National Health Surveillance Agency (ANVISA)

As delineated in ResNo945 and ResNo585, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspection of drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of ResNo945 and ResNo585.

LawNo9.782 states ANVISA is an independent administrative agency linked to the Ministry of Health (MOH) that is responsible for regulating, controlling, and supervising products and services involving public health risks. LawNo9.782 and ResNo585 explain that the goods and products under the agency’s purview include medicines for human use and their active ingredients; immunobiologicals and their active substances, and blood and blood products, and; advanced therapy products and their active components, and other inputs, processes, and technologies.

As indicated in LawNo9.782 and ResNo585, ANVISA is headed by a Collegiate Board of Directors which is responsible for defining ANVISA’s strategic management plans, ensuring compliance with and enforcing regulatory acts relating to health surveillance, and proposing governmental policies and guidelines to the Minister in support of the agency’s objectives.

Additionally, as delineated in ResNo585, with respect to active pharmaceutical ingredients and medicines, the General Management of Medicines (Gerência-Geral de Medicamentos (GGMED)), which operates within ANVISA’s Collegiate Board, coordinates and supervises the organizational units responsible for regulation; manages the implementation of international cooperation activities; improves regulations; assesses quality, safety, and effectiveness; supervises registration/post-registration; and cooperates with inspection activities.

Per ResNo585, the Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is another administrative unit operating within the Collegiate Board. COPEC is responsible for overseeing clinical research on medicines and biological products conducted for registration and post-marketing surveillance purposes; evaluating petitions; carrying out Good Clinical Practice (GCP) inspections; assisting with international cooperation activities related to the regulation of clinical research on medicines involving human beings; and issuing regulations for granting or denying petitions subject to approval for the clinical research of medicines and biological products and decisions resulting from GCP inspections. See ResNo585 for detailed information on GGMED, COPEC, and ANVISA’s organizational structure and administrative units.

International Alignment

Per BRA-65, ANVISA is a regulatory member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ResNo945 indicates that ANVISA has formally adopted the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. (Note: The ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025. However, per the ICH Efficacy Guidelines webpage, ANVISA has not yet implemented it in Brazil).

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

Contact Information

Per BRA-132, the following is ANVISA’s contact information:

ANVISA
Assessoria do Sistema Nacional de Vigilância Sanitária
Setor de Indústria e Abastecimento (SIA)
Trecho 5 – Guará
Brasília – DF
CEP: 71205-050

Phone: (61) 3462-4120 or (61) 3462-6921
E-mail: asnvs@anvisa.gov.br

ANVISA’s Digital Contact Us Form for International Users (BRA-120) may be used to clarify questions and request information.

Phone: 0 800 642 9782 (for general inquiries) (BRA-135). Calls can be made to specific administrative offices posted on BRA-39.

Per BRA-12, the GGMED contact information is as follows:

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

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

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

This profile covers the role of the Department of Health & Human Services (HHS)’s Food & Drug Administration (FDA) in reviewing and authorizing investigational new drug applications (INDs) to conduct clinical trials using investigational drug or biological products in humans in accordance with the FDCAct, 21CFR50, and 21CFR312. Regulatory requirements for federally funded or sponsored human subjects research, known as the Common Rule (Pre2018-ComRule and RevComRule), which the HHS and its Office for Human Research Protections (OHRP) implements in subpart A of 45CFR46, are also examined. Lastly, additional HHS requirements included in subparts B through E of 45CFR46 are described in this profile, where applicable, using the acronym 45CFR46-B-E. (Please note: ClinRegs does not provide information on state-level requirements pertaining to clinical trials.)

Food & Drug Administration

As per the FDCAct, 21CFR50, and 21CFR312, the FDA is the regulatory authority that regulates clinical investigations of medical products in the United States (US). According to USA-92, the FDA is responsible for protecting public health by ensuring the safety, efficacy, and security of human and veterinary drugs, biological products, and medical devices.

An overview of the FDA structure is available in USA-33. Several centers are responsible for pharmaceutical and biological product regulation, including the Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER). Additionally, per USA-88, the Office of Clinical Policy (OCLP) develops clinical research policies, regulation, and guidance in collaboration with the FDA’s medical product centers.

Office for Human Research Protections and Common Rule Agencies

Per USA-93, the OHRP provides leadership in the protection of the rights, welfare, and well-being of human research subjects for studies conducted or supported by the HHS. The OHRP helps ensure this by providing clarification and guidance, developing educational programs and materials, maintaining regulatory oversight, and providing advice on ethical and regulatory issues in biomedical and social-behavioral research.

USA-65 states that the Common Rule (Pre2018-ComRule and RevComRule) outlines the basic provisions for institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the US), informed consent, and Assurances of Compliance. See USA-18 and USA-65 for more information on US departments and agencies that follow the Common Rule, which are referred to as Common Rule departments/agencies throughout the profile.

The RevComRule applies to all human subjects research that is federally funded or sponsored by a Common Rule department/agency (as identified in USA-65), and: 1) was initially approved by an EC on or after January 21, 2019; 2) had EC review waived on or after January 21, 2019; or 3) was determined to be exempt on or after January 21, 2019. (Per USA-74, the RevComRule is also known as the “2018 Requirements.”) For 2018 Requirements decision charts consistent with the RevComRule, including how to determine if research is exempt, see USA-74. For more information about the RevComRule, see USA-66.

Per the RevComRule, the Pre2018-ComRule requirements apply to research funded by a Common Rule department/agency (as identified in USA-65) that, prior to January 21, 2019, was either approved by an EC, had EC review waived, or was determined to be exempt from the Pre2018-ComRule. Institutions conducting research approved prior to January 21, 2019 may choose to transition to the RevComRule requirements. The institution or EC must document and date the institution's determination to transition a study on the date the determination to transition was made. The research must comply with the RevComRule beginning on that date. For pre-2018 Requirements decision charts consistent with the Pre2018-ComRule, including how to determine if research is exempt, see USA-74.

USA-65 indicates that the FDA, despite being a part of the HHS, is not a Common Rule agency. Rather, the FDA is governed by its own regulations, including the FDCAct and 21CFR50. However, the FDA is required to harmonize with the Pre2018-ComRule and the RevComRule whenever permitted by law.

If a study is funded or sponsored by HHS, and involves an FDA-regulated product, then both sets of regulations will apply. See G-RevComRule-FDA for additional information.

International Alignment

Per USA-16, the US is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). The FDA has implemented the Guideline for Good Clinical Practice E6(R3) in US-ICH-GCP, along with other ICH guidance. See USA-19 for the implementation status of all ICH guidelines. Additionally, see USA-22 and USA-47 for links to ICH guidance documents implemented by the FDA.

Contact Information

Food & Drug Administration

As per USA-81, USA-90, and USA-91, the contact information for the FDA is as follows (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

Main FDA Telephone (general inquiries): (888) 463-6332

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
10903 New Hampshire Avenue
Silver Spring, MD 20993-0002
CBER Telephone: (800) 835-4709 or (240) 402-8010
CBER Email (manufacturers assistance): Industry.Biologics@fda.hhs.gov
CBER Email (imports): CBERimportinquiry@fda.hhs.gov
CBER Email (exports): CBERExportCert@fda.hhs.gov

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Division of Drug Information
10903 New Hampshire Avenue
Building 51, Room 1109
Silver Spring, MD 20993
CDER Telephone (drug information): (301) 796-3400
CDER Email: druginfo@fda.hhs.gov

Office for Human Research Protections

Per USA-82, the contact information for the OHRP is as follows:

Office for Human Research Protections
1101 Wootton Parkway, Suite 200
Rockville, MD 20852
Telephone: (866) 447-4777 or (240) 453-6900
Email (general inquiries): OHRP@hhs.gov

Department of Health & Human Services

According to USA-83, the contact information for the HHS is as follows:

US Department of Health & Human Services
Hubert H. Humphrey Building
200 Independence Avenue, S.W.
Washington, D.C. 20201
Call Center: (877) 696-6775

Overview

As set forth in ResNo945 and ResNo585, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs)) for drugs to be registered in Brazil. (Note: Applications are also known as petitions in Brazil). Per ResNo945 and the G-DDCMManual, clinical trials with drugs must have all or part of their clinical development in Brazil. ResNo945 also notes that the DDCM may be submitted at any stage of clinical drug development for one (1) or more phases of clinical trials. However, Phase IV post-marketing trials and non-interventional clinical research are not covered by this regulation and should be initiated after obtaining the relevant ethical approvals in accordance with specific standards to be issued by the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)).

Additionally, pursuant to LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is required to undergo prior ethical analysis by research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). According to ResNo945, clinical trial applications may be submitted in parallel; however, a drug clinical trial can only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

Clinical Trial Review Process

As described in ResNo585, ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is responsible for conducting the review and approval of clinical trial applications (DDCMs). Per ResNo945 and the G-DDCMManual, ANVISA’s technical analysis of a primary DDCM petition will only occur after the filing of at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)). A DEEC is defined as a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) in the DDCM. ResNo945 explains that the absence of the DEEC will result in the rejection of the DDCM without technical analysis. An exception applies to clinical trials involving more than one (1) experimental drug, with a primary DEEC petition that has already been linked to one (1) of the DDCMs of these drugs.

Per LawNo14.874 and ResNo945, ANVISA may request, on one (1) occasion through a technical requirement, clarifications and additional documents during its review of primary DDCM and DEEC petitions, as well as secondary petitions for substantial investigational product (IP) modifications or substantial clinical trial protocol amendments. This action suspends, but does not interrupt, the applicable review deadlines. If ANVISA does not issue a decision within 90 days of receipt, the DDCM and corresponding DEEC will be released upon expiration of the review period, and clinical development may begin after the required ethical approvals have been obtained. See the Timeline of Review section for ANVISA’s petition review timelines.

Pursuant to ResNo945, substantial IP modifications are changes that may affect the quality or safety of the experimental drug, active comparator, or placebo. Per ResNo945 and the G-DDCMManual, substantial IP modifications must be linked as secondary petitions to the corresponding DDCM. Non-substantial IP modifications must always be submitted to ANVISA in the next petition for substantial IP modification or as part of the drug development safety update (DSUR), whichever occurs first. ANVISA will issue a supplementary regulatory act regarding which IP modifications are considered substantial or non-substantial. Refer to the Submission Process and Submission Content sections for IP modification submission process and documentation requirements.

ResNo945 explains that a clinical trial protocol amendment is considered substantial if it meets at least one (1) of the following criteria:

• Protocol changes that interfere with the safety or physical or mental integrity of the participants, or
• A change that is likely to have an impact on the reliability or robustness of the clinical trial data

Per ResNo945 and the G-DDCMManual, substantial protocol amendments must be submitted as secondary petitions linked to the corresponding DEEC. ResNo945 further explains that non-substantial protocol amendments must be submitted to ANVISA in the next petition for a substantial amendment, or, if no substantial amendments by the end of the clinical trial, as part of the final clinical trial protocol monitoring report. ANVISA will issue a supplementary regulatory act to comply with these provisions. See the G-DDCMAmdmts for additional information on protocol amendments. Refer to the Submission Process and Submission Content sections for protocol amendment submission requirements and substantial protocol amendment documentation requirements.

Per BRA-134 and ResNo506, ANVISA also reviews requests for clinical trials using advanced therapy products, which are known as Clinical Development Dossiers for Advanced Therapies (Dossiês de Desenvolvimento Clínico de Produtos de Terapias Avançadas (DDCTA)). See ResNo506 for more information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products in Brazil (i.e., medicines for human use that are based on genes, tissues, or cells). Per ResNo945, in the case of clinical development involving genetically modified organisms (GMOs) or derivatives, an applicant must consult the responsible body, the National Technical Commission on Biosafety – CTNBio (Comissão Técnica Nacional de Biossegurança – CTNBio), in accordance with current legislation.

ResNo945 further delineates that DDCM, DEEC, and secondary petitions submitted to ANVISA prior to the publication of ResNo945 and still awaiting technical analysis will be assessed in accordance with the rules and requirements in force at the time of submission. Sponsors may also request that ANVISA review these petitions according to the optimized analysis procedure requirements described below in this section.

In addition, per ResNo997, ANVISA has established exceptional and temporary measures to optimize the analysis queue for clinical research approvals. Primary and secondary petitions for medicines and biological products that meet the criteria for the optimized analysis procedure based on regulatory reliance (Reliance) are assigned to a specific review queue, which may affect their processing order. Priority petitions that also meet these criteria are given priority over other petitions in the Reliance review queue. See below for more information on the optimized analysis procedure. See BRA-139 and BRA-136 for additional information on ANVISA’s exceptional and temporary review procedures and BRA-138 for frequently asked questions (FAQs) on ResNo997. Note: ResNo997 will remain in effect until December 31, 2026.

Pursuant to ResNo945, ANVISA may, at any time, cancel or suspend the DDCM, any associated clinical trial, or related secondary petitions if:

• It determines the approval conditions have not been met or receives reports of safety, quality, or efficacy issues that significantly affect the trial participants or the reliability or robustness of the clinical trial data
• It concludes that participants are being exposed to significant and unreasonable risks
• It determines that the sponsor has violated the requirements of ResNo945 or failed to comply with the good clinical practice (GCP) principles and IP good manufacturing practice (GMP) requirements

To comply with these provisions, per ResNo945, ANVISA will notify the sponsor of the suspension or cancellation of the DDCM or associated clinical trial and, where appropriate, initiate an administrative and/or investigative proceeding, in accordance with applicable legislation.

ResNo205 establishes specific approval procedures for clinical trials conducted to support the registration of new drugs intended to treat, diagnose, or prevent rare diseases. See the Submission Process section for rare disease clinical trial submission requirements.

Inspection

In accordance with LawNo14.874, ANVISA is authorized to conduct GCP inspections of clinical research centers, sponsors, and contract research organizations (CROs) (clinical research representative organizations (CRPOs) in Brazil). ResNo945 further specifies that ANVISA may inspect clinical trial centers, sponsors, CROs, laboratories, and other institutions involved in IP development to verify compliance with applicable Brazilian legislation and GCP. In addition to ANVISA’s GCP inspection standards, GCP inspections follow the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates, which Brazil has formally adopted. Refer to ResNo945 for more information on ANVISA’s GCP inspection requirements.

RegNo122 also provides guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with GCP. Per BRA-30, ANVISA’s COPEC conducts all clinical trial inspections in accordance with BRA-28. GuideNo35-2020 and GuideNo36-2020 further explain that GCP inspections of sponsors, CRO representatives, and clinical trial centers may be carried out before, during, or after a clinical trial and are classified as routine inspections or inspections based on complaints or suspected irregularities, per RegNo122. The guides also explain that inspections must involve at least two (2) ANVISA inspectors, one (1) of whom serves as the lead inspector and focal point for communication with the clinical trial center or sponsor/CRO(s). Inspections will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.

Priority Submissions

Per ResNo1001, primary DDCM and DEEC petitions, as well as secondary petitions for substantial IP modifications and substantial protocol amendments, may qualify for priority classification. Primary DDCM petitions and secondary petitions for substantial IP modifications are eligible for priority classification if they meet one (1) or more of the following criteria:

• New drug trial in any phase to be carried out in Brazil
• Vaccines of interest to the Ministry of Health (MOH)’s National Immunization Program
• The drug is the subject of an MOH Product Development Partnership or a Local Development and Innovation Program

Per ResNo1001, primary DEEC petitions and secondary petitions for substantial protocol amendments are eligible for priority classification if they meet one (1) or more of the following criteria:

• Clinical trials with drugs, including vaccines, for neglected, emerging, or reemerging diseases, and for medical emergencies in public health
• Clinical trials with drugs, including vaccines, for serious debilitating conditions in situations for which no prophylactic alternative exists
• Clinical trials conducted exclusively with the pediatric population
• Phase I clinical trials conducted exclusively in Brazil

According to ResNo1001, ANVISA must determine eligibility for the priority classification within 45 calendar days of the petition filing date. Once priority classification is granted, ANVISA has 45 days from the first business day after the priority petition is filed to issue its first technical response and 60 days from the applicable filing date to issue a final decision. If ANVISA’s technical area determines that the petition is not eligible for priority classification, the priority request will be denied. See the Submission Process and Timeline of Review sections for detailed priority submission procedures and review timelines.

Optimized Analysis Procedure Submissions

As delineated in ResNo945, ANVISA has adopted a technical evaluation mechanism known as the “optimized analysis procedure,” under which evaluations conducted by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) may be used as a sole or complementary basis for decision-making. AREEs are regulatory authorities whose practices are aligned with those of ANVISA and are therefore considered to be within the scope of regulatory reliance (Reliance). The optimized analysis procedure may be applied based on Reliance on AREE assessments or based on ANVISA-defined criteria regarding the risk or complexity of the clinical trial or the IP. See also BRA-137 for additional information on Reliance.

ResNo945 further states that clinical trials and/or IPs approved under the optimized analysis procedure—based on Reliance, experience with the use of the IP, or authorization by expiration of the review period—may be subject to on-site inspection. Such inspection may result in alteration of the decision, a request for additional evidence, or any other necessary sanitary measure, without prejudice to other applicable legal measures.

