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

Liberia Medicines and Health Products Regulatory Authority

As per the LMHRA-Act, the LibCTReg, and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections. According to the LMHRA-Act, the LMHRA operates as an autonomous government agency that reports to the President of the Republic of Liberia. In addition to its role in authorizing clinical trials, the LMHRA-Act indicates that the LMHRA’s responsibilities also include drug and health care product registration, inspections, import/export control, licensing, quality control, advertising and promotion, and pharmacovigilance and post-marketing surveillance.

Per LBR-30, the Clinical Trials Unit within LMHRA’s Pharmacovigilance & Clinical Trials Department is responsible for coordinating all aspects of clinical trials in Liberia including:

• Receiving and assessing all clinical trial applications submitted to the LMHRA
• Conducting good clinical practice (GCP) inspections of trial sites and GCP training for inspectors and the study team to ensure compliance that is in line with LMHRA regulatory requirements and international best practices
• Reviewing all reports from clinical trial sites and advising management on appropriate regulatory actions
• Investigating the conduct of clinical trials
• Suspending or stopping clinical trials (depending on the magnitude of the offense)
• Serving as secretariat for the Scientific Advisory Committee (SAC) on clinical trials
• Reviewing importation permits for investigational products (IPs) that are required for the conduct of clinical trials
• Conducting pre-submission meetings to discuss issues related to application processes
• Reviewing all reports (safety reports, quarterly reports, Serious Adverse Events (SAE) reports and final or close-out reports) from clinical trial studies conducted

Per the LibCTReg, the LMHRA can establish advisory committees for the review of clinical trial applications and for post-approval safety and compliance issues, if needed, and especially in the event of new/emerging technologies. According to LBR-29, the LMHRA has established a SAC to provide technical support to review clinical trial applications.

Other Considerations

Please note: Liberia is party to the Nagoya Protocol on Access and Benefit-sharing (LBR-3), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see LBR-17.

Contact Information

Per LBR-19, the LMHRA contact information is as follows:

Liberia Medicines and Health Products Regulatory Authority (LMHRA)
2nd & 3rd Floors Clay Building
Sekou Toure Avenue
Mamba Point
Monrovia, Liberia
Phone: (+231) 777-140-555 or (+231) 888-140-555
Email: info@lmhra.gov.lr

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 LMHRA-Act, the LibCTReg, and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) is responsible for reviewing, evaluating, and approving applications for clinical trials using registered or unregistered investigational products (IPs). According to the G-LibClinTrial, proposed clinical trials of registered medicines may include changes to indications, new methods of administration, or new combinations, etc. The G-LibClinTrial specifies that the scope of the LMHRA’s assessment includes all clinical trials (Phases I-IV). In addition, per the LibCTReg and the G-LibClinTrial, the National Research Ethics Board of Liberia (NREB) and LMHRA reviews may be conducted in parallel. However, the G-LibClinTrial and the G-NREB specify that the LMHRA will only issue final approval once NREB (ethics committee (EC)) approval is obtained.

Clinical Trial Review Process

As indicated in LBR-30, the LMHRA’s Clinical Trials Unit within the Pharmacovigilance & Clinical Trials Department is responsible for coordinating all clinical trial activities. According to LBR-29, the LMHRA has established a Scientific Advisory Committee (SAC) to review clinical trial applications.

Per the G-LibClinTrial, the LMHRA will only process an application upon receipt of a completed application and the prescribed fees. Upon receipt, the LMHRA screens the clinical trial application package for completeness and must inform the applicant in writing about the validity of the application or the formal grounds for non-acceptance of the application. After validating the application package is complete, the LMHRA conducts a scientific assessment of the application.

During the clinical trial scientific assessment process, the LibCTReg and G-LibClinTrial also explain that relevant clinical trial decisions, reports, or information from other national regulatory authorities or regional and international bodies can be recognized or used by the LMHRA. The LibCTReg further specifies that the scope/extent of utilization of relevant clinical trial decisions, reports, or information from other national regulatory authorities or regional and international bodies will be at the sole discretion of the LMHRA. In such instances, business and company secrets must remain confidential.

