) Operating Manual for Research Ethics Committees (OMREC - Portuguese) (4th Edition revised and updated) (2008)
National Research Ethics Commission, National Health Council, Ministry of Health
(Guidance) Operational Standard No. 001/2013 (OSNo001) (Portuguese) (September 30, 2013)
National Health Council, Ministry of Health
(Guidance) Operational Standard No. 01/2012 of March 7, 2012 (OSNo01 - Portuguese) (March 7, 2012)
National Health Council, Ministry of Health
(Guidance) Primer: Electronic Import Petition (G-ElecImprtPetition - Portuguese) (Version 4.3) (July 2, 2018)
General Management of Ports, Airports, Borders and Customs Enclosures (GGPAF) and Management of Sanitary Control of Ports, Airports, Borders and Customs Enclosures (GCPAF), ANVISA
(Guidance) Primer: Import Petition through LPCO (G-LPCOImprtPetition - Portuguese) (Version 3.2) (March 31, 2022)
ANVISA, Ministry of Health
(Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials - Synthetic and Semisynthetic Medicines (G-SynthDrugProdManual - Portuguese) (3rd Edition) (2019)
ANVISA, Ministry of Health
(Guidance) Quality Data Submission Manual for Research Products Used in Clinical Trials – Biological Products (G-BiolProdManual - Portuguese) (3rd Edition) (2019)
ANVISA, Ministry of Health
(Guidance) Standard Procedures No. 006 - Evaluation of Research Ethics Committees (SP006REC - Portuguese) (January 10, 2009)
National Health Council, Ministry of Health
(Circular) Circular Letter 060/2012 - CONEP Notice on Citation of Clinical Trial Registries in Research Protocol (CLNo060 - Portuguese) (May 5, 2012)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 038/2014 - Processing of Amendments in the CEP/CONEP System (CLNo038 - Portuguese) (March 12, 2014)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 040 - Investigator Brochure Processing via Plataforma Brasil (PB) (CLNo040 - Portuguese) (March 27, 2015)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 041/2015 - Guidance on CNS Resolution 340 of 2004 (Item V.1.a) (CLNo041 - Portuguese) (March 27, 2015)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 046/2015 - Research Center Inclusion/Exclusion Requirements When Submitting Responses to Pending CONEP Issues (CLNo046 - Portuguese) (April 15, 2015)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 061/2012 - Research Protocol Timeline Management (CLNo061 - Portuguese) (May 4, 2012)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 1/2021 - Guidelines for Research Procedures with Any Step in a Virtual Environment (CLNo1-2021 - Portuguese) (March 3, 2021)
National Research Ethics Commission, Executive Secretariat of the National Health Council, Ministry of Health
(Circular) Circular Letter No. 1/2022 - Use of an Electronic Mail System (E-mail) to Send Administrative Documents from Research Ethics Committees (CEP) (CLNo1-2022 - Portuguese) (February 7, 2022)
National Research Ethics Commission, Executive Secretariat of the National Health Council, Ministry of Health
(Circular) Circular Letter No. 13/2020 - CONEP Requirements for the Processing of Adverse Events in the CEP/CONEP System (CLNo13 - Portuguese) (June 2, 2020)
National Research Ethics Commission, Executive Secretariat of the National Health Council, Ministry of Health
(Circular) Circular Letter No. 17/2017 - Informed Consent Form Update Requirements (CLNo17 - English, unofficial translation) (Portuguese) (July 26, 2017)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 172/2017 - Clarifications Regarding the Selection of Thematic Area (CLNo172 - Portuguese) (April 20, 2017)
National Research Ethics Commission, National Health Council, Ministry of Health
(Circular) Circular Letter No. 3/2020 - Processing of Biobank Development Protocols by E-mail (CLNo3 - Portuguese) (February 4, 2020)
National Research Ethics Commission, Executive Secretariat of the National Health Council, Ministry of Health
(Circular) Circular Letter No. 51/2017 - Additional Clarifications on ICF Text (CLNo51 - English, unofficial translation) (Portuguese) (September 28, 2017)
National Research Ethics Commission, National Health Council, Ministry of Health
(Bulletin) Service Bulletin No. 104 - Document Analysis Procedures Required for DDCM Petitions and Modifications that Potentially Impact Experimental Drug, Active Comparator or Placebo Quality/Safety (ServBltnNo104 - Portuguese) (Effective June 21, 2021)
ANVISA, Ministry of Health
Sources > Additional Resources