Reliance Reviews

ResNo945, RegNo338, and BRA-122 explain that the optimized analysis procedure based on Reliance may be applied, upon sponsor request, to the approval of primary DDCM and DEEC petitions, as well as secondary petitions for substantial modifications to the IP and substantial amendments to the clinical trial protocol. The documents required to support each type of petition or submission may be partially or fully exempted from technical review under the optimized analysis procedure by Reliance. ANVISA will also issue a supplementary normative act to establish the criteria and documents that may be partially or fully exempted from technical analysis under Reliance.

Pursuant to ResNo945, ANVISA will review the AREE documentation for compliance. Per ResNo945 and RegNo338, for the purposes of admissibility for analyzing primary and secondary petitions, the related documents must have been approved by at least one (1) of the AREEs recognized by ANVISA.

Per RegNo338, ANVISA has designated the following AREEs to review primary DDCM and DEEC petition requests, and secondary petition requests for substantial modifications to the IP and substantial amendments to the clinical trial protocol:

• European Medicines Agency (EMA) and its member countries
• Health Canada
• Swiss Agency for Therapeutic Products (Swissmedic)
• Medicines and Healthcare Products Regulatory Agency (MHRA), United Kingdom
• US Food and Drug Administration (FDA)
• Pharmaceuticals and Medical Devices Agency (PMDA), Japan

ANVISA must be given the sponsor’s consent to communicate directly with the AREE about the clinical development process under analysis. ANVISA will also review any commitment terms or conditional approval assumed with the AREE and the details about the respective pending issues and referrals, if applicable.

According to RegNo338, following its evaluation under the optimized analysis procedure by Reliance, ANVISA will issue one (1) of the responses listed below:

• If the criteria for applying the optimized analysis procedure by Reliance are met, the status of the secondary petition request will be updated to "Approved"
• If the secondary petition submitted under the optimized analysis procedure by Reliance are not met, the status of the petition request will be updated to "Not Approved", and all documents linked to the petition will be subject to a full analysis, as described in ResNo945. In this case, an official letter will be sent to the company with the respective justification

ResNo945 and BRA-122 further state that the admissibility of the optimized analysis procedure based on Reliance does not presuppose prioritization of petition analysis, however, per ResNo945, ANVISA may create specific queues for the allocation and analysis of these petitions. BRA-122 also indicates that petitions will be analyzed in accordance with the chronological order of submission (issue date of the file), regardless of whether they fit into the optimized procedure. However, petitions prioritized under the terms of ResNo1001 and ResNo205 may also be included in the criteria for applying the optimized analysis procedure when requested by the applicant.

Additionally, per ResNo945 and BRA-122, ANVISA will be responsible for deciding whether to accept the request for analysis using the optimized procedure, including opting for the ordinary analysis of the petition, regardless of the decision issued by the AREE. Per ResNo945, ANVISA may carry out complementary monitoring actions, such as GCP audits or inspections to monitor DDCMs, DEECs, and secondary petitions approved by the optimized analysis procedure. Monitoring actions include the assessment of information regarding the safety profile, based on national and international alerts, and other duly justified actions, at ANVISA’s discretion, that may contribute to maintaining the approved conditions.

See the Submission Process and Submission Content sections for detailed submission requirements.

Risk and Complexity Based Reviews

As delineated in ResNo945, the optimized analysis procedure may also be applied based on the risk or complexity criteria of the clinical trial or IP. When requested by the sponsor, this type of technical analysis applies to DDCMs and substantial IP modifications. The required documents for each type of petition or submission may be partially or fully exempted from technical analysis according to the assessed risk and complexity of the clinical trial. ANVISA categorizes clinical trial risk as low, moderate, or high. Refer to RegNo338 for more information on risk assessment criteria.

ResNo945 further notes that in cases where the placebo, when used, is identical to the registered IP, differing from it only by the absence of the active pharmaceutical ingredient (API), and/or when the active comparator is identical to the registered drug, ANVISA’s evaluation of the documents present in the Investigational Medicinal Product Dossier (IMPD) or Investigational Product Dossier (DPI) may also be analyzed using the optimized analysis procedure based on risk assessment. Per RegNo338, ANVISA will provide a specific petition characterization form for the sponsor to complete for the proper identification of situations in which the optimized analysis procedure is supported by experience using the IP. BRA-122 further indicates that when ANVISA considers an AREE evaluation of an API and DPI, the Investigator's Brochure (IB) or a clinical protocol, the analysis of these documents may be partially or totally waived, as long as they are the same versions previously analyzed by the AREE, except when it concerns a complex clinical trial, prophylactic and therapeutic vaccines, and biosimilar products.

Overview

In accordance with the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312, institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).

As delineated in 21CFR312 and USA-42, sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"

According to USA-42, the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:

• Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.

• Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.

• Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.

Per the G-PharmeCTD, non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.

As indicated in the G-IND-Determination, in general, human research studies must be conducted under an IND if all of the following research conditions apply:

• A drug is involved as defined in the FDCAct

• A clinical investigation is being conducted as defined in 21CFR312

• The clinical investigation is not otherwise exempt from 21CFR312

The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct.

Further, per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.

Clinical Trial Review Process

As delineated in 21CFR312, the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.

As per USA-41 and USA-94, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312, an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312, the G-InvstgtrHold, and the G-HoldResp for more information on clinical holds.

According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.

As indicated in 21CFR312, the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, at the sponsor's request, the FDA will provide advice on specific matters relating to an IND.

21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.

As per 21CFR312, if no subjects are entered into a clinical study for a period of two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.

21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.

As stated in 21CFR312, the FDA will accept, as support for an IND, a well-designed and well-conducted foreign clinical study not conducted under an IND. The study must have been conducted in accordance with good clinical practice (GCP), and the FDA must be able to validate the data from the study through an onsite inspection if the agency deems it necessary. Although the FDA will not accept a study that does not meet those conditions as support for an IND, the FDA will still examine data from such a study. See 21CFR312 and the G-FrgnCT for more details on submitting data from a foreign clinical study not conducted under an IND as support for an IND.

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Per the G-BiorsrchInspct, the FDA developed a Bioresearch Monitoring (BIMO) program to assess the quality and integrity of data submitted to the FDA in support of regulatory decision-making, as well as to provide for protection of the rights, safety, and welfare of human trial participants involved in FDA-regulated research. The BIMO program, which involves on-site inspections, investigations, and remote regulatory assessments, assesses compliance with statutory requirements and the FDA’s regulations governing the conduct of nonclinical and clinical studies, as well as applicable postmarketing activities. See the G-BiorsrchInspct and USA-20 for more information on FDA inspections and the BIMO program.

Expedited Processes

USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:

• Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
• Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
• Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
• Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need

See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.

Other Considerations

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials. Additionally, see the G-ExplrtryIND for FDA guidance regarding exploratory studies in humans.

For research involving cellular and gene therapy, see the guidance documents at USA-80.

National Health Surveillance Agency (ANVISA)

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

Per BRA-69, ANVISA determines the TFVS fee based on the company’s size and the subject code assigned to the application request. Per the TFVS fee table provided in ResNo857 and OrdNo45, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval. Per BRA-69, users can also obtain their petition fee prior to submission by searching ANVISA’s Consultation System webpage (BRA-44) using the “Subject Consultation” (Consulta de Assuntos) tool. BRA-44 provides the fee value based on the petition description subject code. See BRA-69 for further fees information. See also BRA-129 for additional instructions on searching BRA-44.

Payment Instructions

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

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

Food & Drug Administration

The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.

However, per the FDCAct, the FDARA, and USA-45, the FDA has the authority to collect user fees from persons that submit certain human drug applications for review or that are named in approved applications as the sponsor of certain prescription drug products. See USA-45 for more information.

Overview

As delineated in LawNo14.874, DecreeNo12.651, and ResNo466, Brazil has a decentralized process for the ethical review and approval of clinical trial research. Per LawNo14.874, investigators are required to submit the research documentation, including any amendments, to a research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) for approval. ECs (CEPs) operate under the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)) and are subject to the requirements established by LawNo14.874 and DecreeNo12.651, as well as National Health Council (Conselho Nacional de Saúde (CNS))-issued standards currently in force under the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)).

Note: Brazil is currently transitioning from the CEP/CONEP System under the CNS to SINEP. Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

LawNo14.874 establishes SINEP, and DecreeNo12.651 further defines its framework. SINEP is comprised of INAEP and includes an ethics review component, (Instância de Análise Ética em Pesquisa), which is carried out by the ECs (CEPs). ECs (CEPs) are overseen and credentialed, and where applicable, accredited by INAEP and are responsible for the ethical review of clinical trial protocols involving human beings.

In addition, LawNo14.874 and DecreeNo12.651 explain that the role of the ECs (CEPs) is defined according to the complexity of the ethical review and the degree of risk involved in the research, as follows:

• An EC (CEP) credentialed by INAEP, for the ethical review of low or moderate risk research
• An EC (CEP) credentialed and accredited by INAEP for the ethical review of high-risk research and for the review of low or moderate risk research

CEP/CONEP System (Pre-SINEP Framework)

As per ResNo466, ResNo446, and OSNo001, CONEP is the central body responsible for coordinating the network of institutional ECs (CEPs), and for registering and accrediting the ECs (CEPs). CONEP is a collegiate advisory body directly linked to the CNS, a permanent body within the MOH’s Health System (Sistema Único de Saúde (SUS)) (BRA-53).

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

Ethics Committee Composition

National System of Ethics in Research Involving Human Beings (SINEP)

As stated in LawNo14.874 and DecreeNo12.651, the ECs (CEPs) should be composed of a collegiate and interdisciplinary team, of a consultative and deliberative nature, from medical scientific and non-scientific fields. LawNo14.874 specifies that EC (CEP) members should have the necessary qualifications and experience to analyze all aspects inherent to the research, including medical, scientific, ethical aspects and those related to good clinical practice (GCP). The EC (CEP) is also required to have in its composition one (1) Research Participant Representative (Representante de Participante de Pesquisa (RPP)).

DecreeNo12.651 further explains that the selection of representatives from the scientific community should be made through a public selection process, with criteria that prioritize representation and the promotion of regional, ethnic-racial, gender, and interdisciplinary diversity. These representatives must have academic training and professional experience in the areas of medicine, pharmacy, biotechnology, law, bioethics, or other areas of the human and social sciences, health, and other emerging fields for research involving human beings. An interdisciplinary composition that reflects technical knowledge should also be ensured. The selected specialists must hold a doctoral degree or at least 10 years of professional experience serving on ECs (CEPs) involving human beings or in the analysis, conduct, and development of human research protocols. See DecreeNo12.651 for additional details on the public selection process and appointment procedures.

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

As per OSNo001 and ResNo446, CONEP is an independent and multidisciplinary organization consisting of 30 appointed members and five (5) alternate members. Per ResNo446, CONEP also has an Executive Secretary appointed by the MOH’s Secretariat for Science, Technology and Strategic Inputs and an Assistant Secretary appointed by the CNS to coordinate CONEP’s work and to manage the technical and operational work to be carried out by the Executive Secretary. See ResNo466, OSNo001, and ResNo446 for detailed information on CONEP composition and responsibilities. See also BRA-50 for useful information on CONEP.

Research Ethics Committees (CEPs)

Within the CEP/CONEP System, OMREC indicates that an EC (CEP) should be composed of a minimum of seven (7) members having proven expertise in research. ResNo706, in turn, states the EC (CEP) must be composed of at least nine (9) members with at least two (2) RPPs. Additionally, OSNo001, OMREC, and ResNo706 indicate that the EC (CEP) should be multidisciplinary, represent a balanced gender and age composition, and consist of members embodying community interests and concerns.

OMREC and ResNo706 further state that not more than half of its members should belong to the same professional category. Additionally, per ResNo706, at least half of the members must demonstrate experience in research. Also, any changes to the infrastructure, composition of members or administrative employees must be communicated to CONEP. When there is a change in EC (CEP) member composition, at least one third of the members of the previous composition must be maintained. Changes in EC (CEP) coordination must also be communicated and approved by CONEP. See ResNo706 for additional information. Additional criteria for EC (CEP) membership are also available in Section 2 of OMREC.

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

Terms of Reference, Review Procedures, and Meeting Schedule

National System of Ethics in Research Involving Human Beings (SINEP)

Pursuant to OrderNo1, the internal regulations of the ECs (CEPs) must contain sufficient rules to ensure the regular functioning of the committees, the integrity of deliberations, and compliance with the legal deadlines applicable to the ethical analysis of research. ECs (CEPs) may implement certain administrative changes to their internal regulations immediately after formal notification to INAEP, accompanied by an update to the EC’s (CEP's) internal regulations, when applicable. However, ECs (CEPs) are required to obtain the approval of INAEP Coordination to establish changes that impact the composition, governance, or decision-making structure of the EC (CEP). See OrderNo1 for additional INAEP requirements.

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

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

As described in LawNo14.874 and OrderNo1, EC (CEP) internal regulations and procedures must include at a minimum (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Previously scheduled meetings to deliberate on the ethical adequacy of the research
• Rules for convening and holding ordinary and extraordinary meetings
• Minimum quorum for the meeting to begin and for deliberations
• Rules regarding the composition of the board, disqualification, bias, and conflict of interest
• Rules for drafting minutes and recording resolutions
• Criteria for replacing full members with alternate members and expressly distinguishing between the roles of full member, alternate member, and alternate member acting as a substitute
• Frequency of meetings must be sufficient to ensure the regular functioning of the collegiate body, the timeliness of ethical analysis, compliance with the deadlines established in LawNo14.874, and the possibility of extraordinary meetings whenever necessary
• Description of the responsibilities of the coordinator and the deputy coordinator, if any, as well as the rules for substitution in case of absence
• Consultants or ad-hoc members who may be invited to contribute to the analysis of a specific matter are not part of the EC’s (CEP’s) deliberative body and do not have the right to vote

LawNo14.874 further states that only active EC (CEP) members are permitted to issue opinions and deliberate on the ethical adequacy of submitted research. Once duly credentialed, and where applicable, accredited, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP. ECs (CEPs) will also keep all project related documents on file for a period of five (5) years after the end of the research, with digital archiving permitted.

Also, per LawNo14.874, in the case of research involving a special group, to be established by regulation, the EC (CEP) must ensure, whenever possible, during the protocol discussion, the participation of one (1) representative of the special group as an ad-hoc member; and one (1) consultant familiar with the language, customs, and traditions of the specific community, when the research involves that community. EC (CEP) members may also invite external experts and representatives of vulnerable groups to issue an opinion on specific issues related to the research projects, but these individuals should not have the right to vote. See also the Vulnerable Populations section for requirements applicable to research involving special groups.

As stated in LawNo14.874, the institution hosting the EC (CEP) will promote and support the training of its committee members, with an emphasis on ethical and methodological aspects related to the rights of research participants. The EC (CEP)’s activities are subject to oversight and monitoring by INAEP. Failure by the EC (CEP) to comply with the provisions of LawNo14.874 will result in its de-accreditation by INAEP, in accordance with regulations.

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

CEP/CONEP System (Pre-SINEP Framework)

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

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

ResNo706 further notes that an EC (CEP) is responsible for receiving and considering, from an ethical point of view, the research protocols indicated by CONEP. However, the committee may also refuse the ethical assessment of research protocols indicated by CONEP, upon justification. Per OMREC and ResNo706, the majority of committee members must be involved in the review and approval process, and the necessary quorum must be obtained to approve or deny permission to conduct a study as specified in each EC (CEP’s) SOPs. As per ResNo706, the term of office of EC (CEP) members is valid for four (4) years, with the possibility of reappointment, at the discretion of the CEP. At the end of the term of office, an EC (CEP) member may remain in this role up to 90 days, until a replacement or reappointment takes place.

See OMREC for detailed EC (CEP) procedures and information on other administrative processes. See CLNo25 for guidance on conducting virtual CEP/CONEP System meetings.

Overview

As indicated in 21CFR50, 21CFR56, and 21CFR312, the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)

As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.

The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.

(See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.)

Per the RevComRule, for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule. Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on EC composition, functions, and operations.

Ethics Committee Composition

As stated in 21CFR56, the Pre2018-ComRule, and the RevComRule, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.

At a minimum, each EC must also include the following members:

• One (1) primarily focused on scientific issues
• One (1) focused on nonscientific issues
• One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution

No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.

Additionally, 21CFR56 indicates that efforts must be made to ensure that no EC consists entirely of men or entirely of women, including the institution’s consideration of qualified persons of both sexes, so long as no selection is made to the EC on the basis of gender. No EC may consist entirely of members of one (1) profession.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in 21CFR56, ECs must follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

Per the Pre2018-ComRule and the RevComRule, ECs must establish and follow written procedures for the following:

• Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
• Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
• Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
• Ensuring prompt reporting to the EC, the institution, and the Department of Health & Human Services (HHS)’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination

21CFR56, the Pre2018-ComRule, and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule, the RevComRule, and 21CFR56.

See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.

Per 21CFR56, the Pre2018-ComRule, and the RevComRule, proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.

Refer to the Pre2018-ComRule, the RevComRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.

In addition, per the Pre2018-ComRule, the RevComRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65) must also submit a written assurance of compliance to OHRP. According to USA-59, the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-supported or conducted non-exempt human subjects research. See USA-57 for more information on FWAs.

Overview

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

LawNo14.874 establishes SINEP, and DecreeNo12.651 further defines its framework. Within this system, ECs (CEPs), overseen by INEAP, are responsible for the ethical review of clinical trial protocols involving human beings.