The LibCTReg also states that the LMHRA must inform the NREB if it is in possession of information about other clinical trials that is relevant to the board's assessment of the trial for which it is to issue an expert opinion; this applies especially to information on aborted or otherwise prematurely discontinued investigations. In such instances, business and company secrets must remain confidential. Also, the LMHRA must ensure that the list of approved and rejected clinical trial applications, the summary of evaluation reports, and the status of approved clinical trials are publicly available and periodically updated.

Per G-LibClinTrial, all applications must be evaluated with the same set of criteria based on up-to-date scientific knowledge and ethics standards, regardless of the applicant. The LMHRA may also request additional documents or changes through a query letter. Once a query has been raised and issued to the applicant, the process stops when the LMHRA receives a written response to the query. If the LMHRA requires changes to the application, the applicant must modify the application within an established timeline, or it will be rejected.

As indicated in the G-LibClinTrial, the LMHRA must issue a clinical trial certificate, including the LMHRA clinical trial number, to the applicant upon application approval. The clinical trial certificate may contain conditions required by the LMHRA with respect to the conduct or reporting of the trial. If the application is rejected, the applicant can submit a written appeal to the LMHRA’s Managing Director. Moreover, the information provided in a clinical trial application must not be disclosed by the LMHRA to a third party except with the applicant’s written consent or in accordance with the directive of the LMHRA Board of Directors.

Per the G-LibClinTrial, under certain circumstances, the LMHRA may accept an expedited application and review process for clinical trials (e.g., epidemics or other urgent public health interests requiring fast use of new medicines or health products and/or fast gathering of health product information). The LibCTReg also notes that in the case of emergency situations, the LMHRA may also apply an expedited review process and make exemptions to the documentation requirements for the submission of clinical trial applications. Refer to 2.3 of the G-LibClinTrial for additional information on how to submit an expedited clinical trial application package.

As delineated in the LibCTReg, any amendments to approved clinical trial documentation, trial arrangements, and the IPs referenced in the application must be classified and processed in accordance with the LMHRA guidelines. The G-LibClinTrial explains that depending on the nature of the change, trial amendments are regarded as substantial or non-substantial/minor amendments. Amendments to a clinical trial are regarded as “substantial” when they are likely to have significant impact on the safety or physical or mental integrity of the trial participants and/or the scientific value of the trial. Any substantial amendments to the clinical trial protocol, clinical trial arrangements, or the IP—or a related product deemed to be an amendment—must be approved by the LMHRA and the NREB before such amendments are carried out. Written NREB approval is also required before the LMHRA can reach a decision on an amendment. The LMHRA should respond within 20 calendar days upon receipt of the NREB’s written decision, and may accept or reject the amendment, or recommend a revision of the sponsor’s classification.

Per the G-LibClinTrial, non-substantial/minor amendments, by comparison, can be implemented immediately by the sponsor and should always be documented and notified to the LMHRA and the NREB as soon as possible. See the G-LibClinTrial for additional amendment requirements. See the Submission Process section for amendment submission requirements.

Per the LibCTReg, the LMHRA’s written approval of a clinical trial with IPs involving human participants is based on the conclusion that the anticipated therapeutic and public benefits justify the risk and may be continued only if compliance with this requirement is permanently monitored. An LMHRA authorization may only be refused if:

• The documents submitted are incomplete up to the expiration of an appropriate deadline given to the applicant for their supplementation
• The documents submitted, especially the data on the IP(s) and the trial protocol including the investigator's brochure (IB), do not comply with the current state of scientific knowledge, and especially, the clinical trial is unsuitable for providing proof of IP(s) safety or efficacy
• In the case of trials involving human participants, the documentation requirements (see Section 1 (d) of LibCTReg), particularly insurance coverage for trial participants, are not fulfilled
• The LMHRA is in possession of findings which indicate that the testing facility is not suitable to conduct the clinical trial
• The LMHRA is of the opinion that the number of clinical trial participants to be recruited in the trial is not scientifically justified, or
• The requirements provided for in the general conditions and special preconditions for conducting a clinical trial (see Part II (Section 2) of LibCTReg) are no longer fulfilled

The LibCTReg indicates that, in a clinical trial involving an IP that consists of, contains, or is a combination of genetically modified organisms, unjustifiable harmful effects on the health of third persons and the environment are not to be expected when the trial is conducted according to the state of scientific knowledge and in relation to the trial’s purpose.