(Article) Advanced Research Therapy Product Imports: Pilot Project Migrates to Single Foreign Trade Portal (BRA-86 - Portuguese) (September 20, 2021)
ANVISA, Ministry of Health
(Article) ANVISA Advises on Notification of Serious Adverse Events (BRA-78 - Portuguese) (Last Updated March 26, 2021)
ANVISA, Ministry of Health
(Article) ANVISA is Approved for Pharmaceutical Inspection Cooperation Scheme - PIC/S (BRA-55 - Portuguese) (Last Updated December 1, 2020)
ANVISA, Ministry of Health
(Article) ANVISA: An Introduction to a New Regulatory Agency with Many Challenges (BRA-1) (2018)
Huynh-Ba, Kim and Beumer Sassi, Alexandra; AAPS Open
(Article) Brazil’s Regulatory Environment Offers Positive Changes for Clinical Trials (BRA-2) (June 2018)
Fagundes, P., Dresel, P., and Miller, E.; Regulatory Focus
(Article) Clinical Research: Guidelines on Scheduling a Meeting (BRA-89 - Portuguese) (May 24, 2021)
ANVISA, Ministry of Health
(Article) Clinical trials: New Flow for Requesting a Global Transfer of Responsibility (BRA-96 - Portuguese) (Last Updated November 25, 2021)
ANVISA, Ministry of Health
(Article) DDCM Petition Procedure Changed (BRA-58 - Portuguese) (Last Updated April 8, 2020)
ANVISA, Ministry of Health
(Article) Evolution of DDCM Electronic Petition – Check It Out (BRA-75 - Portuguese) (Last Updated July 10, 2020)
ANVISA, Ministry of Health
(Article) Import No. 046/2021 – Inclusion of Products in ANVISA’s Administrative Treatment (BRA-94 - Portuguese) (Last Updated September 20, 2021)
Siscomex, Government of Brazil
(Article) Measure Expands the Authorization of Clinical Trials with Drugs in Brazil (BRA-92 - Portuguese) (Last Updated November 4, 2021)
ANVISA, Ministry of Health
(Article) The New Brazilian General Data Protection Law - A Detailed Analysis (BRA-76) (August 15, 2018)
Monteiro, Renato Leite; IAPP
(Article) Validity of the ICH E6(R2) Guide (BRA-30 - Portuguese) (Version 1.0) (Last Updated December 4, 2020)
ANVISA, Ministry of Health
(Document) 2020/2021 Activities Report - Coordination of Clinical Research on Medicines and Biological Products - COPEC (BRA-60 - Portuguese) (4th Edition) (March 28, 2022)
General Management of Medicines and Biological Products (GGMED), Coordination of Clinical Research in Medicines and Biological Products (COPEC), ANVISA
(Document) Bylaws of CONEP/CNS (BRA-16 - Portuguese) (June 6, 2001)
National Health Council, Ministry of Health
(Document) Clinical Trials Handbook Americas - Brazil (BRA-79) (2019)
Baker McKenzie; Frizzo, Henrique Krüger; de Moraes, Carla Bacchin F.; Marconi, Beatriz Marconi
(Document) Enhanced Electronic Petition System (BRA-14 - Portuguese) (Last Updated May 16, 2018)
ANVISA, Ministry of Health
(Document) Guarantee of Access to Post-Clinical Trial Drugs (BRA-17) (2011)
ABRACRO
(Document) Guidance on Scheduling Meetings with COPEC (BRA-19 - Portuguese) (Last Updated December 10, 2020)
ANVISA, Ministry of Health
(Document) Location of Available Documents on the ANVISA Portal (COPEC) (BRA-98 - Portuguese) (21th Edition) (March 10, 2022)
ANVISA, Ministry of Health
(Document) Nagoya Protocol on Access and Benefit-sharing (BRA-63) (2011)
Convention on Biological Diversity, United Nations
(Document) New Procedure for Petitioning DDCM Documents (BRA-59 - Portuguese) (Version 07) (March 2020)
General Management of Medicines and Biological Products (GGMED), Coordination of Clinical Research in Medicines and Biological Products (COPEC), ANVISA
(Document) OECD Principles of Good Laboratory Practice (GLPs) (as revised in 1997) (BRA-15) (1998)
Environment Directorate, Organisation for Economic Co-operation and Development
(Document) Ordinance No. 45 - Annex I - Table of Discounts of the Health Surveillance Inspection Rate Values Currently Updated by the Interministerial Ordinance MF-MS-45/2017 (BRA-11 - Portuguese) (Effective February 9, 2017)
ANVISA, Ministry of Health
(Document) Petitioning Step by Step (BRA-67 - Portuguese) (Date Unavailable)
ANVISA, Ministry of Health
(Document) Pharmaceutical Inspection Co-operation Scheme (PIC/S) Brochure (BRA-100) (August 2019)
Pharmaceutical Inspection Co-operation Scheme (PIC/S)
(Document) Plataforma Brasil - Researcher User Manual (BRA-91 - Portuguese) (Version 3.2) (Last Updated December 10, 2018)
National Health Council, Ministry of Health
(Document) Questions & Answers: Top Questions about RDC 09/2015 (Conduct of Clinical Trials) (BRA-8 - English, unofficial translation) (Portuguese) (2nd Edition) (January 31, 2018)
ANVISA, Ministry of Health