As delineated in LawNo14.874 and DecreeNo12.651, the primary scope of information reviewed by ECs (CEPs) under SINEP relates to protecting the dignity, safety, and well-being of research participants throughout the conduct of research. ECs (CEPs) are responsible for acting independently and autonomously in the ethical analysis, review, and approval of research protocols and their amendments, as well as for evaluating the methods and materials used to obtain and document the free and informed consent of research participants.

As part of their ethical review, LawNo14.874 indicates that ECs (CEPs) are also responsible for requesting additional information for research participants when deemed essential to protect their rights, safety, and well-being. They must ensure research project and other documents adequately address relevant ethical issues and comply with applicable regulatory requirements, including those related to good clinical practice (GCP). ECs (CEPs) should also ensure that adequate means are provided for obtaining consent from the research participant or the legal representative and that they pay special attention to protecting the welfare of participants deemed to be vulnerable. DecreeNo12.651 further states that research involving special groups, due to their vulnerability or unique ways of life, may require differentiated ethical, methodological, or analytical treatment at all stages, as will be established in regulations to be issued by INAEP. (See the Vulnerable Populations and Pregnant Women, Fetuses & Neonates sections for additional information about these populations).

See OrderNo5 for INAEP's ethical guidance regarding bioequivalence, bioavailability, and other pharmacokinetic studies involving drugs with cytotoxic, genotoxic, teratogenic, mutagenic, or other high systemic toxicity risks.

In accordance with LawNo14.874 and DecreeNo12.651, the EC (CEP) review process must be guided by the following principles (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Protection of the dignity, safety, and well-being of the research participants
• Promotion of technical-scientific development and responsible innovation
• Guarantee of independence, transparency, and public disclosure in procedures and decisions
• Equality in the application of criteria and procedures for the review of research projects, based on the risk-benefit ratio, which must be favorable to the research participant and to society
• Efficiency, timeliness, and quality in the review and issuance of opinions
• Interdisciplinary and plural composition of the ECs (CEPs) as a qualifying element of ethical judgment
• Social oversight, with the participation of research participant representative(s)
• Respect for GCP

CEP/CONEP System (Pre-SINEP Framework)

ResNo466, ResNo251, and the G-ClinProtocols-FAQs state that the primary scope of information assessed by ECs (CEPs) and CONEP, jointly known as the CEP/CONEP System, relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in research.

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

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

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

Exemption from Review

Pursuant to Article 26 of ResNo674, CLNo12 provides additional guidance on research that is exempt from ethical assessment by the CEP/CONEP System. Exempt research includes protocols that fall exclusively within the following categories: public opinion surveys with unidentifiable participants; research using publicly accessible or public domain information; census research conducted by government agencies; research using only information or data already available in aggregate form, without the possibility of individual identification; research conducted exclusively with scientific texts for literature review purposes; research that aims at the theoretical deepening of situations that emerge spontaneously in professional practice, provided no identifiable data are disclosed; education, teaching, extension or training activities conducted solely for instructional purposes by undergraduate students, technical course students, or professionals in specialization programs, without the purpose of scientific research; market research; scientific research carried out with cells, tissues, organs, and organisms of nonhuman origin, including their biological products, provided there is no interaction with research participants or the collection or use of human biological material; and activities intended solely to describe or analyze productive or administrative processes exclusively for organizational development purposes.

Role in Clinical Trial Approval Process

National System of Ethics in Research Involving Human Beings (SINEP)

Pursuant to DecreeNo12.651, the review of protocol authorization requests for clinical research may be carried out through an integrated ethical and sanitary assessment procedure established between INAEP and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). The procedure should prioritize studies involving products intended to address public health emergencies declared by a competent authority.

Per LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is required to undergo prior EC (CEP) ethical review. According to ResNo945, clinical trial applications may be submitted in parallel; however, a drug clinical trial can only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

In addition, ResNo945 requires the EC (CEP) to review and approve any protocol amendments prior to those changes being implemented. There is no stated expiration date for an EC (CEP) approval in ResNo945. LawNo14.874 further notes that the EC (CEP) research ethics review process will be conducted using the information and documents to be established in specific regulations. All documents requested by the EC (CEP) must be specified in an act issued by the MOH, in EC (CEP) regulations or rules, and be relevant to the matter analyzed.

As explained in OrderNo2, LawNo14.874 establishes two (2) timeframes in the EC (CEP) ethical review process: verification of the completeness of the documentation within 10 working days from the date of protocol submission, and issuance of the ethical opinion within 30 days from the date of accepting all of the research documentation. Before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor or require adjustments to the research documentation. EC (CEP) review will be suspended during this time, and the investigator will be given time to respond to the requests made by the EC (CEP). However, the investigator’s failure to respond within the EC (CEP) deadline may result in cancellation of the study's review process. Per LawNo14.874, at the discretion of the EC (CEP), the investigator may participate in the meeting to provide clarification about the research, but the investigator is prohibited from attending the meeting while the final decision is being made. See the Timeline of Review section for detailed timeline information.

Upon completion of EC (CEP) review, LawNo14.874 indicates that the EC (CEP) opinion will be one (1) of the following: approval of the research; non-approval of the research; or, suspension, when approved research that is already in progress needs to be interrupted for safety reasons. The investigator may initially appeal the decision to the EC (CEP) that issued the opinion, and appeal one (1) final time to INAEP. All those involved in conducting, monitoring, evaluating, or approving the research with direct access to the study records to verify compliance with the procedures and applicable legislation, as well as the validity or integrity of the data, must ensure the preservation of data confidentiality and the anonymity of the research participant, in accordance with current legislation.

Per LawNo14.874, after the research begins, if there is a need for a change that interferes with the risk-benefit balance or the approved documentation, the EC (CEP) that initially reviewed the research must analyze and issue an opinion for an amendment to the research project submitted by the coordinating investigator. The amendment may only be implemented after approval by the EC (CEP), in accordance with this law, except when the safety of the research participant depends on its immediate implementation. The provisions for the initial research project review are also applicable to amendments to the research project.

In addition, LawNo14.874 provides that research conducted involving human beings that does not comply with the provisions of this law constitutes an ethical infraction and subjects the offender to disciplinary sanctions provided for in the legislation of the professional council to which the sponsor or the contract research organization (CRO) is affiliated, without prejudice to applicable civil and criminal sanctions. For the purpose of applying these disciplinary sanctions, the EC (CEP) or INAEP will notify the competent professional councils of the ethical infraction committed. Failure to comply with the provisions of LawNo14.874, and failure to comply with the GCP standards per ResNo945, constitutes a health infraction and subjects the offender to the penalties provided for in LawNo6.437, and in specific health regulations, without prejudice to applicable civil and criminal sanctions.

Risk-Based Framework

Decree No. 12.651 further provides that EC (CEP) ethical reviews under SINEP use a risk-based approach from which the degree of risk is classified, considering various factors, including:

• The nature of the intervention or procedure adopted in the research
• The degree of invasiveness and the potential for harm to the research participant
• The population involved, with particular attention to groups in situations of vulnerability
• The use of emerging technologies, sensitive data, or artificial intelligence in healthcare
• The degree of scientific uncertainty regarding the effects of the object of study
• The existence of direct benefits from the research to the participant and to the community
• The complexity of the study design
• The stage of clinical development of the product or technology being evaluated
• Clinical research conducted on a multicenter or international basis

Based on risk classification, per DecreeNo12.651, simplified procedures may be adopted for the submission of documentation, as well as for the review and authorization of clinical research studies. Research protocols are also processed according to their risk level. BRA-143 further clarifies that risk classification must stem from a multidimensional analysis that balances the risks and benefits to the health, safety, dignity, and well-being of the participants with the legitimate interest in the advancement of scientific knowledge.

Additionally, LawNo14.874 and DecreeNo12.651 delineate that the role of ECs (CEPs) is defined according to the complexity of the ethical review and the degree of risk involved in the research, distinguishing between INAEP-credentialed ECs (CEPs), which review low- and moderate-risk research, and INAEP-credentialed and accredited ECs (CEPs), which are authorized to review high-risk research as well as studies involving low or moderate risk levels. Within this framework, and in accordance with the review workflow indicated in DecreeNo12.651, CONEP serves as the appellate body until INAEP members take office. BRA-142 further specifies that, pending further INAEP guidance, responsibility for the ethical review of low- and moderate-risk research protocols should rest with credentialed ECs (CEPs) affiliated with the MOH (e.g., foundations, institutes, hospitals, etc.), while the responsibility for the ethical review of high-risk protocols, specifically those listing the MOH as the proposing institution, should rest with credentialed and accredited ECs (CEPs), as described in DecreeNo12.651. See also BRA-143 and BRA-142 for additional guidance.

High-Risk Research Protocols

Under the SINEP system, per BRA-143, eight (8) accredited ECs (CEPs) are responsible for reviewing all high-risk protocols (see BRA-143 for a list of accredited ECs (CEPs)). Exceptions to this workflow requirement include biobank development protocols, which have been temporarily suspended per BRA-142, as well as certain categories of protocols for which the MOH serves as the proposing institution.

In addition, per BRA-143, high-risk protocols that have already been reviewed and approved by an accredited EC (CEP) should be returned to the original EC (CEP) that conducted the review, thereby preserving the ethical opinion issued and the validity of the decision rendered by the competent body. Protocols that do not fall under the high-risk classification should be returned to the researchers, thereby retaining the opinion previously issued by the originating EC (CEP). BRA-141 also notes that accredited ECs (CEPs) will conduct ethical reviews of high-risk protocols, in accordance with ResNo466 and CLNo172, until INAEP issues specific regulations on risk classification.

Priority Review for SUS Strategic Research

Per LawNo14.874 and DecreeNo12.651, research of strategic interest to the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53) and relevant to responding to public health emergencies is given priority in ethical analysis and is subject to special analysis procedures, including deadlines. These procedures will be further delineated in a separate act to be issued by INAEP, as provided in DecreeNo12.651.

DecreeNo12.651 also specifies that clinical research intended for the sanitary registration of medicines or medical devices is prioritized within SUS when the research is:

• Funded, in whole or in part, with public resources derived from government agencies or from funds for the promotion of science, technology, and innovation
• Aimed at the treatment, prevention, or diagnosis of socially determined, emerging, or re-emerging diseases; severe or debilitating clinical conditions for which no therapeutic or prophylactic alternative is available; and rare diseases
• Targeting the pediatric population, for which no therapeutic or diagnostic alternative is available
• The subject of the MOH Productive Development Partnership, a Local Development and Innovation Program, or related initiatives within the scope of the Health Economic-Industrial Complex
• The active pharmaceutical ingredient is manufactured domestically
• Involves new medicines, medical devices, and advanced therapies for which clinical development and production are carried out domestically
• Involves vaccines of interest to the MOH’s National Immunization Program

See the Timeline of Review section for detailed SUS timeline information.

Multicenter Research

Pursuant to LawNo14.874, DecreeNo12.651, OrderNo3, and BRA-141, multicenter research conducted across different research centers by more than one (1) researcher follows a single protocol. The ethical review of multicenter research is conducted by a single EC (CEP), preferably the EC (CEP) linked to the coordinating research center, which issues the opinion and notifies the other participating center ECs (CEPs) of its decision. Per OrderNo3, the EC (CEP) responsible for the initial approval has formal decision-making authority over the ethical review and monitoring of multicenter research, as well as the authority to assess amendments to the original project. OrderNo3 further recommends that the coordinating EC (CEP) provide participating center ECs (CEPs) with at least five (5) working days to submit comments on local population vulnerabilities, regional particularities, or local institutional arrangements before issuing the final ethical opinion, while ensuring compliance with the 30-working day ethical review period.

OrderNo3 further provides that participating center ECs (CEPs) may not conduct a parallel ethical review of an approved protocol or independently suspend the approved multicenter protocol. However, if serious irregularities or unforeseen imminent risks to research participants within its institution are identified, the participating center EC (CEP) must issue a technical recommendation to the management of the institution or research center to adopt measures to immediately halt research activities at that site. It must also, preferably within 24 hours, communicate the matter and forward the technical recommendation to the EC (CEP) responsible for the ethical review and to INAEP so that those bodies may take the appropriate measures. Additionally, participating center ECs (CEPs) act as local ethical protection bodies and conduct material and institutional monitoring of research at their respective centers. Their responsibilities include receiving complaints from research participants at their institutions; receiving local serious adverse event notifications; recording and promptly forwarding the information received to the coordinating EC (CEP) and INAEP; and monitoring compliance with the approved single protocol at their institutions. See OrderNo3 for additional guidance regarding the implementation of the single ethical review process for multicenter research.

BRA-141 further explains that the single ethical review process does not eliminate local responsibilities or authorizations. Participating centers are still obligated to ensure adequate conditions for the execution of the study, including verifying technical and physical infrastructure, organizing logistics and recruitment in a manner compatible with local realities, and maintaining ongoing institutional responsibility for the protection, integrity, and well-being of participants under their supervision.

Additionally, BRA-141 states that, provided there is a favorable ethical opinion from the responsible EC (CEP), an additional opinion from a local CEP is not required to validate the commencement of activities at centers already included in the approved protocol. However, the participating center must verify the scope of the opinion to ensure that the center and the activities to be conducted at that specific site are included in the protocol. See also BRA-141 for additional INAEP guidance on single EC (CEP) reviews. See the Submission Process section for submission requirements for single EC (CEP) reviews.

CEP/CONEP System (Pre-SINEP Framework)

As per ResNo466, the EC (CEP) (and CONEP, if applicable) must approve a protocol before research may begin. Per OSNo001, the EC (CEP) must also review and approve protocol amendments before they are implemented. If applicable, CONEP may also review protocol amendments. (See CLNo038 for the criteria CONEP uses to process protocol amendments.) ResNo466 and OSNo001 specify that research development and submission, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via Platforma Brasil (BRA-34). See CLNo24 and CLNo24-Note for CONEP’s general clinical trial guidelines for investigators and ECs (CEPs).

Additionally, CLNo040 specifies that if investigational brochure (IB) updates result in modifications to the detailed protocol and/or the informed consent form (ICF), then a protocol amendment must be submitted. The EC (CEP) will analyze the updated IB together with the amendment and supporting documents and, if necessary, request amendments and/or clarifications.

Per CLNo29, in the case of an appeal, only the responsible investigator who received a substantiated opinion of non-approval may appeal through the CEP/CONEP System via Platforma Brasil (BRA-34). The appeal must be filed within 30 calendar days, counting from the first day following issuance of the non-approval opinion. The EC (CEP) must review submitted appeals and issue a substantiated opinion within 30 calendar days following receipt. If the EC (CEP) determines that the requirements and justifications presented in the appeal are sufficient to continue the ethical analysis, the appeal will be approved or remain pending if the protocol requires adjustments prior to approval. If the EC (CEP) does not approve the appeal, the investigator may appeal to CONEP. CONEP must issue a substantiated opinion of approved, pending, or not approved within 45 days of receiving the appeal. If CONEP does not approve the appeal, the investigator, upon receiving the non-approval opinion from CONEP, may file an appeal directly to CONEP. Based on its analysis of the appeals submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal following the final appeal request, the appeal process is terminated, the research protocol is archived, and no further appeal requests are permitted. There is no stated expiration date for an EC (CEP) approval in ResNo466 or OSNo001. See the Timeline of Review section for detailed timeline information.

CONEP Review Pathways

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

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

EC analysis varies according to the type of research and modulation factors (i.e., consent process, confidentiality, and/or research methods), and requires the reviewer to verify the documentation the investigator submits in Plataforma Brasil (BRA-34). See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.

There are four (4) ways of processing protocols in the CEP/CONEP System: express, simplified, collegiate, and special collegiate; the modulation factors per Annex II of ResNo674 provides additional characteristics to further modify the protocol processing method to be used. See ResNo674 and BRA-4 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures.

High-Risk Research Protocols

As per ResNo674, the CNS has published protocol risk classification and processing guidelines for use in the CEP/CONEP System to provide criteria for assessing the risk level of research protocols. Per ResNo466, ResNo446, and CLNo172, CONEP determined that protocols falling within special thematic areas—such as human genetics, human reproduction, indigenous populations, genetically modified organisms, and the establishment and operation of biobanks—are considered high risk. Refer to ResNo466, ResNo446, and ResNo340 for a complete list of the special thematic areas. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., protocols on the establishment and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically; and CLNo26 for information on submitting research protocols involving human bodies and/or anatomical parts. ResNo674 also notes that CONEP is solely responsible for the registration of biobank development protocols, and the research classification and modulation factors used to further characterize protocols in BRA-34 will not be applicable.

Priority Review for SUS Strategic Research

Per ResNo580, the MOH’s Secretary of Science, Technology and Strategic Inputs refers protocols to CONEP that are determined to be of strategic public health interest for SUS (BRA-53). ResNo580 recognizes strategic research protocols as those studies that may contribute to public health, justice, reduction of social inequalities and technological dependencies, and those that address public health emergencies.

Multicenter Research

Per ResNo346, for multicenter research protocols, the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. CONEP will only evaluate the first protocol submitted and then send its final opinion to the original EC (CEP) and the other participating institutions. ResNo674 similarly explains that the initial analysis of the research protocol using the research classification procedure will occur at the EC (CEP) of the coordinating center or the accredited EC (CEP), when applicable, and will be subsequently forwarded for analysis by the EC (CEP) of the other co-participating centers and/or institutions, after approval. See ResNo346 for additional multicenter protocol processing information.