(See the Submission Process and Submission Content sections for detailed submission requirements and the Timeline of Review section for additional LMHRA timeline information.)

The LibCTReg further explains that the LMHRA must suspend a clinical trial authorization for a limited period of time if at least one (1) of the following conditions is true:

• It becomes known that one (1) of the grounds for refusal previously indicated existed at the time the trial authorization was issued (see also Part II (Section 6 (1) of LibCTReg)
• The conditions surrounding the clinical trial do not correspond to the information contained in the authorization application
• The facts presented give reason to doubt the safety or the scientific basis of the clinical trial

Per the LibCTReg, the LMHRA must withdraw a clinical trial authorization when scientific justification for resuming the trial is not provided to address the reasons previously indicated for suspension. The LMHRA must also immediately inform the NREB through a written communication stating the grounds for its action. Before the LMHRA issues a decision, the applicant must be allowed a deadline of 10 working days to submit a statement, unless the LMHRA orders the immediate interruption of the clinical trial. The lodging of an objection and an action to rescind the withdrawal or the order to suspend the authorization should not have a suspensive effect. If the authorization to conduct a clinical trial is withdrawn or suspended, the clinical trial may not be continued. Also, if the LMHRA, in the context of its activities, becomes aware of facts which justify the assumption that one (1) or more of the investigators or the sponsor or the sponsor’s representative no longer fulfills their obligations with regard to the proper conduct of the clinical trial, the LMHRA must immediately inform this individual(s) and must order remedial measures to be taken by the individual(s).

Pursuant to Part VIII of the LMHRA-Act, the LibCTReg states that any person(s), institution(s), corporate entity(ies), their designees, or legal representatives who violates the clinical trial authorization procedures, the serious adverse event notification requirements, and/or the suspension/withdrawal provisions delineated in the LibCTReg will be liable to pay administrative fines. See the LibCTReg for details.

Inspection

As stated in the LibCTReg, the LMHRA should inspect a clinical trial site to ensure that the general public is adequately protected against the adverse event risks related to a clinical trial with IP(s); and, to confirm that the PI and the sponsor, including the sponsor’s representatives, are strictly adhering to the specific and general conditions to which the trial was authorized. The G-LibClinTrial also indicates that the LMHRA may inspect clinical trial sites and/or the sponsor's/contract research organization (CRO)’s premises and/or the manufacturer’s premises to ensure that the clinical trials comply with good clinical practice (GCP) provisions before, during, or after the trial is conducted.

Per the LibCTReg and the G-LibClinTrial, NREB representatives may accompany the LMHRA during clinical trial site inspections, or, per the LibCTReg, they may choose to do the inspections independently. The G-LibClinTrial also notes that the LMHRA may include other relevant regulatory authorities in the inspection. The PI and/or the sponsor/CRO and/or the manufacturer must be notified in writing of the inspection unless the LMHRA has reasonable cause to believe that the approved protocol is being violated. In this case, an unannounced inspection may be conducted. Following these inspections, the LMHRA must prepare an inspection report, and the report will be made available to the PI and/or sponsor while safeguarding the confidential aspects. The report may also be made available to the NREB and other regulatory authorities upon their request. Additionally, the LibCTReg specifies that the LMHRA, based on its findings, may also request additional information, suspend or stop a trial, or withdraw authorization to conduct a clinical trial, if the agency is of the opinion that the participant safety may be jeopardized, the scientific reasons for conducting the trial have changed, or the integrity of the data is compromised.