(Document) Roadmap for Preparing Reports on Biobanks for Research Purposes (BRA-97 - Portuguese) (Version 02) (February 2, 2022)
National Research Ethics Commission, National Health Council, Ministry of Health
(Document) Technical Note 008/2017 - Information on Updating the Health Surveillance Inspection Fee (TFVS) (BRA-10 - Portuguese) (January 30, 2017)
ANVISA, Ministry of Health
(Document) Technical Note 09/2015 - Clarifications on Relative Bioavailability Studies to Show Pharmacokinetic Interaction for Purposes of Registering of Fixed-Dose Combinations or Consent in the Clinical Drug Development Dossier-DDCM (BRA-6 - English, unofficial translation) (Portuguese) (September 3, 2015)
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), Brazilian Health Surveillance Agency (ANVISA)
(Document) Technical Note 118/2016 - Clarifications on Comparative Pharmacokinetic Studies of Biological Products (BRA-7 - English, unofficial translation) (Portuguese) (April 15, 2016)
Coordination of Therapeutic Equivalence (CETER), Coordination of Clinical Research in Drugs and Biological Products (COPEC), General Management of Drugs (GGMED), Brazilian Health Surveillance Agency (ANVISA)
(Document) Technical Note 12/2021 - Guidance for Scheduling Hearings with the Coordination of Clinical Research in Medicines and Biological Products (COPEC) (BRA-90 - Portuguese) (May 21, 2021)
ANVISA, Ministry of Health
(Document) Technical Note No. 01/2022: Guidelines on Completing the Clinical Trial Submission Form (FAEC) Regarding the Expiration Date of Medicines and Products to be Imported for Conducting Clinical Trials in Brazil, Pursuant to RDC No. 9/2015 (BRA-95 - Portuguese) (February 2, 2022)
ANVISA, Ministry of Health
(Document) The Use of the WHO-UMC System for Standardised Case Causality Assessment (BRA-31) (Date Unavailable)
The Uppsala Monitoring Centre (UMC), World Health Organization (WHO)
(Document) Updated Health Surveillance Inspection Fees (BRA-12 - Portuguese) (Last Updated April 6, 2017)
ANVISA, Ministry of Health
(Document) VigiMed: Adverse Event Reporting System in Drug Use - Questions and Answers (BRA-85 - Portuguese) (Version 1.0) (July 2019)
ANVISA, Ministry of Health
(International Guidance) Guidance on Regulations for the Transport of Infectious Substances 2019-2020 (WHO/WHE/CPI/2019.20) (BRA-54) (Effective January 1, 2019)
World Health Organization
(International Guidance) ICH Guideline E2B (R3) on Electronic Transmission of Individual Case Safety Reports (ICSRs) - Data Elements and Message Specification - Implementation Guide (BRA-88) (Step 5 Version) (July 2013)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports (E3) (BRA-27) (Step 4 Version) (November 30, 1995)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(International Guidance) Integrated Addendum to ICH E6(R1): Guideline for Good Clinical Practice E6(R2) (BRA-28) (Portuguese) (Step 4 Version) (November 9, 2016)
International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use
(Webpage) ANVISA - Advisory Board (BRA-36 - Portuguese) (Last Updated September 29, 2020)
ANVISA, Ministry of Health
(Webpage) ANVISA - Document Status Query Tool (BRA-102 - Portuguese) (Current as of May 10, 2022)
ANVISA, Ministry of Health
(Webpage) ANVISA - Electronic Contact Form (BRA-68 - Portuguese) (Last Updated February 10, 2021)
ANVISA, Ministry of Health
(Webpage) ANVISA - Electronic Petition - Request System (BRA-38 - Portuguese) (Last Updated March 19, 2021)
ANVISA, Ministry of Health
(Webpage) ANVISA - Fees - General Information (BRA-69 - Portuguese) (October 7, 2020)
ANVISA, Ministry of Health
(Webpage) ANVISA - New Drug Registration (BRA-40 - Portuguese) (November 17, 2020)
ANVISA, Ministry of Health
(Webpage) ANVISA - Ombudsman (BRA-35 - Portuguese) (Last Updated April 6, 2022)
ANVISA, Ministry of Health
(Webpage) ANVISA - Payment Terms (BRA-43 - Portuguese) (Last Updated January 19, 2021)
ANVISA, Ministry of Health
(Webpage) ANVISA - Petitioning - General Definitions (BRA-41 - Portuguese) (Current as of May 11, 2022)
ANVISA, Ministry of Health
(Webpage) ANVISA - Protocol Filing FAQs (BRA-42 - Portuguese) (Last Updated December 21, 2020)
ANVISA, Ministry of Health
(Webpage) ANVISA - Public Service Center (BRA-99 - Portuguese) (Current as of May 10, 2022)
ANVISA, Ministry of Health
(Webpage) ANVISA - Reporting of Serious Adverse Events in Clinical Trials (BRA-37 - Portuguese) (Last Updated May 28, 2021)
ANVISA, Ministry of Health