Foreign Research

As delineated in ResNo292, ResNo446, and ResNo466, applications with coordination and/or sponsorship originating outside of Brazil require additional review by CONEP. Per ResNo446, an exception applies to studies conducted entirely outside Brazil that have been approved by an EC (CEP) or equivalent body in the country of origin.

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 ensuring 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.

Overview

21CFR56, 21CFR312, the Pre2018-ComRule, and the RevComRule state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC must also 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). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for additional EC responsibilities and requirements.

Role in Clinical Trial Approval Process

In accordance with 21CFR56 and 21CFR312, the FDA must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC may approve, require modifications in (to secure approval), or disapprove the research.

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the EC must ensure the following requirements are met prior to approving the study:

• Risks to participants are minimized and are reasonable in relation to anticipated benefits
• Participant selection is equitable
• Informed consent will be sought from each prospective participant or legal representative/guardian, and will be appropriately documented (the RevComRule also requires information regarding whether informed consent was appropriately waived)
• The research plan makes adequate provision for monitoring the data collected to ensure the safety of participants, where appropriate
• Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate (per the RevComRule, the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data)

Per the RevComRule, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

See 21CFR56, the Pre2018-ComRule, and the RevComRule for additional details on criteria for EC approval of research.

Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the HHS that must also comply with FDA regulations.

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that changes in approved research may not be initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants.

Per 21CFR56, the Pre2018-ComRule, the RevComRule, and the G-IRBContRev, an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.

See the G-IRBResp for FDA guidance for ECs on reviewing the adequacy of investigators and research sites, and determining if an IND or investigational device exemption is required. The FDA’s G-SubRecruit also provides guidance for ECs on reviewing participant recruitment methods.

Per the FDA’s G-IRBReview, an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview.

As stated in the G-IRBWaiver, sponsors and sponsor-investigators may request a waiver of EC requirements for drug and biological product studies regulated by the FDA. The most common circumstance for which the FDA receives a waiver request is when a sponsor wishes to conduct a foreign clinical study under an IND. In this case, typically sponsors utilize an independent ethics committee (IEC) that operates in accordance with good clinical practice (GCP). See the G-IRBWaiver for more information.

Additionally, see the G-IRBTransfer for FDA guidance on the regulatory responsibilities of ECs, clinical investigators, and sponsors when oversight of a previously approved, ongoing clinical investigation under the FDA’s jurisdiction is transferred from one (1) EC to another EC.

Expedited Review

21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:

• Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
• Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
• Under the RevComRule, research for which limited EC review is a condition of exemption

21CFR56, the Pre2018-ComRule, and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.

Continuing Review and Re-approval

21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.

In addition, per the G-IRBContRev, research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev.

The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:

• Research eligible for expedited review
• Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
• Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care

Exemptions under the Revised Common Rule

Per the RevComRule, certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.

Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:

• Scholarly and journalistic activities
• Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
• Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
• Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions

USA-32 notes that the regulations do not specify who at an institution may determine that research is exempt, and that institutions should implement exemption policies that most effectively address the local setting and programs of research. The HHS retains final authority as to whether a particular human subjects research study conducted or supported by HHS is exempt.

See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-32 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, continuing review, and exempt research.

Cooperative Research Studies

In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-18 and USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.

Designed to complement the RevComRule, per the NIHNotice16-094 and the NIHNotice17-076, the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.

For more information on multicenter research, see the FDA’s G-CentralIRB and G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS’ Office for Human Research Protections (OHRP)’s G-ComRuleCnsstncy.

National System of Ethics in Research Involving Human Beings (SINEP)

Under the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)), LawNo14.874 and DecreeNo12.651 do not specify fees for research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) under the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)).

CEP/CONEP System (Pre-SINEP Framework)

According to ResNo466, OMREC, and ResNo706, under the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System, which is composed of the CEPs and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), CONEP does not permit ECs (CEPs) to charge a fee to review clinical trial protocols. OMREC further explains that financing to support ethical reviews should come from a specific scientific committee budget designated within each institution.

Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.

Overview

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising ECs (CEPs) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will also continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

LawNo14.874 establishes the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)), and DecreeNo12.651 further defines SINEP’s framework. Within this system, research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)), overseen by the Ministry of Health (MOH)’s INAEP, are responsible for the ethical review of clinical trial protocols involving human beings.

In accordance with DecreeNo12.651 and per OrdNo85, the MOH, through the Secretariat of Science, Technology, and Innovation and the Health Economic-Industrial Complex (SECTICS/MS), established a temporary working group (Grupo de Trabalho Temporário (GTT)) to support the drafting of complementary and regulatory procedures regarding the functioning of INAEP and the implementation of SINEP. The group is also responsible for:

• Assisting in providing guidance on operational decisions and contributing to the continuity of ethical evaluations during the transition of CONEP’s activities to INAEP
• Conducting a survey of current regulations on ethics in research with human beings that require adaptation
• Proposing supplementary regulations to support the operation of SINEP and INAEP
• Proposing courses of action related to the transition of CONEP's activities to INAEP

In addition, per OrdNo8, the Secretariat of Science, Technology and Innovation in Health of the MOH (SCTIE/MS) established the MOH’s Technical Monitoring Committee of the National Research Platform Involving Human Beings to make recommendations, provide information, and develop proposals to improve the development process of the National Research Platform Involving Human Beings. The committee will have a duration of 12 months, which may be extended for another 12 months, if justified. See OrdNo8 for detailed committee information. See also the Submission Process and Initiation, Agreements & Registration sections for additional information on the National Research Platform, also referred to as the human research platform in DecreeNo12.651.

National Research Ethics Authority (INAEP)

Per LawNo14.874, DecreeNo12.651, and ResNo1, INAEP, an interdisciplinary and independent collegiate body, established within the scope of the MOH, is responsible for the following (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Issuing regulatory standards on research ethics
• Evaluating the effectiveness of the SINEP
• Credentialing and accrediting ECs (CEPs) to ensure they are qualified to perform the ethical review of research, according to the degree of risk involved
• Monitoring, supporting, and overseeing the ECs (CEPs) in relation to the review of research protocols and in compliance with the pertinent standards
• Promoting and supporting the training of EC (CEP) members, with special emphasis on ethical and methodological aspects
• Acting as an appeals court for decisions issued by ECs (CEPs)
• Contributing to a culture of ethical responsibility in research and in scientific, technological, and innovative development to reconcile the protection of research participants with process efficiency—particularly regarding emerging technologies—and in compliance with ethical standards
• Formulating and approving its internal regulations

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

As per ResNo466, OSNo001, and ResNo446, CONEP was created by the MOH to provide ethical oversight of clinical research and to safeguard the rights and welfare of human beings involved in clinical studies. CONEP reports to the CNS, the advisory body to the MOH.

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

• Examining the ethical aspects of research involving human beings
• 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

LawNo14.874 and DecreeNo12.651 transferred responsibility for EC (CEP) accreditation from CONEP to INAEP. Because EC (CEP) accreditation under the former CEP/CONEP framework remains relevant during the transition to the SINEP framework, both the current INAEP accreditation provisions and the former CONEP accreditation procedures are summarized below.

National System of Ethics in Research Involving Human Beings (SINEP)

National Research Ethics Authority (INAEP)

Pursuant to LawNo14.874 and DecreeNo12.651, INAEP is responsible for accrediting and certifying ECs (CEPs) to ensure that they are able to conduct ethical research reviews in accordance with the degree of risk involved. Per DecreeNo12.651, until INAEP completes a new evaluation, ECs (CEPs) already accredited and certified to conduct ethical reviews of research involving human beings are deemed accredited and certified by INAEP. See BRA-143 for additional guidance on the responsibilities of accredited ECs (CEPs) and a current list of INAEP-accredited ECs (CEPs).

Additionally, BRA-142 establishes an automatic extension, granted on an exceptional basis, for a period of one (1) year for accredited ECs (CEPs) whose accreditation expired during the 2025 fiscal year. The extension is calculated from the original expiration date to ensure the regular and uninterrupted continuity of EC (CEP) operations. The extension does not waive or supersede the accreditation renewal process. Sponsoring institutions must continue to comply with the renewal requirements in ResNo706.

Per DecreeNo12.651, INAEP will establish criteria, requirements, and procedures for suspension and cancellation.

CEP/CONEP System (Pre-SINEP Framework)

National Research Ethics Commission (CONEP)

Under the CEP/CONEP framework, ECs (CEPs) were required to register with and obtain accreditation from CONEP in accordance with ResNo466 and ResNo706. ResNo706 established the eligibility requirements and procedures for CEP registration, accreditation, and renewal. See ResNo706, CNSResNo506, and SP006REC for additional information on the former CONEP accreditation process.

ResNo706 also established the procedures governing the suspension and cancellation of EC (CEP) accreditation. Suspension temporarily interrupted an EC's (CEP's) receipt of new research protocols while requiring continued oversight of protocols already under its responsibility. Cancellation revoked the EC's (CEP's) registration in the CEP/CONEP System and provided for the transfer of its protocols to another EC (CEP). See ResNo706 for additional information on the former CONEP suspension and cancellation procedures.

Overview

As delineated in 21CFR56 and 45CFR46-B-E, the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system (USA-28) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP).

Registration, Auditing, and Accreditation

In accordance with the G-IRBReg-FAQs and USA-61, EC registration with the HHS OHRP system (USA-28) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56, or by the HHS that the EC is in full compliance with 45CFR46-B-E. Neither EC competence nor expertise is assessed during the registration review process by either agency.

Food & Drug Administration

According to 21CFR56 and the G-IRBReg-FAQs, the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system (USA-28). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.

As stated in 21CFR56 and the G-IRBReg-FAQs, any EC not already registered in the HHS OHRP system (USA-28) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.

21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.

See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements.

Office for Human Research Protections

Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-18 and USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.

Per USA-59, a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (Pre2018-ComRule or RevComRule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.

See USA-57 for more information on FWAs.

As stated in 45CFR46-B-E and USA-61, all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system (USA-28). EC registration becomes effective for three (3) years when reviewed and approved by OHRP. Per 45CFR46-B-E, an individual authorized to act on behalf of the institution operating the EC must submit the registration information.

Per USA-59, an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.

See 45CFR46-B-E, USA-58, and USA-61 for detailed registration requirements and instructions.

Overview

As stated in ResNo945 and the G-DDCMManual, the sponsor, the designated contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or the sponsor-investigator must apply to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to obtain clinical trial approval by submitting a Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)) for a drug that will have all or part of its development in Brazil for registration purposes. (Note: Applications are also known as petitions in Brazil).

Pursuant to LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is required to undergo prior ethical analysis by research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). ResNo945 explains that clinical trial applications can be submitted in parallel, however, a clinical drug trial may only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

As delineated in ResNo466 and OSNo001, the National Health Council (Conselho Nacional de Saúde (CNS))’s National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))/CEP system is responsible for the ethical analysis of research protocols involving human beings. Per ResNo466, the principal investigator (PI) is responsible for submitting the protocol to the EC (CEP) or CONEP and obtaining ethical approval prior to initiating the research.

Note: Brazil is currently transitioning from the CEP/CONEP system under the CNS to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will also continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available.

Regulatory Submission

Primary Petitions

As per ResNo945, a primary DDCM petition may be submitted to ANVISA at any stage of clinical drug development for one (1) or more clinical trial phases. ResNo945 and the G-DDCMManual further note that a DDCM must also be filed with at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) for analysis. A DEEC is a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) within the DDCM. Each DEEC must be filed as a separate process for an individual clinical trial and linked to the corresponding DDCM. Per the G-DDCMManual, DEECs are submitted as primary petitions and assigned a case number and specific subject for each clinical trial to be conducted in Brazil that has not been previously submitted to ANVISA. Only DEECs from clinical trials conducted in Brazil may be submitted. ResNo945 further indicates that the sponsor, CRO, or sponsor-investigator may link additional DEECs to a submitted DDCM at any time after the initial submission.

ResNo945 provides the following additional DDCM submission requirements:

• The person responsible for submitting the DDCM to ANVISA must also submit all subsequent petition submissions related to the DDCM
• A CRO may only submit a DDCM if the sponsor does not have a head office or branch in Brazil
• A DDCM submission by a sponsor-investigator must be done through the primary sponsor, and
• If a sponsor-investigator wishes to conduct a clinical trial involving a drug with an approved DDCM, the sponsor-investigator may, with the initial DDCM owner’s permission, use the information previously submitted to ANVISA without resubmitting all of the required documentation. If the sponsor-investigator does not obtain authorization from the initial DDCM owner, all the required information supporting the proposed development rationale must be submitted to ANVISA through updated, indexed literature

Additionally, ResNo205 establishes specific approval procedures for clinical trials conducted to support the registration of new drugs intended to treat, diagnose, or prevent rare diseases. Petitions may be submitted as an initial DDCM, a secondary petition linked to the original DDCM, or a DEEC linked to the original DDCM or submitted as a new process. Sponsors must determine, when submitting an initial DDCM, a secondary DDCM petition, or a DEEC, whether the petition pertains to a rare disease drug. See ResNo205 for detailed rare disease clinical trial submission requirements.

Per OrdNo54, applicants may request in-person or virtual hearings with ANVISA to clarify matters that, due to their complexity, cannot be resolved through the service channels established and publicized on the ANVISA website. BRA-90 further specifies that applicants may request pre-submission meetings with ANVISA's Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., a DDCM, secondary petition, or DEEC) or a clinical trial application previously submitted to ANVISA. However, according to BRA-146, ANVISA has replaced the Parlatório System referenced in OrdNo54 and BRA-90 with the ANVISA Hearing System for scheduling hearings. See BRA-146 and BRA-147 for additional information on scheduling a hearing.

In addition, per ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, but if the sponsor deems it necessary, then ANVISA should hold the meeting within 60 days of the request.

ResNo903 further states that when a sponsor or CRO transfers responsibility for submitting a DDCM petition and the linked specific clinical trial processes for an investigational product (IP) to ANVISA, the succeeding company must update the related clinical trial registration data via a petition for global transfer of responsibility for the clinical trial. See ResNo903 for additional information. See also the Submission Content section for specific documentation requirements, and the Insurance & Compensation and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

See ResNo506 for more information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products (i.e., medicines for human use that are based on genes, tissues, or cells).

Secondary Petitions

As explained in the G-DDCMManual, secondary petitions must be linked to the corresponding process. Secondary petitions related to a DDCM must also be filed with the Petition Consent Form (BRA-21). Examples of DDCM petitions include: Substantial Modification to the Investigational Product (BRA-127); Investigational Drug Development Safety Update Report (DSUR); Cancellation of DDCM on Request; Global Transfer of Responsibility for DDCM; Temporary Suspension of DDCM; Reactivation of Suspended DDCM; Investigational Drug Development Plan (PDME) Update Notification; and Investigator’s Brochure (IB) Update Notification.

Similarly, per the G-DDCMManual, secondary petitions related to a DEEC must be linked to the corresponding clinical trial process. Examples of DEEC petitions include: Alteration of the Clinical Trial Submission Form (FAEC) (BRA-22); substantial amendment to clinical protocol; Annual Report on Clinical Trial Protocol Monitoring; Cancellation of Clinical Trial Protocol on Request; Global Transfer of Responsibility for Clinical Trial Protocol; Temporary Suspension of Clinical Trial Protocol; and Reactivation of Suspended Clinical Trial Protocol.

As stated in ResNo945 and the G-DDCMManual, sponsors must submit substantial IP modifications to ANVISA as secondary petitions linked to the corresponding DDCM. ResNo945 indicates that non-substantial IP modifications must be submitted to ANVISA in the next petition for substantial IP modification, or as part of the DSUR, whichever occurs first. The G-DDCMAmdmts further notes that these modifications may be made at any time after initial DDCM submission, including before ANVISA issues its final decision. See the G-DDCMAmdmts for detailed submission instructions, the G-ResNo945-FAQs for technical procedures for submitting DDCM and DEEC petitions, including secondary petitions, and the Submission Content section for documentation requirements.

As per ResNo945 and the G-DDCMManual, petitions for substantial amendments to clinical trial protocols must also be filed as a secondary petition linked to the corresponding DEEC. ResNo945 further explains that non-substantial clinical trial protocol amendments must always be submitted to ANVISA in the next substantial amendment petition, or as part of the final clinical trial protocol monitoring report, in cases where there are no substantial amendments by the end of the clinical trial. See the G-DDCMAmdmts for detailed submission instructions for protocol modifications. See also BRA-125 for the Substantial Amendment to Clinical Trial Protocol form. Refer to the Submission Content section for DEEC petition content requirements and substantial protocol amendment documentation requirements.

ResNo1001 further provides that primary DDCM and DEEC petitions and secondary petitions for substantial IP modifications and substantial protocol amendments may be classified as priority if they meet the applicable criteria. Priority classification may be requested upon submission of these petitions or at any time following submission through a specific petition for that purpose. These requests may only be submitted by the company recognized by ANVISA (i.e., the sponsor) as responsible for the respective petition. If ANVISA’s technical area does not confirm priority classification, the request will be denied. When filing or submitting a specific prioritization request, the company must attach a document indicating which criterion(s) established in ResNo1001 justify priority classification. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections.

See ResNo742, G-ResNo945-FAQs, BRA-6, and BRA-7 for requirements related to submitting DEECs linked to DDCMs for comparative bioavailability/bioequivalence studies and comparative pharmacokinetic studies with biosimilar products.