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).

Liberia Medicines and Health Products Regulatory Authority

The LibCTReg and the G-LibClinTrial require proof of payment of the clinical trial application fee in the application dossier. Per LibCTReg, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) charges a non-refundable fee to submit a clinical trial application for authorization. As delineated below, authorization fees vary depending on the phase and institution conducting the study:

• Industry Funded (Phase I): $25,000 USD
• Industry Funded (Phase II): $20,000 USD
• Industry Funded (Phase III): $15,000 USD
• Clinical Research Organization (CRO) Funded Phase I: $10,000 USD
• CRO Funded Phase II: $8,000 USD
• CRO Funded Phase III: $6,000 USD
• Investigator/Local Phases III & IV: $2,500 USD
• Academic Research Trial (Individual): $2,000 USD
• Amendment (Substantial) to Clinical Trial Protocol: $1,000 USD
• Administrative Charges: $500 USD
• Material Transfer Agreement (MTA) Fees: $1,500 USD
• Good Clinical Practice (GCP) Inspections: $1,000 USD

Payment Instructions

No information is currently available regarding payment instructions.

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

Per the G-ACRE-IRB and the G-NREB, all research involving human participants should be reviewed by an ethics committee (EC). According to the NatResHlthPlcy, Liberia has two (2) ethics committees (ECs): the National Research Ethics Board of Liberia (NREB) and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) (formerly known as the University of Liberia-Pacific Institute for Research and Evaluation Institutional Review Board (UL-PIRE-IRB)). (Note: The UL-PIRE Africa webpage has not yet been updated to reflect the transition to ACRE IRB.)

Per LBR-38, the NREB has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

National Research Ethics Board of Liberia

As explained in the G-NREB, the NREB is an advisory institution that reports to the Ministry of Health (MoH), and its members are appointed by the Minister of Health. The G-NREB states that the board ensures all research related protocols within and outside of Liberia are in compliance with internationally recognized ethical standards (including the Belmont Report (LBR-11), the Declaration of Helsinki (LBR-27), the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (LBR-8), and the Council for International Organizations of Medical Sciences (CIOMS’) International Ethical Guidelines for Health-related Research Involving Humans (LBR-2)), as well as Liberia’s applicable regulations and guidelines. In addition, per the G-NREB and LBR-12, the NREB is responsible for reviewing research proposals involving human participants to assess their compliance with ethical principles, regulatory requirements, and international guidelines, and for approving research protocols that meet ethical standards and providing recommendations for addressing any ethical concerns.

Per the NatResHlthPlcy, the G-NREB, and LBR-12, the NREB is also 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):

• Ensuring that researchers obtain informed consent from participants and that participants’ rights, privacy, and confidentiality are protected
• Evaluating the potential risks and benefits of research projects and ensuring that the risks are justified and minimized
• Developing and disseminating policies, guidelines, and standards for ethical conduct in research
• Providing guidance and support to researchers, research institutions, and ECs on ethical issues related to research involving human participants
• Fostering awareness and understanding of ethical principles and regulatory requirements among stakeholders in the research community
• Conducting training programs, workshops, and seminars to educate researchers, EC members, and other stakeholders on ethical principles and best practices in research ethics
• Building the capacity of research institutions and ECs to effectively review and oversee research involving human participants
• Promoting a culture of ethical conduct and responsible research practices within the research community
• Monitoring compliance with approved research protocols and ethical standards throughout the duration of research projects
• Conducting periodic reviews or audits of research activities to ensure adherence to ethical principles and regulatory requirements
• Investigating and addressing any allegations of research misconduct or breaches of ethical standards
• Establishing guidelines for the ethical review of health research protocols for use by other review boards
• Providing advice on ethical research issues to the MoH and related government ministries and agencies
• Engaging with the public, policymakers, and other stakeholders to raise awareness of ethical issues in research and to foster dialogue on ethical considerations
• Advocating for the protection of research participants’ rights and the promotion of ethical conduct in research at the national and international levels
• Collaborating with relevant government agencies, institutions, and organizations to advance the ethical governance of research
• Establishing and maintaining a repository of all protocols reviewed in the country along with completed research/study reports