(Webpage) ANVISA - Who's Who (BRA-39 - Portuguese) (Last Updated September 29, 2020)
ANVISA, Ministry of Health
(Webpage) ANVISA - Obtain Authorization to Import Drug Substance (BRA-103 - Portuguese) (Last Updated March 4, 2022)
ANVISA, Ministry of Health
(Webpage) ANVISA - Request Product Import Licensing Subject to Sanitary Surveillance through LPCO (BRA-104 - Portuguese) (Last Updated March 14, 2022)
ANVISA, Ministry of Health
(Webpage) Brazil Platform (BRA-93 - Portuguese) (Last Updated November 23, 2020)
Ministry of Health
(Webpage) Brazilian Clinical Trials Registry (ReBEC) - FAQs (BRA-46) (Current as of May 11, 2022)
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)
(Webpage) Brazilian Clinical Trials Registry (ReBEC) (BRA-45) (Current as of May 11, 2022)
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)
(Webpage) CEP - Frequently Asked Questions (BRA-70 - Portuguese) (Current as of May 11, 2022)
Institutional Ethics Committee, Pontifical Catholic University of Goiás
(Webpage) Country Profile: Brazil (BRA-81) (Current as of May 11, 2022)
Access and Benefit-sharing Clearing-house, Convention on Biological Diversity, United Nations
(Webpage) Integrated Foreign Trade System (SISCOMEX) - Single Portal (BRA-80 - Portuguese) (Current as of May 11, 2022)
Siscomex, Government of Brazil
(Webpage) International Clinical Trials Registry Platform (ICTRP) (BRA-52) (Current as of May 11, 2022)
World Health Organization
(Webpage) Learning to Export - Siscomex Single Portal (BRA-87 - Portuguese) (Last Updated December 29, 2021)
Siscomex, Government of Brazil
(Webpage) National Health Council - About Us (BRA-49 - Portuguese) (September 24, 2018)
National Health Council, Ministry of Health
(Webpage) National Health Council - Plataforma Brazil (BRA-33 - Portuguese) (Current as of May 11, 2022)
National Health Council, Ministry of Health
(Webpage) National Research Ethics Commission (CONEP) (BRA-50 - Portuguese) (Current as of May 11, 2022)
National Health Council, Ministry of Health
(Webpage) Plataforma Brazil Login (BRA-34 - Portuguese) (Current as of May 11, 2022)
Ministry of Health
(Webpage) Recognition of GLP Compliance (BRA-48 - Portuguese) (Current as of April 6, 2022)
Ministry of Health
(Webpage) Unified Health System (SUS): Structure, Principles and How it Works (BRA-53 - Portuguese) (Last Updated May 10, 2022)
Ministry of Health
(Webpage) Union Collection Guide (BRA-51 - Portuguese) (Current as of May 11, 2022)
Ministry of Economy
(Webpage) VigiMed (BRA-83 - Portuguese) (Current as of May 11, 2022)
ANVISA, Ministry of Health
Sources > Forms
(Form) Annexes to the Manual for Submission of Modifications, Amendments, Suspensions and Cancellations - 5th Edition (BRA-13 - Portuguese) (Date Unavailable)
ANVISA, Ministry of Health
(Form) ANVISA Serious Adverse Event Notification Spreadsheet (BRA-84 - Portuguese) (Date Unavailable)
ANVISA, Ministry of Health
(Form) Clinical Trial Report – Annual or Final (BRA-23 - Portuguese) (Last Updated December 3, 2020)
ANVISA, Ministry of Health
(Form) Clinical Trial Submission Form (FAEC) (BRA-22 - Portuguese) (Version 4.0) (Last Updated August 16, 2018)
ANVISA, Ministry of Health
(Form) Cover Sheet for Research Involving Human Beings (BRA-20 - Portuguese) (January 2013)
National Research Ethics Commission, National Health Council, Ministry of Health
(Form) End of Clinical Trial Notification Form in Brazil (BRA-24 - Portuguese) (Version 2.0) (Last Reviewed on October 22, 2020)
ANVISA, Ministry of Health
(Form) Industry Petition Form (BRA-71 - Portuguese) (Date Unavailable)
ANVISA, Ministry of Health
(Form) Online Adverse Event Notification Form for Advanced Therapy Products (BRA-101 - Portuguese) (Current as of May 11, 2022)
ANVISA, Ministry of Health
(Form) Petition Request Form for Consent to the Clinical Drug Development (DDCM) Dossier Process (BRA-21 - Portuguese) (Version 1.2) (Last Updated June 21, 2021)
ANVISA, Ministry of Health
(Form) Start of Clinical Trial Notification Form in Brazil (BRA-25 - Portuguese) (Version 2.0) (Last Reviewed October 22, 2020)
ANVISA, Ministry of Health
Sections Country Announcement
Country pages have been redesigned to provide more space for summary content. Specific source details can be accessed via pop-up by clicking the source links in the summary content. Additionally, all country-specific sources can be found at the bottom of each country page, accessible via the left-hand menu or the “View all sources” links at the top of each section.
X
Country Announcement
x