In addition, for regulatory submission purposes, the G-SUSARs indicates that DSURs must be submitted as secondary electronic petitions linked to the DDCM process using petition subject 10825 – CLINICAL TRIALS – Safety Update Report of the Development of the Investigational Drug. See also the Safety Reporting section for additional DSUR reporting requirements.

As delineated in ResNo945, RegNo338, the G-DDCMManual, and BRA-122, the sponsor may request the optimized analysis procedure based on regulatory trust practices (Reliance) or the risk or complexity criteria of the clinical trial or the IP. The request must be submitted as a secondary petition before ANVISA begins its technical analysis of the corresponding DDCM petition. Per ResNo945 and RegNo338, for primary and secondary petitions to be considered under Reliance, the related documents must have been approved by at least one (1) of the Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) recognized by ANVISA. The AREE-approved documents must be the same versions as those submitted to ANVISA. The G-DDCMManual further explains that under the Reliance procedure, certain documentation may be exempt from technical analysis if the applicable criteria are met. However, all documents required for the applicable petition or process must still be submitted.

Per ResNo945, RegNo338, the G-DDCMManual, BRA-122, and BRA-123, applicants must submit a secondary petition requesting analysis under the Reliance procedure using one (1) of the following subject codes:

• 12102 – Clinical Trials – Optimized analysis procedure for DEEC
• 12103 – Clinical Trials – Optimized analysis procedure for Substantial Amendment to the Clinical Protocol
• 12104 – Clinical Trials – Optimized analysis procedure for Approval in the Process of the DDCM
• 11634 – Clinical Trials – Optimized Analysis Procedure for Substantial Modification to IP

In addition, per the G-DDCMManual and BRA-122, separate requests for analysis under Reliance must be submitted for each DDCM or DEEC petition because the petitioning system does not permit one secondary petition to be linked to another. Refer to the G-DDCMManual and BRA-122 for additional information. See also the Scope of Assessment section for detailed optimized analysis procedure requirements by Reliance or the risk assessment of the clinical trial or IP.

For requests to ANVISA to apply the optimized analysis procedure based on risk assessment using IP experience, the G-DDCMManual indicates that there is no specific subject code. Therefore, a company may request the application of the optimized analysis procedure by either one (1) of these options:

• In the Clinical Trial Submission Form (FAEC) (BRA-22), marking the option "(X) to the question, “We request the application of the optimized analysis procedure, pursuant to Article 8 of IN No. 338/2024", or answering "yes" to the question "Request for the application of the optimized analysis procedure (based on the risk assessment supported by the experience of using the investigational product).” (Note: Per BRA-123, BRA-22 should be completed electronically in ANVISA’s Solicita Electronic Petition Request System (BRA-56)).
• In the Petition Form for Substantial Modification of the Investigational Product (BRA-127), answering "yes" to the question "Request for the application of the optimized analysis procedure (based on the risk assessment supported by the experience of using the IP), pursuant to Article 8 of IN No. 338/2024".

Electronic Filing

Per ResNo945 and the G-DDCMManual, the original DDCM and all related processes and petitions (e.g., secondary petitions and DEEC(s)) must be submitted electronically. ResNo947 also notes that documents to be filed with ANVISA must be submitted exclusively via the agency’s electronic petitioning systems for filing documents, except in specified cases. BRA-38 specifies electronic petitioning is carried out via the Solicita Electronic Petition Request System (BRA-56). See BRA-47 and BRA-38 for instructions on how to login to the Solicita System.

The G-DDCMManual explains that when the DDCM has been submitted, the sponsor must electronically file all the documents corresponding to the initial DDCM petition’s subject code. Per BRA-123, due to the simplification in the DDCM and DEEC subject codes, the sponsor or the CRO should use the following to submit DDCM and DEEC documentation: 12405 – Clinical Trials - Approval in process of the Clinical Drug Development Dossier (DDCM) - Medicines and Biological Products; and 12406 – Clinical Trials - Approval in process of the Specific Clinical Trial Dossier (DEEC) - Medicines and Biological Products. For secondary petitions, subject codes 10820 and 10824 should be used.

ResNo945 also specifies that the submitted documentation must support textual searches, copying, and contain bookmarks and hyperlinks that facilitate navigation. Refer to BRA-47 for instructions for submitting DDCM checklist documents and clinical drug research forms via BRA-56. See the G-DDCMManual and BRA-47 for additional DEEC petition submission instructions. See also ResNo947 for further details on ANVISA’S electronic filing requirements.

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

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

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

See also BRA-47 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition Consent Form. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

As indicated in the G-DDCMManual, ANVISA recommends that the DDCM and associated documents (especially the clinical protocol, the PDME, and the IB) be submitted in Portuguese. If a translated version of the submission is not provided, ANVISA’s technical area reviewer may issue a requirement for the sponsor to provide a free translation of the submitted documentation. ResNo947 also states that documents filed with ANVISA must be presented in Portuguese, however, documents submitted in English and Spanish will also be accepted, and a request for translation of the documents may be submitted. When translation is necessary, in the absence of a specific rule requiring translation in the sworn version, a free translation may be accepted.

Ethics Review Submission

National System of Ethics in Research Involving Human Beings (SINEP)

According to LawNo14.874, the investigator is responsible for submitting a research project to the EC (CEP) for approval. The submission should include the research documentation and any amendments.

DecreeNo12.651 also states, for multicenter research, studies conducted in different research centers by more than one (1) investigator should be submitted as a single protocol to one (1) EC (CEP). BRA-141 further provides that the submission of documents (e.g., infrastructure, recruitment, etc.) specific to each institution is still required. See also BRA-141 for additional INAEP guidance for institution-specific requirements for single EC (CEP) reviews.

In addition, per BRA-143 and BRA-142, research protocols previously submitted to CONEP that fall within special thematic areas traditionally considered high-risk, as defined in ResNo466 and ResNo446, must be forwarded to accredited ECs (CEPs) for ethical review in accordance with DecreeNo12.651. BRA-143 further states that this requirement applies to both protocols that have already been filed and those to be submitted prior to INAEP’s issuance of new guidelines. All high-risk protocols must be submitted to one (1) of the eight (8) accredited ECs (CEPs) listed in BRA-143. Exceptions to this workflow requirement include biobank development protocols, which have been temporarily suspended per BRA-142, as well as certain categories of protocols for which the MOH serves as the proposing institution.

CEP/CONEP System (Pre-SINEP Framework)

Per ResNo466, the PI must obtain ethical approval from the EC (CEP), and, if applicable, from CONEP. 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 review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil EC (CEP) and investigator manuals. Please refer to Scope of Review and Oversight of Ethics Committee sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. See also CLNo183 for instructions on linking investigator/institutions to the responsible EC (CEP) in submissions; CLNo062 for guidance on submitting documentation required for CONEP analysis; and CLNo046 for instructions on submitting requests for inclusion/exclusion of research center(s).

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

OSNo001 further states that, 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.

Additionally, per ResNo580, for co-sponsored or cooperative research projects as described in ResNo466, the protocol submission must include a referral document from the Secretary of the MOH’s Secretariat of Science, Technology and Strategic Health Inputs. When this document is included, the EC (CEP) of the proposing institution may conduct its review without the need for additional CONEP review.

Overview

As delineated in 21CFR312, USA-42, and USA-52, the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.

In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Submission

According to 21CFR312, meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.

A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA.

Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.

According to the G-PharmeCTD, which implements FDCAct requirements, and as described in USA-34 and USA-53, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.

As stated in USA-34, the electronic submission of eCTD v4.0 to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) is supported for new INDs, as well as certain other submission types, beginning September 16, 2024. Only new applications may be submitted in v4.0, and forward compatibility functionality is not yet available. Electronic submissions made in eCTD format must utilize either v3.2.2 or v4.0, which are both currently supported by the FDA.

The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting CBER or CDER. See USA-35 for more information on requesting an application number.

For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, USA-34, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.

According to the G-eCTDspecs, eCTD submissions sized 10 GB and under for most applications must be submitted via the Electronic Submissions Gateway (ESG), and the FDA also recommends the use of the ESG for submissions greater than 10 GB when possible. However, USA-44 specifies that the Electronic Submissions Gateway Next Generation (ESG NextGen) should be utilized for all electronic submissions to the FDA. See USA-102 for the ESG NextGen Unified Submission Portal (USP) Login and USA-37 for ESG NextGen submission user guides.

As indicated in the G-eCTDspecs, the FDA also accepts physical electronic media on a USB drive for submissions greater than 10 GB. For specific instructions on how to submit physical electronic media, email CDER at esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov. See the G-eCTDspecs for additional physical electronic media information.

The IND must be submitted in English. As indicated in 21CFR312, the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.

Based on information provided in 21CFR312, for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports. According to USA-41 and USA-94, paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:

Drugs (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Therapeutic Biological Product (submitted by Sponsor-Investigators):

Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266

Center for Biologics Evaluation and Research-Regulated Products:

Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002

(Note: Per USA-94, CBER also accepts electronic media via mail, but electronic or email submission is preferred.)

For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.

Ethics Review Submission

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.

Regulatory Authority Requirements

Clinical Drug Development Dossier (DDCM)

As delineated in ResNo945 and the G-DDCMManual, the following documentation must be submitted to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to file a clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) via the Solicita Electronic Petition Request System (BRA-56) (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• DDCM Petition Consent Form (BRA-21)
• Investigational Drug Development Plan (PDME)
• Investigator’s Brochure (IB)
• Investigational Medicinal Product Dossier (IMPD) (including information on active pharmaceutical ingredient (API), investigational drug, and placebo and modified comparator drug)
• DEEC (see detailed requirements listed below)
• Declarations on compliance with Good Clinical Practice (GCP), Good Laboratory Practice (GLP), and Good Manufacturing Practice (GMP)
• GCP Certificate or equivalent document for the completed or ongoing clinical trials must be attached to the DDCM, if applicable
• Declaration of commitment to distribute and use IPs only after DDCM and corresponding initial and subsequent Specific Clinical Trial Dossiers (Dossiês Específicos de Ensaio Clínico (DEECs)) authorization. This declaration should only be attached to the DDCM if the sponsor is interested in receiving the Import Document (DI) before completion of the DDCM review and approval. If the declaration is submitted with the DDCM, the DI will be issued to allow early importation for both the initial DEECs submitted with the DDCM, and any subsequent DEECs submitted after DDCM approval.

Additionally, per ResNo903, when a sponsor or contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) transfers responsibility for submitting a DDCM and its linked specific clinical trial processes for an IP, the succeeding company must update the related clinical trial registration data via a petition for global transfer of responsibility for the clinical trial. The petition must be accompanied by the following documents:

• Petition Consent Form duly completed and signed (BRA-21)
• Declaration of the corporate or commercial transaction carried out (see Declaration form in Annex I of ResNo903)

See ResNo903 for additional information. See also the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

Specific Clinical Trial Dossier (DEEC)

Per ResNo945 and the G-DDCMManual, the DEEC petition submission should include the following:

• Clinical Trial Submission Form (FAEC) (BRA-22)
• Clinical trial protocol containing the minimum information described in the International Council for Harmonisation’s Guideline E6(R2) (BRA-28) and its updates
• Statistical analysis plan (PAE), at least in draft version, for phase 3 and adaptive clinical trials
• Opinion of the relevant country/region's scientific advisory board on the clinical trial, if applicable
• Pediatric investigation plan of the relevant country/region, if applicable
• Sample investigational drug label
• Proof of clinical trial registration, in the same version of the clinical protocol submitted to ANVISA, in 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.) If proof of registration is unavailable at the time of DEEC submission, it must be submitted with the notification of clinical trial commencement.)

Substantial IP Modifications

Per ResNo945 and the G-DDCMManual, for substantial IP modifications, the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM that must include the following (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Copy of the previously approved IMPD or Investigational Product Dossier (DPI), with the proposed modifications highlighted (track changes format), and a table comparing the current situation with the proposed changes, including the justification for each change and an assessment of its impact on clinical development
• GMP certificate or equivalent document for the IP, if applicable
• Petition Form for Substantial Modification to the Product under investigation (BRA-127)
• Other information in accordance with each proposed modification

See the G-DDCMAmdmts for detailed submission instructions. ResNo945 also indicates that non-substantial IP modifications must be submitted to ANVISA in the next petition for substantial IP modification, or as part of the drug development safety update report (DSUR), whichever occurs first.

Substantial Protocol Amendments

As per ResNo945 and the G-DDCMManual, for substantial clinical trial protocol amendments, the sponsor must submit to ANVISA an electronic secondary petition linked to the corresponding DEEC (see BRA-125 for the Substantial Amendment to Clinical Trial Protocol form) that must include the following: (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Copy of the previously approved clinical protocol with the proposed modifications highlighted (track-changes format), and a table comparing the current situation with the proposed changes, including the justifications for each change and an assessment of the impacts on clinical development
• Updated Clinical Trial Submission Form (FAEC) (BRA-22), in both clean and track changes versions, together with the new clean version of the clinical protocol. (Note: Per BRA-123, BRA-22 should be completed electronically in ANVISA’s Solicita Electronic Petition Request System (BRA-56)).

See the G-DDCMAmdmts for detailed submission instructions for protocol amendments. See also G-ResNo945-FAQs for additional guidance on substantial protocol amendments.

ResNo945 further explains that non-substantial clinical trial protocol amendments must always be submitted to ANVISA in the next substantial amendment petition, or as part of the final clinical trial protocol monitoring report, in cases where there are no substantial amendments by the end of the clinical trial.

Optimized Analysis Procedure (Reliance) Submissions

Pursuant to ResNo945, to request the optimized analysis procedure by Reliance, the sponsor must submit official proof issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) of approval of the clinical protocol, clinical protocol amendment, official proof of the DDCM, or substantial IP modification of the IMPD or DPI, as applicable. If official proof is unavailable, a declaration signed by the sponsor's legal and technical representatives (see BRA-124) must be presented with due justification and additional information, if applicable.

Per RegNo338, ANVISA will provide a specific petition characterization form for the sponsor to complete for the proper identification of situations in which the optimized analysis procedure is supported by experience using the IP. For each type of petition, the optimized analysis procedure based on risk assessment may be applied to the documents listed below:

• IB, for low-risk clinical trial categories involving medicine used as registered in Brazil or by an AREE, without substantial modifications; and fixed-dose combinations with registered APIs already used concomitantly in medical practice, for the same indication, target population, and dosage regimen (without clinically significant pharmacokinetic and/or pharmacodynamic interaction)
• IMPD or DPI, for low-risk clinical trial categories and moderate risk clinical trial categories involving a new therapeutic indication, target population, and/or dosage regimen

RegNo338 further specifies that, under the optimized analysis procedure by Reliance, ANVISA will review the following documents:

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

Ethics Committee Requirements

National System of Ethics in Research Involving Human Beings (SINEP)

According to LawNo14.874, investigators are responsible for submitting research documentation, including any amendments, for research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval.

No other information is currently available regarding specific EC (CEP) submission documentation requirements. However, LawNo14.874 states that the information and documents required for the ethical review process will be established in specific regulations.

CEP/CONEP System (Pre-SINEP Framework)

As per OMREC and OSNo001, in accordance with CEP/CONEP System requirements, researchers are required to submit the following documentation online via BRA-34 for review by an EC (CEP) (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Cover Sheet for Research Involving Human Beings (completed by investigator in Plataforma Brasil (BRA-34))
• Clinical research protocol (in Portuguese)
• Background, justification, and registration in the country of origin for drug and device health products
• Description of materials, methods, rationale, expected results, and bibliography
• Critical risk and benefit analysis
• Duration
• Responsibilities of investigator, institution, and sponsor
• Criteria for project suspension or termination
• Location of implementation of various project steps
• Necessary infrastructure and agreement of the institution
• Statement of Commitment from the principal investigator (PI)
• Informed consent form (ICF) (See Informed Consent topic for additional information)
• Detailed research financial budget and investigator remuneration
• Ownership of information
• Characteristics of the participant population, and justification for the use of vulnerable groups
• Number of participants locally and globally (multicenter)
• Description of methods that affect research participants
• Sources of material and details of the specific collection
• Recruitment plans, inclusion and exclusion criteria
• PI/investigator(s) Curriculum Vitaes (CVs)
• List of the participating institutions and associated protocols
• Coordinating center
• EC (CEP) designated to monitor the study’s progress
• Research project schedule
• Foreign Research or Foreign Cooperation documentation (commitments and advantages for research participants and the country; identification of the national investigator and co-responsible institution; EC approval document in the country of origin or justification; response to the need for personnel training in Brazil; and lists of participating centers abroad and in Brazil)
• Research with new drug, vaccine, and diagnostic test document requirements (current clinical trial phase and demonstration of compliance with previous clinical trial phases; drug substance registration in the country of origin and status of research; IB; clinical information from previous trial phases; justification for using placebo or wash out period; access to the drug, if its superiority is proven; investigator’s statement of commitment; justification for inclusion of healthy participants; forms of recruitment)

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

Clinical Protocol

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

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

For complete protocol requirements, refer to OMREC and OSNo001.

Regulatory Authority Requirements

As specified in 21CFR312, an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:

• Cover sheet (Form FDA 1571 (USA-76)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
• Table of contents
• Introductory statement and general investigational plan
• Investigator’s brochure (IB)
• Protocols
• Chemistry, manufacturing, and control data
• Pharmacology and toxicology data
• Previous human experience with the IP
• Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
• Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)

For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions. Also see USA-100 for Phase 1 IND resources, and USA-101 for information on first in human Phase 1 INDs.

Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials.

The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc.

According to the G-PedStudyPlans, a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA). An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans.

See 21CFR312 and the G-IPCharge for additional submission requirements if a sponsor is seeking FDA authorization to charge for the use of its own IP in a clinical trial.

Ethics Committee Requirements

Each EC has its own application form and clearance requirements, which can differ regarding application content requirements.

Clinical Protocol

Per the NIHNotice17-064, and as provided in USA-29 and USA-27, the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.

Additionally, the G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. According to the G-DecentralCT, the protocol should include specific instructions for limiting variability in the data collected. The protocol should specify which visits will be conducted at traditional clinical trial sites, which visits will be conducted remotely, and which visits can be left to participants’ choice. See the G-DecentralCT for additional guidance.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on clinical protocol contents.

Overview

As stated in ResNo945, clinical trial applications may be submitted in parallel, however, a drug clinical trial may only be initiated after approval is obtained by both the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).

Regulatory Authority Approval

As set forth in LawNo14.874, ANVISA must complete its review of a primary clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento de Medicamentos Clínico (DDCM)), within 90 business days. If ANVISA does not issue a response within that period, clinical development may be initiated, provided that the DDCM petition contains the relevant ethical approvals. ResNo945 further specifies that, upon receipt of the DDCM and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions, ANVISA has 90 business days from the date of issuance of the DEEC document to evaluate the application. If ANVISA fails to issue a response within 90 days of receipt, the DDCM and corresponding DEEC are deemed released, and clinical development may begin once the relevant ethical approvals have been obtained. The 90-day review period also applies to primary petitions for new DEECs subsequently linked to the DDCM, and to secondary petitions for substantial investigational product (IP) modifications and substantial protocol amendments. See Scope of Assessment section for detailed DDCM and DEEC submission requirements.

Additionally, per ResNo945, ANVISA will begin technical review of the DDCM only after at least one (1) DEEC has been filed. The DEEC must be filed within 15 business days of the DDCM’s issuance date. If no DEEC is filed within this period, the DDCM with be rejected without technical review, except for clinical trials involving more than one (1) IP, where the DEEC has already been linked to one (1) of the corresponding DDCMs.

LawNo14.874 and ResNo945 further explain that ANVISA may, on a single occasion, request additional clarifications and documents through a technical requirement during the analysis of primary DDCM and DEEC petitions, as well as secondary petitions for substantial IP modification or substantial clinical protocol amendment. ANVISA’s technical requirement suspends, but does not interrupt, the applicable analysis deadlines. ResNo945 also notes that the sponsor must comply with the technical requirement within 30 business days of ANVISA’s confirmation of receipt. See also G-ResNo945-FAQs for additional guidance on submitting DDCM and DEEC petitions.

Under RegNo457, when a sponsor uses the continuous submission procedure to file specified Investigational Medicinal Product Dossier (IMPD) quality documents, the clinical trial may begin (or a substantial IP modification may be implemented) if ANVISA does not respond within 30 calendar days after the pending documents are filed, provided all other applicable ethical and regulatory requirements have been met.

BRA-122 also explains that petitions submitted to request ANVISA evaluation under the optimized analysis procedure based on regulatory trust practices (Reliance) that have not been analyzed within ANVISA’s 90-day review period will be released due to the expiration of the review period, in accordance with ResNo945 and LawNo14.874. The status of these petitions will be updated to “Added to process”. See BRA-122 for additional information. See the Scope of Assessment and Submission Process sections for detailed criteria and procedures to submit optimized analysis procedure petitions.

In addition, per ResNo997, ANVISA has established exceptional and temporary measures to optimize the analysis queue for clinical research approvals. Certain primary and secondary clinical research petitions for medicines and biological products that meet the criteria for applying the optimized analysis procedure by Reliance will be assigned to a specific queue, which may affect their processing order. Priority petition submissions that also meet these criteria will be analyzed before other petitions in the specific queue. See the Scope of Assessment section for details. See also BRA-139 and BRA-136 for additional information on ANVISA’s exceptional and temporary review procedures and see BRA-138 for frequently asked questions related to ResNo997.

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

Priority Submissions

Pursuant to ResNo1001, priority classification may be requested upon submission of a primary DDCM and DEEC petition, a secondary petition for substantial IP modifications and substantial protocol amendments, or at any time following submission through a specific petition for that purpose. ANVISA must determine eligibility for priority classification within 45 days of the filing date of the relevant petition. If priority classification is requested through a separate petition after the original petition is filed, ANVISA must determine eligibility within 45 days of the filing date of the prioritization request.

ResNo1001 further states that once priority classification is granted, ANVISA has 45 days, counted from the first business day after submission of the priority petition, to issue its first technical response and 60 days from the applicable filing date to issue a final decision. When priority classification is requested through a separate petition after the original petition is filed, the 45-day and 60-day review periods are counted from the filing date of the prioritization request. For secondary petitions filed for substantial IP modifications and substantial protocol amendments, the deadlines are also counted from the respective filing date. ANVISA requests for clarification or additional technical information suspend these review periods until the requested information is submitted. The 60-day review period may be extended once, by up to one-third of the original deadline (20 days), through a reasoned decision issued at least 15 working days before the original deadline expires. See the Scope of Assessment and Submission Process sections for additional information on priority classification requirements and submission procedures.

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

See the Scope of Assessment section for further information on priority submissions. See also G-ResNo945-FAQs for additional guidance on submitting priority petitions.

Ethics Committee Approval

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising ECs CEPs and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will also continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available.

National System of Ethics in Research Involving Human Beings (SINEP)

As explained in OrderNo2, LawNo14.874 establishes two (2) timeframes in the EC (CEP) ethical review process: verification of the completeness of the documentation within 10 working days from the protocol submission date, and issuance of the ethical opinion within 30 days from the date of accepting all of the research documentation. Before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor or require adjustments to the research documentation. Such requests may suspend the ethical review period for up to 20 business days. LawNo14.874 specifies that the investigator will have 10 working days, extendable for an additional 10 working days upon justification, to respond to the requests made by the EC (CEP), and the study analysis process may be canceled in case of non-compliance with the deadline. See OrderNo2 for additional details regarding the calculation, suspension, and continuation of ethical review timelines.

LawNo14.874 further states that the investigator may initially appeal the decision to the EC (CEP) that issued the opinion within 30 business days and may file a final appeal to INAEP within 30 business days. The EC (CEP) must decide the initial appeal within 30 business days, and INAEP must decide the final appeal within 30 business days. See the Scope of Review section for details on the EC (CEP) review processes. See also BRA-117 for additional information.

Additionally, per LawNo14.874 and DecreeNo12.651, the EC (CEP) opinion regarding research of strategic interest to the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53) and relevant to responding to public health emergencies will be issued within a period of 15 business days from the date of receipt of the authorization request. DecreeNo12.651 further specifies that the 15-day period may be extended in instances duly justified by the technical complexity of the subject matter or by the need for supplementary documentation.

CEP/CONEP System (Pre-SINEP Framework)

As delineated in OSNo001 and BRA-91, the 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 EC (CEP)’s review of the protocol documentation for completeness should be accomplished within 10 days following submission. Per BRA-91, the review period must be counted from the date the project entered “Ethical Assessment” (i.e., after going through the validation of documents which takes around 10 days and when the Certificate of Presentation for Ethical Assessment (Certificado de Apresentação de Apreciação Ética (CAAE)) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment. If these deadlines have expired, BRA-91 further suggests that the investigator responsible for the research project, contact the EC (CEP) to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation. Additionally, per CLNo040, if an amended project needs to go through CONEP’s appraisal, the deadline for document validation is 15 days and for ethical review, 45 days.

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

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

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

Overview

As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA)'s review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.

Regulatory Authority Approval

Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95, respectively.

According to USA-41 and USA-42, clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.

Ethics Committee Approval

Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial.

Overview

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS))'s CEP/CONEP System—comprising research ethics committees (ECs) (Comitê de Ética em Pesquisa (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—to the National System of Ethics in Research Involving Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos (SINEP)). Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available.

Per LawNo14.874, DecreeNo12.651, and ResNo945, all research involving human beings is subject to prior ethical analysis by ECs (CEPs). According to ResNo945, clinical trial applications (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs)) may be submitted in parallel by the sponsor, the designated contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or the sponsor-investigator; however, a clinical trial can only be initiated after approval is obtained by both the EC (CEP) and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).

Also, according to ResNo466 and OSNo001, applications with coordination or sponsorship originating outside Brazil require an additional review and approval by CONEP, unless the co-sponsor is the Brazilian Government. See the Scope of Review and Oversight of Ethics Committees sections for detailed information on INAEP and CONEP responsibilities and other studies requiring CONEP approval. No waiting period is required following the sponsor’s receipt of these approvals.

In addition, per ResNo945 and G-DDCMManual, the sponsor or the designated CRO is required to obtain an import license from ANVISA for the shipment of the investigational product (IP) to be used in the trial. (See the Manufacturing & Import section for additional information).

ResNo945 and the G-DDCMManual also specify that clinical trials should be conducted in compliance with the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. LawNo14.874 and ResNo466 also state that the ethical analysis of research involving human beings should comply with good clinical practice (GCP) and ethical and scientific principles. Further, per ResNo945 and the G-DDCMManual, clinical trials must be conducted in accordance with Good Laboratory Practice (GLP) or equivalent standards, including the Organisation for Economic Co-operation and Development (OECD)’s Principles on GLP (BRA-15). Refer to BRA-15 for additional information on GLP requirements.

ResNo945 further states that the clinical trial start date form in Brazil (BRA-25) must be filed as a secondary petition to the corresponding Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) within 30 business days after each start date.

Clinical Trial Agreement

As per LawNo14.874, the sponsor is responsible for establishing the contract between the parties involved in the research.

In addition, per ResNo945, any trial-related functions that are transferred to a CRO must also be specified in writing in a document signed by the sponsor and CRO. In the case of delegating responsibilities and activities, a written document must also be signed between the parties.

Clinical Trial Registration

As per ResNo945 and the G-DDCMManual, the sponsor must register the clinical trial in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE). According to BRA-52, the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)) (BRA-45) is a primary registry in the ICTRP network. See also BRA-45 and BRA-46 for further information about ReBEC. If proof of registration is not available at the time of the DEEC submission, it must be submitted together with the Start of Clinical Trial Notification Form in Brazil (BRA-25).

In addition, per BRA-32, ANVISA’s Clinical Trials (Ensaios Clínicos) tool, accessed via ANVISA’s Consultation System webpage (BRA-44), provides public information about the status of each clinical trial, the trial location, and the investigators responsible for conducting the trial. See BRA-32 and BRA-129 for additional instructions on searching BRA-44.

Pursuant to DecreeNo12.651, the MOH, under the SINEP framework, will also establish an integrated online system, referred to as a human research platform, for the registration, submission, evaluation, and monitoring of research involving human beings. See DecreeNo12.651 and LawNo14.874 for additional information.

Overview

In accordance with 21CFR312, USA-41, and USA-42, a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA), which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56, ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.

As per 21CFR312, once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).

See the G-CTPrtcptn for FDA guidance on enrollment practices to enhance participation in clinical trials.

Clinical Trial Agreement

Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (USA-77). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312, the G-1572FAQs, and USA-40 for further information.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on clinical trial agreements.

Clinical Trial Registration

The FDAMA, the FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank (USA-78). Per the FDAAA and 42CFR11, the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.

42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA. See the G-3674Cert for additional FDA guidance on certifying compliance with applicable requirements, including the requirement to register applicable clinical trials.

The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78). See USA-98 for the NIH’s definition of a clinical trial.

See 42CFR11, the NIHTrialInfo, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.

Safety Reporting Definitions

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

• Adverse Event/Experience (AE) – Any undesirable experience occurring to a participant during a clinical trial, whether or not considered related to the investigational product(s) (IP). An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a medicinal (investigational) product, whether or not related to the IP
• Adverse Drug Reaction or Adverse Reaction (ADR) – A harmful and unintentional response attributed to a drug and which occurs at doses normally used for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any adverse medical occurrence with an IP that at any dose results in death, risk of death, persistent or significant disability, congenital anomaly/birth defect and situations that require or extend patient hospitalization
• Suspected Serious, Unexpected Adverse Drug Reaction (SUSAR) – An adverse reaction that is simultaneously serious and unexpected, with the reasonable possibility of a causal relationship between the investigational drug and active comparator. One whose nature or severity is inconsistent with the IP (i.e., the investigator’s brochure (IB), Safety Information Summary (SIR) or package insert)

Safety Reporting Requirements

Investigator Responsibilities

As set forth in LawNo14.874, the investigator should promptly communicate all serious or unexpected AEs to the sponsor, the health authority, the research ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)), and the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)). ResNo945, and the G-SUSARs, specify that the investigator must inform the sponsor within 24 hours of all SAEs from the date of knowledge of the event. ResNo945 further explains that investigators must monitor and report to the sponsor, in accordance with good clinical practice (GCP) and the study protocol, the occurrence of all AEs, including those that come to their attention after the end of the clinical trial. The investigators must also provide any requested information and express their opinion regarding the causality between the AE and the IP. Per the G-SUSARs, upon becoming aware of an AE, the investigator should classify it for causality, severity, intensity, and expected/unexpectedness as per Annex 1 in the G-SUSARs. Further, if the investigator becomes aware of an AE after the completion or termination of the clinical trial, and there is suspicion of a possible causal relationship with the IP, the sponsor should be informed as soon as possible.

As explained in the G-SUSARs, the investigator is also responsible for adopting immediate safety measures to protect the clinical trial participant against any imminent risk, and for reporting the occurrence of all AEs to the sponsor. The participant affected by an AE should receive appropriate care and safety measures until resolution or stabilization of their clinical condition, as described in the clinical protocol. Upon becoming aware of an AE, the investigator must classify it regarding causality, severity, intensity, and expectedness, in accordance with the AE classification criteria delineated in Annex 1 in the G-SUSARs.

LawNo14.874 further specifies that the confidentiality of technical research information must be lifted when necessary for the analysis of SAEs. In the event of an SAE, the participant, their legal representatives, or their successors may disclose details relating to the former's participation in the research. Also, per the G-SUSARs, in the event of a possible SUSAR, the investigator should only break the concealment of treatment assignment for safety reasons, if the breaking of blinding is relevant to the safety of the trial participant, when immediate action needs to be taken.

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

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

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

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

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

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

Sponsor Responsibilities

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

• Promptly notifying the investigator, the institution, the competent ethical review entities, and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), about discoveries that may adversely affect the safety of the research participant, compromise the conduct of the research or affect the approval granted by the EC (CEP)
• In the case of clinical trials, issuing reports on serious or unexpected ADRs to the IPs, notifying the institutions and investigators involved and ANVISA
• Promptly notifying ANVISA of all serious or unexpected AEs whose causality is possible, probable, or defined in relation to the IP

ResNo945 and the G-SUSARs also state that the sponsor is required to report SUSARs to ANVISA and is permitted to delegate the reporting responsibility to the contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil). In the case of sponsor-reported SUSARs, where the investigator’s interpretation differs from that of the sponsor, both reports should be submitted with their respective justifications. Per ResNo945, SUSAR notifications to ANVISA must be made independently of the submission of the IB, amendments, reports, or early termination of the clinical trial. The G-SUSARs further notes that the sponsor must also inform the investigators involved in the clinical trial about the SUSARs and adopt the necessary measures to update the safety documents, such as the IB, drug package insert (in the case of a registered drug), and other related documents. Additionally, the sponsor must notify ANVISA about additional occurrences (follow-ups) of SUSARs until the IB is updated. (See Quality Requirements section for detailed IB requirements)

ResNo945 and the G-SUSARs also state that in the event of a possible SUSAR, the sponsor must break the blinding only for the participant who was affected by the SUSAR to notify ANVISA. Where possible, the blinding should be preserved for those responsible for the analysis and interpretation of study results and those responsible for continuing the clinical trial, such as study managers, monitors, and investigators. Therefore, these professionals must continue to receive SUSARs blindly.

As per ResNo945, when an event is related to the disease and represents a primary efficacy outcome of a clinical trial, the protocol must clearly define the event and indicate that it is not subject to notification.

As per ResNo945, when an event is related to the disease and represents a primary efficacy outcome of a clinical trial, the protocol must clearly define the event and indicate that it will not be subject to notification. If the event described is characterized as a SUSAR, it must be reported, as it may require a possible change in the safety profile. Medication errors, pregnancy, or uses not foreseen in the protocol, including misuse and abuse of the product under investigation, are subject to the same reporting obligations as ADRs. In the case of pregnancy, the investigator and the sponsor must accompany the mother and child. The G-SUSARs also state that any pregnancy that occurs in a participant during a clinical trial should be followed until its outcome, and the baby should be followed for the necessary period. See the Pregnant Women, Fetuses & Neonates section for additional information on this population.

As per ResNo945, the sponsor should ensure all relevant information pertaining to SUSARs occurring in Brazil is documented and electronically reported to ANIVSA within a maximum of seven (7) calendar days after first knowledge. ResNo945 indicates that additional information on the monitoring of SUSAR events should be included in the assessment within eight (8) calendar days from the notification date. Additionally, per ResNo945, the sponsor must notify ANVISA of any other SUSARs which are not fatal or life-threatening, within 15 calendar days from the date of first knowledge. Per the G-SUSARs, for clinical studies that are already in progress and have been previously approved, the notifications must be adequate to the requirements set forth in ResNo945.