Atlantic Center for Research and Evaluation Institutional Review Board

As stated in the G-ACRE-IRB, the ACRE IRB is mandated by the Board of Directors of the ACRE Africa Center, and is tasked with ensuring quality and consistency in its review of social, behavioral, clinical, and biomedical research protocols that comply with LBR-2 and the national ethical guidelines for research on human participants. However, as noted above, per LBR-28, the ACRE IRB does not review and approve clinical trial protocols. Some members of the ACRE IRB also serve on the NREB and provide expertise in the review of clinical trial protocols.

Ethics Committee Composition

National Research Ethics Board of Liberia

According to the G-NREB, the NREB is composed of 21 members who jointly represent a diverse community with a range of expertise. The G-NREB notes that the majority of the board members are clinicians, scientists, and national subject matter experts. Per LBR-18, the NREB board typically consists of experts in various fields related to research ethics, such as medicine, public health, social sciences, ethics, law, and community representatives. Board members may include researchers, ethicists, healthcare professionals, legal experts, and representatives from government agencies and civil society organizations. LBR-38 further specifies that the NREB membership includes, but is not limited to, a sociologist, an infectious disease scientist, a biologist, a lawyer, a pharmacist, an epidemiologist, a statistician, a bioethicist, a mental health specialist, a health system strengthening specialist, a religious elder, community elders, surgeons, clinicians, and public health specialists.

In addition, per LBR-18, although the NREB organization structure may vary based on its specific mandate, size, and operational requirements, the board typically consists of a chairperson/executive director, a secretariat or administrative staff, ethics review committees/panels, and advisory groups that may provide specialized expertise or support for specific activities or initiatives.

Atlantic Center for Research and Evaluation Institutional Review Board

As specified in the G-ACRE-IRB, the ACRE IRB members (full, regular, and ad-hoc) must be recommended by the ACRE IRB Chair and appointed by the ACRE Board of Directors. The IRB Executive Committee should consist of the Coordinator, the Chair, and two (2) members of the IRB recommended by the Chair in consultation with the Coordinator. The IRB Secretariat, which will handle administrative functions, should also include the Coordinator, IT Officer, and Finance Officer.

The ACRE IRB must be comprised of 12 members with the qualifications and experience, individually and collectively, to review and evaluate the scientific, medical, and ethical aspects of research protocol submissions. The ACRE IRB membership must include the following from diverse backgrounds to undertake an impartial and adequate review of research proposals:

• Scientists (including, but not limited to, professionals in natural science, social science, and behavioral science)
• Non-scientists (health practitioners, legal experts representing the community, and civil society)

In addition, the ACRE IRB must ensure social inclusivity and gender sensitivity in its membership and in the recruitment of ad-hoc reviewers. The board must include adequate representation across age, gender, community, etc., to safeguard the interests and welfare of all segments of society. ACRE IRB members must be drawn from both public and private institutions within the country.

Terms of Reference, Review Procedures, and Meeting Schedule

National Research Ethics Board of Liberia

Pursuant to the G-NREB, the NREB follows standard operating procedures (SOPs) as well as applicable ethical guidelines and regulations to ensure compliance with research ethics principles and to uphold societal interests. The NREB may seek subject matter expert opinions regarding specific research protocols and/or ethical issues, provided that the experts have no conflict of interest, including participation in the research, financial interest in the outcome, and/or involvement in competing research, among other reasons.

NREB members should meet bi-monthly for regular meetings and adhere to the board’s threshold requirement to review a minimum of three (3) complete applications at each meeting. When applicable, the NREB director may also convene ad-hoc meetings. All complete applications submitted by the deadline must be reviewed at the next regularly scheduled meeting, if the minimum applications threshold is met. Members are encouraged to attend all meetings and the quorum required for voting is two-thirds of the NREB membership. Members who cannot attend a meeting due to unforeseen reasons must inform the NREB director two (2) weeks prior to the scheduled meeting. If unable to attend, members must also advise the NREB director regarding their views or concerns on specific agenda items one (1) week prior to a scheduled meeting. Meeting agendas and research protocols should be distributed to members no later than three (3) weeks before a regular meeting. Refer to the G-NREB and LBR-12 for detailed committee requirements.