Details on the most recent Brazil updates are available here.

National Health Council (CNS) Update 

The Brazilian National Health Council (CNS) has issued Resolution No. 674 of May 6, 2022. The resolution classifies research according to level of intervention in the human body and provides the corresponding levels of review and timelines. The resolution will take effect when Plataforma Brazil is updated to account for the different review types and associated processes.

The ClinRegs team will review the resolution and update the profile where appropriate.

COVID-19 Guidance

  • Ordinance No. 913 (effective May 22, 2022) – declared an end to Brazil’s public health emergency related to COVID-19.

     National Health Surveillance Agency (ANVISA)  

  • Resolution No. 683 (May 12, 2022) – extends the validity of a number of resolutions issued during the public health emergency to May 21, 2023, including:
    • Resolution No. 534 (August 23, 2021) – provides guidance regarding the continuous submission of clinical development dossiers of COVID-19 vaccines by Brazilian public universities or publicly funded institutions.
    • Resolution No. 573 (October 29, 2021) – Amends ANVISA’s technical reviews 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 as delineated in ResNo9.

    National Research Ethics Commission (CONEP)

  • Circular Letter No. 16/2022/CONEP/SECNS/MS (July 4, 2022) – provides updated guidance on the processing of research protocols related to SARS-CoV-2 (Covid-19) and revokes several documents previously issued by CONEP.
  • Circular Letter No. 2/2021-CONEP/SECNS/MS (May 30, 2021) - guides the submission of research protocols with vaccines against COVID-19, in order to ensure research ethics, protection of participants, and compliance with the CEP/CONEP System Resolutions.

Google Translate Links: The Google Translate links provided in the profile are for information purposes only and may not always work as expected. ClinRegs does not control the quality or accuracy of translated content.

This message was reviewed on September 13, 2022
Are you an expert in Brazil’s clinical research requirements?
x
Click here to learn how you can help keep ClinRegs up to date.
Use the symbols below to refine your search
SymbolExplanation
No symbol At least one of the keywords must be present
Search example: serious adverse event
Result: Will contain serious and/or adverse and/or event
+ Leading plus sign indicates that the word must be present
Search example: serious +adverse event
Result: Will contain adverse and may contain serious and/or event
- Leading minus sign indicates that the word must not be present
Search example: serious adverse -event
Result: Will contain serious and/or adverse but won’t contain event
“ ” Exact phrase must be present
Search example: “serious adverse event”
Result: Will contain the phrase serious adverse event
Call for online focus group participants!
x

ClinRegs content is published in English. ClinRegs offers translations of the content through Google Translate, which is an external translation service. ClinRegs does not control the quality or accuracy of translated content and may result in unexpected and unpredictable degradation of portions of text, images and the general appearance on translated pages.