In addition, per ResNo945 and the G-SUSARs, the sponsor must systematically collect, monitor, and evaluate all AEs, including non-serious AEs, that occur throughout clinical development and be responsible for the safety of clinical trial participants. The G-SUSARs also notes that the results of these evaluations must be submitted to ANVISA in the Drug Development Safety Update Report (DSUR) or whenever requested.

ResNo945 explains that safety information originating from other countries where clinical development is taking place must be communicated to ANVISA if it implies a change in the benefit-risk profile of the experimental drug, including safety actions taken by other agencies. The sponsor must also inform the investigators involved in the clinical trial about SUSARs and adopt procedures for updating the IB, in addition to reassessing the risks and benefits for the participants.

Further, per the ResNo945 and the G-SUSARs, the sponsor must establish a monitoring plan to manage AEs that occur following a trial’s completion/termination. ResNo945 further explains that the plan should justify the proposed period, which takes into account the IP(s), the participants, and the clinical trial. Throughout the clinical development of the IP, the sponsor and the investigator must adopt immediate safety measures to protect the trial participants in the event of a SAE/SADR. The trial participant suffering from an AE must receive care and appropriate safety measures must be taken until their clinical condition is resolved or stabilized, as described in the clinical protocol.

Per BRA-73, Brazil has also implemented the ICH Guideline E2B (R3) on Electronic Transmission of Individual Case Safety Reports (ICSRs) - Data Elements and Message Specification - Implementation Guide (BRA-88).

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

Other Safety Reports

As described in ResNo945 and the G-SUSARs, DSURs must be sent annually to ANVISA, until the end of the clinical development of the IP in Brazil. Each DSUR must be filed within 60 calendar days of either the annual anniversary of ANVISA’s approval of the clinical trial application, or the annual anniversary of the date established in the international development program, as applicable. ResNo945 and the G-SUSARs also note that the DSURs must be prepared in accordance with the format described in the current version of the ICH Harmonised Tripartite Guideline: Development Safety Update Report (E2F) (BRA-72). The SAE/AE data collected by the sponsor that occur throughout clinical development must be submitted to the Independent Data and Safety Monitoring Committee (IDMC or Data Safety Monitoring Board (DSMB)), if established, and the results of this assessment must be forwarded to ANVISA in the DSUR, in English, and upon request by ANVISA. See also the Site/Investigator Selection section for additional DSMB requirements.

Further, per the G-SUSARs, the sponsor must submit a single document containing data pertinent to all dosage forms and concentrations, all indications, and study participant populations associated with the IP. If this is not possible, a justification must be provided in the introductory section of the DSUR report. For concomitantly administered medicinal products, the sponsor may refer a single DSUR encompassing the IP and the other concomitantly administered therapies; or file separate reports for each IP product. For fixed-dose combinations, the sponsor must request a single DSUR covering all IPs. All safety-related modifications to the DDCM that are considered insubstantial must be also submitted to ANVISA as part of the DSUR.

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

Form Completion & Delivery Requirements

As per BRA-83, VigiMed (BRA-83) is ANVISA’s online system for citizens, health professionals, drug registration holders, and study sponsors to report suspected SAEs related to drugs and vaccines. In accordance with ResNo945, BRA-37 indicates that upon registration with BRA-83, companies (sponsors) must submit SUSARs exclusively via BRA-83. In addition, ResNo945 states that SUSAR notifications should be submitted individually and contain all the information requested in the fields present in the electronic notification system and as provided in the ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (BRA-66) and its updates.

In addition, per the G-SUSARs, any relevant safety events that alter the benefit-risk ratio of the IP or clinical trial(s) must be reported to ANVISA as soon as possible, using submission subject code 12378 - CLINICAL TRIALS - Safety monitoring linked to the respective process (DDCM or DEEC), and concurrently sending an email to vigimed.pesquisa@anvisa.gov.br, communicating the submission of the documents.

Per BRA-37, sponsors of clinical trials with medicines and biological products that have not yet been registered with VigiMed-Pesquisa Clínica should complete VigiMed’s Registration/Change of Registration form (BRA-131) and send it to this email address: vigimed.pesquisa@anvisa.gov.br. See also BRA-130 for the VigiMed Company User Manual, and BRA-145 for general instructions on using VigiMed.

Safety Reporting Definitions

In accordance with 21CFR312, the G-SpnsrRpt, the G-InvstRpt, the US-ICH-E2A, 42CFR11, and USA-99, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US) (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
• Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
• Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
• Serious Adverse Event (SAE)/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
• Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed in the study population; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
• Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if, in the view of either the investigator or sponsor, its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death

According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the Pre2018-ComRule, and the RevComRule for further information.

See USA-18 and USA-65 for more information on Common Rule departments/agencies, and the Regulatory Authority section for additional guidance on when the Pre2018-ComRule and the RevComRule apply to research.

Additionally, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the Food & Drug Administration (FDA) has implemented in US-ICH-GCP, for guidance on safety reporting.

Safety Reporting Requirements

Investigator Responsibilities

As delineated in 21CFR312 and the G-InvstRpt, the investigator must comply with the following reporting requirements:

• SAEs, whether or not considered drug related, must be reported immediately to the sponsor
• Study endpoints that are SAEs must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
• Non-SAEs must be recorded and reported to the sponsor according to the protocol specified timetable
• Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others

The G-InvstRpt adds that although the investigator must immediately report any SAE to the sponsor, more data may be collected and submitted after submitting the initial report. For the purposes of the G-InvstRpt, the FDA interprets “immediately” to be as soon as feasible after the investigator recognizes an event is an SAE and obtains relevant information for the sponsor. The FDA recommends that this timeframe for submitting initial information also be specified in the protocol and anticipates that the timeframe for submission of initial information will generally not exceed one (1) calendar day.

Sponsor Responsibilities

As delineated in 21CFR312, the G-SpnsrRpt, and USA-99, the sponsor must report in an investigational new drug application (IND) safety report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event. The sponsor is required to notify the FDA and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. Any relevant information obtained by the sponsor that pertains to a previously submitted IND safety report must be submitted as a follow-up IND safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.

Per 21CFR312, the G-SpnsrRpt, and USA-99,the sponsor must also report the following to the FDA in an IND safety report:

• Any findings from animal or in vitro testing, epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report) that suggest a significant risk in humans exposed to the drug, regardless of whether they are conducted under the IND or by the sponsor
• Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB

In each IND safety report, the sponsor must identify all IND safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312, the G-SpnsrRpt, and USA-99 for more details on these safety reporting requirements.

The G-SpnsrRpt notes that the sponsor is ultimately responsible for evaluating the available information and deciding whether there is a reasonable possibility that the drug caused the adverse event, and therefore that the event meets the definition of a suspected adverse reaction. Aggregate analyses are needed for (1) anticipated SAEs for which it is difficult or impossible to make a causal determination based on a single case or a small number of cases; or (2) expected serious suspected adverse reactions that must be reported if there is a clinically important increase in the rate over that described in the protocol or IB. See the G-SpnsrRpt for additional FDA guidance on aggregate analyses.

The FDA’s G-DecentralCT indicates that to protect the safety and welfare of trial participants in a decentralized clinical trial, sponsors should implement a safety monitoring plan that takes the decentralized nature of the clinical trial into account and ensures that adverse events and medication errors are appropriately collected and adequately addressed. As in any clinical trial, the safety monitoring plan should describe how participants are expected to respond to and report adverse events, including where to seek medical assistance locally when necessary, and where to receive follow-up care. See the G-DecentralCT for more information.

As part of the clinical trial results information submitted to ClinicalTrials.gov (USA-78), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:

• All SAEs
• All adverse events, other than SAEs, that exceed a frequency of five (5) percent in any arm of the trial
• All-cause mortalities

Per 42CFR11, this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if a responsible party submits a certification that: 1) the FDA has not approved, licensed, or cleared the investigational product (IP) being studied for any use before the primary completion date of the trial; and 2) the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval.

See 42CFR11 for detailed adverse event reporting requirements.

Form Completion & Delivery Requirements

The G-SpnsrRpt indicates that as of April 1, 2026, IND safety reports of serious and unexpected suspected adverse reactions (which contain individual data from one (1) or more participants) should be submitted as individual case safety reports (ICSRs) to the FDA’s Adverse Event Monitoring System (AEMS) (formerly FDA Adverse Event Reporting System (FAERS)) (USA-50). As per the G-SpnsrRpt, the G-INDElecSubs, and USA-46, sponsors must submit such IND safety reports to USA-50 using either the Electronic Submissions Gateway Next Generation (ESG NextGen) or the Safety Reporting Portal (SRP) (USA-51). See USA-102 for the ESG NextGen Unified Submission Portal (USP) Login, as well as USA-37 and USA-44 for more information on ESG NextGen. Also see USA-46 for more information on making submissions to USA-50.

The G-SpnsrRpt notes that other types of required IND safety reports (overall findings or pooled analyses from published and unpublished in vitro, animal, epidemiological, or clinical studies and reports of increased rates of occurrences of expected serious suspected adverse reactions) should be submitted by the sponsor in a narrative format in electronic common technical document (eCTD) format, and should not be submitted to USA-50.

See USA-99 for additional information on submitting IND safety reports.

According to the G-SpnsrRpt and the G-INDElecSubs, submissions regarding non-commercial INDs are exempt from the above electronic submission requirements. The G-SpnsrRpt states that sponsors with INDs that are exempted from the electronic submission requirement, and who are not submitting IND safety reports of serious and unexpected suspected adverse reactions to USA-50 or the other types of IND safety reports with eCTD format submission requirements, should submit IND safety reports in an alternate electronic format or using other means of rapid communication. When utilizing an alternate electronic format (see the G-AltrntElecSubs) or other means of rapid communication, Form FDA 3500A (USA-75) may be used. For additional information on other reporting using Form FDA 3500A (USA-75), see the G-SpnsrRpt and USA-48.

Per USA-90, fatality reports to the Center for Biologics Evaluation and Research (CBER) should be sent to fatalities2@fda.hhs.gov.

Interim and Annual Progress Reports

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

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

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

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

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

Final Report

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

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

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

Other Reporting Requirements

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

Interim and Annual Progress Reports

As specified in 21CFR312, the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56, the Pre2018-ComRule, and the RevComRule, the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must have written procedures for determining which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review.

21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:

• Title, purpose, and description of patient population, and current status
• Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
• Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
• Description of the general investigational plan for the coming year
• Updated investigator’s brochure, if revised
• Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
• Brief summary of significant foreign marketing developments with the drug
• A log of any outstanding business for which the sponsor requests a reply, comment, or meeting

As indicated in 42CFR11, trial updates must be submitted to ClinicalTrials.gov (USA-78) according to the following guidelines:

• Not less than once every 12 months for updated general trial registration information
• Not later than 30 calendar days for any changes in overall recruitment status
• Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome

Additionally, see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for guidance on clinical trial reports.

Final Report

As indicated in 21CFR312, an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.

Additionally, per 42CFR11, the responsible party must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the responsible party submits a certification that indicates: 1) the FDA has not approved, licensed, or cleared the IP being studied for any use before the primary completion date of the trial; and 2) the sponsor intends to continue with product development and is either seeking, or may at a future date seek, FDA approval. The clinical trial results information must include data on the following:

• Participant flow
• Demographic and baseline characteristics
• Outcomes and statistical analysis
• Adverse event information
• The protocol and statistical analysis plan
• Administrative information

See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data. See the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E3 Structure and Content of Clinical Study Reports (US-ICH-E3 and the US-ICH-E3-QA) for additional guidance on report structure.

As per LawNo14.874 and ResNo945, a sponsor is defined as a natural or legal person, under public or private law, that supports research through financing, infrastructure, human resources, or institutional support. ResNo466 defines a sponsor as an individual, company, institution, or organization that supports research through the initiation, management, or financing of a clinical trial.

LawNo14.874 further explains that a sponsor may authorize a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) to perform one (1) or more trial-related tasks and functions. ResNo945 specifies that a CRO is any company regularly installed in Brazil contracted by the sponsor or by the sponsor-investigator, which partially or totally assumes, together with the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), the sponsor's responsibilities. Any trial-related functions that are transferred to a CRO must also be specified in writing in a document signed by the sponsor and CRO. Per LawNo14.874 and ResNo945, although the sponsor may transfer their trial-related functions, the sponsor still has definitive responsibility for the quality and integrity of the clinical trial data.

ResNo945 also defines a sponsor-investigator as the natural person responsible for conducting and coordinating clinical trials, alone or in a group. The sponsor-investigator uses their own financial and material resources from national or international research funding entities or by private entities and other non-profit entities, while maintaining immediate and independent control over the study. When a clinical trial is developed by a sponsor-investigator, the institution with which the individual is linked is the primary sponsor. The primary sponsor may delegate responsibilities to the investigator, who will be responsible for conducting the clinical trial at the institution, and the sponsor-investigator will serve as the secondary sponsor. In the case of delegating responsibilities and activities, a written document must be signed between the parties.

In addition, per ResNo903, when a sponsor or CRO transfers responsibility to another company for submitting a clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) and the associated clinical trial processes for an investigational product (IP) to ANVISA, the succeeding company must update the relevant clinical trial registration data via a petition for global transfer of responsibility. See ResNo903 for additional information. See BRA-96 for more information on the global transfer of responsibility clinical trial request process. See also the Submission Content section for specific documentation requirements, and the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

As per 21CFR312 and 21CFR50, a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312 and 21CFR50 define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.

In addition, 21CFR312 states that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO). Any trial-related responsibilities transferred to and assumed by a CRO must be described in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations.

As indicated in 21CFR312, a sponsor may be either domestic or foreign.

Overview

As set forth LawNo14.874, the sponsor is responsible for selecting the investigator(s) and the institution(s) that will carry out the research, taking into account the qualifications necessary for conducting and supervising the research.

In addition, per ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for guidance on sponsor responsibilities related to site/investigator selection.

See also CLNo046 for the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidance on submitting requests for inclusion/exclusion of research center(s).

Foreign Sponsor Responsibilities

As specified in the ResNo945, the sponsor may transfer any or all of the sponsor’s study related duties and functions to a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil). However, the sponsor is ultimately responsible for the study data’s quality and integrity. Any study related duties, functions, or responsibilities transferred to and assumed by a local representative or CRO must be specified in writing. However, as per ResNo945, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or branch in Brazil.

Data Safety and Monitoring Board

LawNo14.874 states that, whenever possible, an independent data monitoring committee (Data Safety Monitoring Board (DSMB)) should be established to periodically evaluate the progress of the research, safety data, and critical points of efficacy and recommend to the sponsor whether to continue, modify, or interrupt a research study. In addition, ResNo945 indicates that it is desirable that an Independent Data and Safety Monitoring Committee (IDMC) (DSMB) be established by the sponsor to evaluate, at defined intervals or as needed in an emergency, the progress of the clinical trial, the safety data and the critical efficacy endpoints, and recommend to the sponsor whether to continue, modify, interrupt, or suspend a trial. The G-SUSARs also suggests that a DSMB be established, regardless of the clinical phase. The decision on the need to set up a DSMB must consider several factors including:

• Clinical and scientific relevance to the clinical trial
• Potential acceptable benefits and risks for the protection of participants
• Type of population
• Trial design, including objective(s) and outcome(s)
• Relevance of the committee to the integrity of the research

See also G-DSMB-BRA for DSMB operational guidelines.

Multicenter Studies

Refer to BRA-28 for sponsor guidance on conducting multicenter studies.

Overview

As set forth in 21CFR312, the sponsor is responsible for selecting the investigator(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:

• Signed investigator’s statement (Form FDA 1572 (USA-77))
• Curriculum vitae
• Clinical protocol
• Financial disclosure information

As addressed in the G-1572FAQs, Form FDA 1572 (USA-77) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA)'s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.

In addition, 21CFR312 indicates that prior to the start of the study, the sponsor must provide the investigator(s) with the investigator’s brochure. The sponsor is also responsible for providing the investigator(s) with the information needed to conduct an investigation properly.

See G-InvstgtrResp for more information on investigator responsibilities.

As per the G-InvstgtrAdmin, the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.

The G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT notes that because decentralized clinical trials may involve many contracted services, sponsors should ensure proper coordination of decentralized elements (e.g., use of remote trial personnel for at-home visits, use of local health care providers (HCPs), direct shipping of the investigational product to participants, etc.). Such contracted services may be performed by networks of local HCPs (e.g., local clinic networks, pharmacy chains). Sponsors should ensure these networks of local HCPs are qualified to perform the contracted activities. Sponsors should also keep a record of these networks and other contracted service providers, including their roles and assigned activities. See the G-DecentralCT for additional guidance.

Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on investigator selection, qualifications, and training.

Foreign Sponsor Responsibilities

No information is currently available.

Data and Safety Monitoring Board

As per 21CFR50, Data and Safety Monitoring Boards (DSMBs), (also known as Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation.

Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-18 and USA-65), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS)/NIH requirements.

Multicenter Studies

The RevComRule delineates that for all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, the G-CentralIRB, and G-CoopRes for additional information.

See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.

Insurance

As indicated in ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for guidance on sponsor responsibilities related to insurance coverage.