Atlantic Center for Research and Evaluation Institutional Review Board

As delineated in the G-ACRE-IRB, the ACRE IRB Chair must be the head and chief spokesperson of the board and must conduct meetings in accordance with the policies, regulations, and timetable approved by the board. ACRE IRB members must be appointed initially for a term of three (3) years, which must be renewable and is subject to the ACRE IRB Board of Directors’ decision. To maintain continuity in ACRE IRB operations, at least one-third of the membership must be retained at any given time. The outgoing Chair must be an ex-officio member of the incoming ACRE IRB. ACRE IRB members and consultant reviewers must be provided with all relevant SOPs by the Secretariat to guide in the review process of all submitted protocols. ACRE IRB members are required to review, discuss, and consider protocols submitted to the board for evaluation to safeguard the rights, safety, and well-being of study participants; review progress reports and monitor ongoing research studies appropriately; evaluate final reports and outcomes; maintain absolute confidentiality in all document deliberations at board meetings; state conflicts of interest, where applicable; and participate during deliberations. Members with a conflict of interest will recuse themselves from the review of submissions with which they have a conflict, except to answer specific questions posed by the board. Additionally, per LBR-28, ACRE IRB reviews are conducted virtually via the Zoom platform.

G-ACRE-IRB further provides that the ACRE IRB must convene a meeting every month or when deemed necessary. The Chair, or a delegated board member, must call the meeting to order, provided there is a quorum. If there is no quorum, the meeting must be rescheduled. A quorum must be greater than 50% of the voting board members at any given event. A quorum must consist of regular and/or alternate board members (persons formally selected by the board to substitute for regular members who are unavailable), and it must include at least one (1) member whose primary background is science related, and one (1) member whose primary background is not science related. Special/independent consultants cannot be used to establish a quorum. Members who are recused from the review of a protocol cannot be used to establish a quorum. A simple majority vote of ACRE IRB members in attendance is required for a protocol to be approved. The ACRE IRB Chair may also invite individuals with competence in special areas to assist in the review of issues that require expertise beyond, or in addition to, that available on the board. These individuals will be required to sign a confidentiality agreement before they review a protocol or attend a board protocol discussion, however, they are not permitted to vote. The consultant will provide the Chair with a written report to be shared with all reviewers summarizing relevant information.

Additionally, G-ACRE-IRB indicates that during IRB meetings, all deliberations must be recorded either electronically or written manually. The Secretary should also prepare meeting minutes, which include a summary of each protocol that has been considered for approval. The IRB Chair should confirm the accuracy and completeness of the minutes by signing and archiving them, together with the meeting’s agenda and other relevant attachments. Refer to G-ACRE-IRB for detailed information on ACRE IRB administrative processes.

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

According to G-NREB and G-ACRE-IRB, the primary scope of information assessed by ethics committees (ECs) in Liberia relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a study. The NatResHlthPlcy states that Liberia has two (2) ECs: the National Research Ethics Board of Liberia (NREB) and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) (formerly the University of Liberia-Pacific Institute for Research and Evaluation Institutional Review Board (UL-PIRE-IRB)). However, per LBR-38, the NREB has sole responsibility to review all clinical trial protocols. Per LBR-28, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB.

The G-NREB and the G-ACRE-IRB also state that the ECs are responsible for ensuring independent, timely, and competent reviews of all ethical aspects of the clinical research protocol. The ECs must also act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants, and they must verify the adequacy of confidentiality and privacy safeguards.

Atlantic Center for Research and Evaluation Institutional Review Board

The G-ACRE-IRB is tasked with ensuring quality and consistency in the ACRE IRB’s review of social, behavioral, clinical, and biomedical research protocols that comply with the Council for International Organizations of Medical Sciences (CIOMS’) International Ethical Guidelines for Health-related Research Involving Humans (LBR-2) and the national ethical guidelines for research on human participants. (Note: While the G-ACRE-IRB includes references clinical trials, per LBR-28, due to a MOU between the NREB and the ACRE IRB in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB.) See the G-ACRE-IRB for the ACRE IRB’s research review processes and guidelines regarding initial review, protocol amendments, and oversight.

Role in Clinical Trial Approval Process

As per the LibCTReg and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) and the NREB must approve a clinical trial application prior to the sponsor or the representative initiating the clinical trial. Per the LibCTReg and the G-LibClinTrial, the NREB and LMHRA reviews may be conducted in parallel. However, the G-LibClinTrial and the G-NREB specify that the LMHRA will only issue final approval once NREB ethical approval is obtained. In addition, per the LibCTReg and the G-LibClinTrial, any substantial amendment to the approved clinical trial research protocol must be approved by the LMHRA and the NREB before such amendments are carried out.

Additionally, per the LibCTReg, the LMHRA must inform the NREB if it has information about other clinical trials that is relevant to the board's assessment of the clinical trial on which it is to issue an expert opinion; this applies especially to information on aborted or otherwise prematurely discontinued investigations. In such instances, business and company secrets must remain confidential.

As per the G-NREB, a protocol will be reviewed if the number of submitted protocols meets the board’s threshold requirement to review a minimum of three (3) complete applications at each meeting.

As delineated in the LibCTReg, the NREB provides its opinion on a clinical trial application in accordance with its written standard operating procedures (SOPs). According to LBR-20, upon receipt of a research proposal, the NREB conducts a preliminary screening to ensure that all required documents and information are included and that the proposal meets the applicable submission requirements. Incomplete or insufficient proposals may be returned to researchers with instructions for revisions or additional information. Following a preliminary screening, an ethics review committee/panel composed of experts in relevant fields, such as medicine, public health, ethics, law, and community representatives is then assigned by the NREB. Committee members review the proposals independently or collectively, depending on the complexity of the research and the availability of resources. The ethics review committee/panel thoroughly evaluates each research proposal based on established ethical review criteria.

Per LBR-31, the NREB follows established ethical review criteria to evaluate research proposals to help ensure that research studies adhere to ethical principles and protect the rights, welfare, and dignity of research participants. The ethical criteria delineated in LBR-31 include informed consent, beneficence, justice, privacy and confidentiality, respect for participants’ rights and dignity, scientific validity and integrity, and compliance with regulatory requirements. See LBR-31 for details.

Per LBR-20, the committee members also assess the ethical implications of the proposed research, including the risks and benefits to participants, the adequacy of the informed consent process, the protection of vulnerable populations, and the equitable distribution of research burdens and benefits. The review process may involve discussions, debates, and deliberations among committee members to reach consensus on the ethical acceptability of the research proposals. See also LBR-23 for additional EC review guidelines.

LBR-20 further explains that the NREB communicates the outcomes of the ethical review process to researchers, including decisions on protocol approval, conditional approval pending revisions, or rejection. Researchers receive feedback and recommendations from the EC to address any ethical concerns raised during the review process and may be required to revise their proposals, provide additional information, or address specific ethical issues before final approval is granted.

The LibCTReg also notes that a request for clinical trial authorization from the NREB may only be refused in the following cases:

• The documents submitted are incomplete after the expiration of an appropriate deadline given to the applicant for their supplementation
• The documents submitted—including the trial protocol, the investigator’s brochure, the methods for selecting trial participants, and informed consent/assent materials—do not correspond to the current state of scientific knowledge, and particularly when the clinical trial is unsuitable for providing IP(s) proof of safety or efficacy, or
• The applicable requirements specified in the general conditions for conducting clinical trials (see Part II (Section 1) of LibCTReg) are not fulfilled