Compensation

Injury or Death

As specified in the LawNo14.874 and ResNo945, the sponsor is responsible for providing compensation and health assistance to research participants who have suffered as a result of their participation in the research. ResNo945 further specifies that the sponsor is responsible for all expenses related to procedures and examinations, especially those related to diagnosis, treatment, monitoring, and hospitalization of the clinical trial participant, and should take other actions necessary to resolve adverse events related to the clinical trial.

Additionally, per ResNo466, the investigator, the sponsor, and the institutions and/or organizations involved in the different phases of the research must provide immediate assistance, as well as be responsible for providing full assistance to research participants with regard to complications and damages arising from the research. Research participants should also be ensured that the conditions for monitoring, treatment, comprehensive assistance and guidance, including in-screening studies, will be in place as long as necessary. LawNo14.874 also notes that the institutions and organizations involved in the research will be jointly responsible for its conduct and will provide full assistance to the participants for complications and damages arising from the research.

Trial Participation

LawNo14.874 delineates that remuneration of the participant, or the granting of any type of advantage for their participation in research, is prohibited. However, the following do not constitute remuneration or advantage for the research participant:

• Reimbursement of transportation, food expenses, or provision of material supplies in advance
• Other types of reimbursement required, depending on the research project

LawNo14.874 further states that compensation is permitted for healthy volunteers participating in Phase I clinical trials or bioequivalence studies, when the participant is registered in a national registry of volunteers for bioequivalence and Phase I studies, and provided that the participant is not simultaneously enrolled in more than one (1) research study.

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

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

Post-Trial Access

Note: Brazil is currently transitioning from the National Health Council (Conselho Nacional de Saúde (CNS)) CEP/CONEP System—comprising research ethics committees (ECs) (Comitê de Ética em Pesquisa (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))—under the CNS to SINEP. Until the Ministry of Health (MOH)’s National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)) issues implementing regulations under DecreeNo12.651, elements of the CEP/CONEP System remain in effect. Per DecreeNo12.651 and CLNo51-2024, CNS-issued standards that do not contradict LawNo14.874 will continue to apply until INAEP issues new regulations. DecreeNo12.651 further states that CONEP has been assigned the role of the appellate body until INAEP members take office. The ClinRegs team will provide updates on the implementation of INAEP regulations as they become available. See also BRA-117 for additional information on LawNo14.874, and BRA-11 and BRA-89 for information on DecreeNo12.651.

National System of Ethics in Research Involving Human Beings (SINEP)

Pursuant to DecreeNo12.651, and in accordance with LawNo14.874, under SINEP, the sponsor must submit a post-trial access plan to the EC (CEP)) before the clinical trial begins. The plan must present and justify the need to provide participants with free access to the investigational product (IP) after completion of the trial. LawNo14.874 further states that, when post-trial access to the IP is required, the sponsor must prepare a post-trial supply program in accordance with the regulations. To guarantee continued access to the IP after the trial concludes, the program must provide for ongoing participant safety monitoring. The program should only be initiated after regulatory approval. The request for such approval must be submitted in a timely manner to ensure the research participant can transition to the post-trial period without interruption of treatment.

Additionally, per LawNo14.874, at the end of the clinical trial, the investigator, following consultation with the sponsor and the research participant, must carry out an individualized assessment to determine the need to continue the IP for each participant. DecreeNo12.651 further specifies that the sponsor must ensure free supply of the IP whenever the responsible researcher considers it to be the best therapeutic alternative for the participant’s clinical condition, based on available evidence and a favorable assessment of the risk-benefit ratio, in accordance with LawNo14.874. See also BRA-141 for additional INAEP guidance on post-trial access.

LawNo14.874 further explains that assessment of the need for continued IP supply after the clinical trial must be carried out in accordance with the following criteria:

• The severity of the disease and its threat to the participant's continued life
• The availability of satisfactory therapeutic alternatives for the participant’s treatment, considering their location
• If the experimental drug addresses an unmet clinical need
• If the evidence of benefit to the participant outweighs the evidence of risk with the use of the experimental drug

Per LawNo14.874, the free supply of the IP within the scope of the post-trial supply program may be interrupted, upon submission of justification to the EC (CEP), for assessment, only in any of the following situations:

• The research participant chooses to stop participating, or the participant cannot freely and validly express their consent
• A cure has been identified for the disease or health problem targeted by the clinical trial, or a satisfactory therapeutic alternative has been introduced, a fact duly documented by the investigator
• The lack of benefit from the participant’s continued use of the IP, considering the risk-benefit relationship outside the trial context or the emergence of new evidence of risks related to the IP’s safety profile, a fact duly documented by the investigator
• The occurrence of an adverse reaction that, at the investigator’s discretion, makes it impossible to continue using the IP, even in the face of potential benefits
• The impossibility of obtaining or manufacturing the IP for technical or safety reasons, duly justified, and provided that the sponsor provides an equivalent or superior therapeutic alternative available on the market
• A lapse of five (5) years, counted from the commercial availability of the experimental drug in the country
• The availability of the IP in the public health network

LawNo14.874 further notes that in the case of reactions arising from the study itself, the sponsor must ensure appropriate and necessary health care or measures for the research participant.

CEP/CONEP System (Pre-SINEP Framework)

Under the CNS' CEP/CONEP System, 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 participating in the trial and the end of the study, as delineated in ResNo466.

Further, ResNo563 states that for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining ANVISA registration. ResNo38 also indicates that the sponsor or the contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) should guarantee access to the post-trial drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the 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-Trial Medicine Supply Programs (see BRA-126 for form).

In addition, per ResNo903, the global transfer of sponsor or CRO responsibility for clinical trials is also applicable to expanded access programs, compassionate use programs, and post-trial drug supply. See ResNo903 for additional information. See also the Submission Content section for specific documentation requirements, and the Submission Process, Insurance & Compensation, and Manufacturing & Import sections for additional requirements related to global transfer of responsibility for the clinical trial.

Insurance

The United States (US) regulations do not require insurance.

Compensation

The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s). Also see the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, which guides sponsors on providing compensation.

Injury or Death

As specified in 21CFR50, the Pre2018-ComRule, and the RevComRule, for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.

Trial Participation

As per the FDA’s G-SbjctPayment, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.

Quality Assurance/Quality Control

As set forth in LawNo14.874, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems based on standard operating procedures (SOPs), to ensure that research is conducted and data is generated, documented, and reported in compliance with the protocol, good clinical practices (GCP), and other applicable regulatory requirements. The sponsor is responsible for QC during each stage of data processing to ensure its reliability and correct handling, and for maintaining the quality and integrity of research data, even if some or all functions have been transferred to a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil).

In addition, per ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28) and its subsequent updates for use with this regulation. See BRA-28 for guidance on sponsor responsibilities related QA and QC systems throughout the conduct of the trial.

ResNo945 also notes that in the case of a clinical trial initiated by the investigator, the institution to which the investigator is linked will be the primary sponsor. While the primary sponsor cannot delegate the quality assurance, auditing, and monitoring activities of clinical trials to the sponsor-investigator, the primary sponsor may delegate these responsibilities to a CRO. The primary sponsor must present its own or outsourced structure with QA and monitoring.

Monitoring Requirements

LawNo14.874 notes that the investigator is responsible for providing, when requested, direct access to research records and documents for the monitor, the auditor, other representatives of the sponsor, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), the National Research Ethics Authority (Instância Nacional de Análise Ética em Pesquisa (INAEP)), and ANVISA; allowing the sponsor to monitor and audit the research; and allowing ANVISA, INAEP, and the EC (CEP) to conduct inspections.

Additionally, in the event of a routine inspection by ANVISA, RegNo122 states that the agency will notify the institution at least 15 calendar days in advance of the visit. Both the sponsor and/or the CRO are responsible for preparing for the inspection. ANVISA must also notify the principal investigator (PI) of the scheduled visit to the center to be inspected, when applicable, by means of a GCP Inspection Notification Letter. For more detailed information on ANVISA’s inspection process, refer to RegNo122. See also Scope of Assessment section for detailed ANVISA inspection requirements. See GuideNo35-2020 and GuideNo36-2020 for additional guidance on GCP inspection requirements.

See ResNo926 for information on ANVISA’s inspection requirements for research centers to obtain a Certification of Good Practices to conduct bioavailability/bioequivalence drug studies. See also BRA-28 for additional sponsor monitoring requirements.

Premature Study Termination/Suspension

Pursuant to LawNo14.874, the sponsor is responsible for promptly communicating the reasons for the suspension or premature termination of the research to the investigators involved, the executing institution, ANVISA, and the EC (CEP) that approved the study, where applicable. Within 30 business days, the coordinating researcher must submit to the EC (CEP), the discontinuation notification, the technical-scientific justifications underpinning the decision, and a detailed report containing the results obtained up to the time of the study’s interruption. In the case of a clinical trial, in addition to the documentation specified, the coordinating researcher and the sponsor are required to submit a plan for the follow-up and assistance necessary for the participants in the discontinued study. The discontinuation of research for reasons the EC (CEP) deems non-substantive will be considered an ethical infraction and will subject the offender to the sanctions delineated in LawNo14.874. See LawNo14.874 for additional details related to sanctions. DecreeNo12.651 also provides that INAEP will regulate the plan for monitoring and assisting participants in discontinued trials in accordance with the provisions delineated above per LawNo14.874.

ResNo945 further explains that the sponsor may, at any time, suspend or cancel a Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)) or approved clinical trial, provided that the appropriate justifications are submitted, as well as a plan for monitoring the participants, if the trial has already been initiated. Per ResNo945 and the G-DDCMAmdmts, once a DDCM has been cancelled, no clinical trials related to it may be continued in the country. Per ResNo945 and the G-DDCMManual, suspensions and cancellations must be filed with ANVISA, in the form of a secondary petition attached to the corresponding DDCM. ResNo945 and the G-DDCMAmdmts also note that the petition must be submitted within 15 business days following the decision to suspend or cancel a DDCM or clinical trial.

In addition, ResNo945 and the G-DDCMAmdmts state that in cases where the sponsor temporarily suspends the DDCM or clinical trial, as an immediate safety measure, the sponsor must notify ANVISA within seven (7) calendar days from the date of suspension. ResNo945 also notes that the reasons, scope, interruption of treatment, and suspension of participant recruitment must be clearly explained in the temporary suspension notification. The request for reactivation of a suspended clinical trial protocol or DDCM must be accompanied by the appropriate justifications, and the sponsor must await authorization from ANVISA to restart the clinical trial. As per the G-DDCMAmdmts, the temporary suspension can be reactivated with the submission of a secondary petition to ANVISA. Refer to the Submission Content section for instructions on submitting a secondary petition to suspend or cancel a DDCM or clinical trial.

Per ResNo945, the sponsor may, at any time, request that ANVISA discontinue its analysis of the DDCM, the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)), and secondary petitions. The withdrawal request must be accompanied by the appropriate justifications and applies only to petitions in which ANVISA’s decision has not yet been published in the Official Gazette of the Union (Diário Oficial da União (DOU)). Temporary suspension, cancellation, reactivation, and withdrawal of DDCM, DEEC, and secondary petitions may only be implemented after ANVISA has issued a statement, which must be issued within 30 business days, by means of publication of its decision in the DOU. However, in the case of a temporary DDCM or clinical trial suspension as a safety measure, ANVISA’s implementation must be immediate, and the analysis carried out within 10 calendar days.

See also BRA-28 for guidance on sponsor responsibilities related to premature trial termination/suspension.

Quality Assurance/Quality Control

Per the US-ICH-E19, the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the US-ICH-E19 for more information.

Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.

The G-DecentralCT provides FDA recommendations for clinical trials with decentralized elements. The G-DecentralCT states that to account for multiple sources of data collection in a decentralized clinical trial, the sponsor should include at least the following in a data management plan or other trial-related documents: data origin and data flow from all sources to the sponsor (e.g., a diagram that depicts the flow of data from creation to final storage); methods and technologies used for remote data acquisition from trial participants, trial personnel, and contracted service providers (e.g., local clinical laboratory facilities and local health care providers who perform trial-related activities); and a list identifying service providers for data collection, handling, and management.

The G-DecentralCT further indicates that to protect the safety and welfare of trial participants in a decentralized clinical trial, sponsors should implement a safety monitoring plan that takes the decentralized nature of the clinical trial into account and ensures that adverse events and medication errors are appropriately collected and adequately addressed. When applicable, the safety monitoring plan should describe the type of information that will be collected by a digital health technology, how that information will be used and monitored, and what action trial participants or personnel should take in response to abnormal findings or electronic alerts. See the G-DecentralCT for additional information.

See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research, and see the G-RemoteData for recommendations on the use of digital health technologies for remote data acquisition from participants in clinical investigations that evaluate medical products. Furthermore, see the G-ESourceData for FDA guidance regarding the capture, review, and retention of electronic source data, particularly for use in filling the predefined fields in an electronic case report form.

Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.

The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 investigational new drug application (IND) regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.

See the FDA’s G-EnrchStrat for enrichment strategies that can be used in clinical investigations intended to demonstrate the effectiveness of drug and biological products, and the G-DataCollect for recommendations on the use of a standardized approach for collecting and reporting race and ethnicity data in submissions for clinical trials.

Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.

See USA-97 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data. Additionally, see USA-6 for other scientific data sharing policies, including genomic data.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving quality management, assurance, and control. Additionally, see USA-69 for 10 guiding principles that industry and product developers can consider when using artificial intelligence (AI) to advance drug and biological product development.

Monitoring Requirements

The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:

• Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely, or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
• Target on-site monitoring by identifying higher-risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).

For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA. Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving monitoring and auditing.

Premature Study Termination/Suspension

As delineated in 21CFR312, if the sponsor determines the investigational product (IP) presents an unreasonable and significant risk to the participants, the sponsor must discontinue the associated study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining stock of the IP and provide the FDA with a full report on the sponsor’s actions.

The G-InfrmdCnsnt, which is the FDA’s discussion of the regulations in 21CFR50, further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an IP that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow up may be available or necessary.

21CFR312 indicates that if the FDA terminates an IND based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on sponsor responsibilities involving premature termination or suspension of a trial.

Electronic Data Processing System

As specified in ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (BRA-28), and its subsequent updates for use with this regulation. Refer to BRA-28 for sponsor requirements when using electronic trial data processing systems.

Records Management

As delineated in ResNo945, the sponsor must be responsible for storing clinical trial data for a period of five (5) years after the last approval of a registration request for registration in Brazil. The sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, or a marketing application receives the last approval.

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

Electronic Data Processing System

As per the Food & Drug Administration (FDA)’s G-DecentralCT, electronic systems can be used to perform multiple functions to manage decentralized clinical trial (DCT) operations. Training should be provided to all parties (e.g., trial personnel, local health care providers, and trial participants) who are using electronic systems to support the conduct of DCTs. Electronic systems that are used to produce and process trial records required by the FDCAct and FDA regulations are subject to 21CFR11. These systems must ensure data reliability, security, privacy, and confidentiality.

See 21CFR11 and the G-Part11 for general FDA regulations and guidance on electronic records and systems. Additionally, see the G-ElecSyst for guidance specific to clinical investigations.

Also see the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for guidance on data handling and processing, including the use of computerized systems.

Records Management

According to 21CFR312, the sponsor must maintain complete and accurate records showing financial interest paid to clinical investigators by the sponsor, as well as records concerning all other financial interests of investigators.

As set forth in 21CFR312, the sponsor must retain the above records and reports for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued and the FDA has been notified. Additionally, upon request from the FDA, the sponsor must permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.

Also see the ICH’s Guideline for Good Clinical Practice E6(R3), which the FDA has implemented in US-ICH-GCP, for additional guidance on record keeping and management.

Responsible Parties

The LGPD delineates that the “controller” is responsible for decisions regarding the processing of personal or sensitive personal research data. Within this context, the controller may carry out studies as a research body, guaranteeing, whenever possible, the anonymization of personal data.

Per CD-ANPD-No18, which regulates the performance of the person responsible for processing data, the “person in charge” is appointed by the controller and operator to act as a communication channel between the controller, data subjects, and the National Data Protection Authority (Autoridade Nacional de Proteção de Dados (ANPD)). The person in charge may be a natural person, member of the organizational structure of the processing agent or external to it, or a legal entity, and must be able to communicate with the holders and with the ANPD, clearly, precisely, and in Portuguese. Additionally, the exercise of activity of the person in charge does not presuppose registration with any entity or any specific certification or professional training. See CD-ANPD-No18 for details on the activities and duties of the person in charge and how conflicts of interest are handled. Refer to G-CD-ANPD-No18 for additional guidance and good practices for data processing agents.

Data Protection

As set forth in C-AmndtNo115, the protection of personal data is a guaranteed fundamental right in Brazil. The LGPD further delineates data protection principles (e.g., purpose, adequacy, necessity, free access, data quality, transparency, security, prevention, non-discrimination, and accountability) with which the controller must comply. The protection and anonymity of the personal data of research participants is also regulated by LawNo14.874, and applied subsidiarily to the LGPD.

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

The LGPD also provides a definition for sensitive personal data or information that encompasses health related considerations. Sensitive personal data refers to personal data about racial or ethnic origin; religious belief; political opinion; union membership or organization of a religious, philosophical, or political nature; data relating to health or sexual life; and genetic or biometric data, when linked to a natural person. See also LGPD for guidance on implementing a privacy governance program, and see the LGPD and BRA-76 for detailed information on data protection requirements in Brazil.

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