Per the G-NREB, a principal investigator (PI) will be contacted in writing (by letter or email) if the NREB determines that additional materials are required to complete its review. PIs may also be asked to be available to provide presentations and/or be contacted during the meetings. The G-NREB further explains that, where applicable, the NREB should notify PIs in writing of its decision within two (2) weeks following a board meeting, after a complete review of the protocols. The NREB will also communicate its decisions to the NREB Secretariat. An approval expiration date is not specified. Pursuant to the G-NREB, PIs may also re-submit previously considered protocols, which will require a full NREB review. Per LBR-20, once all the ethical requirements have been met, the NREB grants final approval for the research proposals to proceed.

As indicated in the G-NREB, the NREB Secretariat reviews continuing review reports submitted by the PI at least eight (8) weeks prior to the approved protocol’s expiration date. If the NREB has not reviewed and approved a continuing review request by the current expiration date, study activities should cease until the board determines whether continuation of the research is in the best interest of all previously enrolled participants. Prior to the expected NREB approval expiration date, the NREB also reviews continuing review submissions for ethical approval extension requests to continue research project implementation. See LBR-6 for the NREB Continuing Review Form. See the Progress Reporting section for additional information on continuing review.

Additionally, per LibCTReg, the NREB’s clinical trial authorization must be suspended or withdrawn if the NREB subsequently becomes aware that grounds for a refusal as referred to in the clinical trial authorization procedures (see Part II (Section 5 (1)) of LibCTReg) existed at the time the authorization was issued. The authorization must be withdrawn if the NREB subsequently becomes aware that at least one (1) of the following is true:

• Requirements regarding the suitability of the investigator, the investigator’s deputy, or the trial site are no longer fulfilled
• Trial participants are no longer properly insured or the prerequisites for an exception to the insurance obligation no longer exist
• Modalities for selecting trial participants no longer correspond to the current state of medical knowledge and, especially, the clinical trial is unsuitable for providing proof of the IP(s) safety or efficacy
• Prerequisites for the inclusion of persons pursuant to the general conditions and special preconditions for conducting a clinical trial (see Part II (Sections 1-2) of LibCTReg) are no longer fulfilled. The NREB must inform the LMHRA through written communication.

For protocol amendments, per the G-NREB, the NREB must review and approve any protocol amendments prior to implementation. The NREB secretariat must first consult with the NREB Chair to determine the type of review required (full board review or expedited review based on the risk). Protocols that pose no or minimal risk to participants, have no formal informed consent process, or are subject to NREB continuing review, may be considered exempt and may qualify for expedited review. Refer to the G-NREB for detailed information on decision types and various review processes the NREB uses to consider protocol submissions.

Additionally, the G-NREB explains that, as a condition of research protocol approval, the NREB requires the PI to provide regular updates to the Secretariat from the date of approval. LBR-20 also notes that researchers are required to report any significant deviations from the approved protocol or ethical concerns arising during the course of the research to the NREB for review and guidance. The NREB may also provide ongoing monitoring and oversight to ensure continued compliance with ethical standards and regulatory requirements. The G-NREB specifies that the NREB must conduct site visits at appropriate intervals, which may, in certain cases, be unannounced to ensure the integrity of the study.

Reviews During Public Health Emergencies

As delineated in the G-CTEmergncy, in the event a public health emergency is declared in Liberia or a neighboring country by the World Health Organization (WHO), the Ministry of Health (MoH), or the National Public Health Institute of Liberia (NPHIL), the NREB will expedite the initiation of research. During such emergencies, many processes (i.e., drafting documents, translations, and obtaining approvals) will occur in parallel, rather than sequentially, as is typical during non-emergency situations.

Per the G-CTEmergncy, in addition to the NREB review form (if applicable), the following checklist will be included to streamline fast-tracking of epidemic-related research:

• Identify the research as epidemic or outbreak-related to facilitate fast-tracking
• Specify whether prior research data on the disease exists, referencing relevant local and international studies
• Ensure the inclusion of at least one (1) (preferably two (2)) PIs or co-PIs from the country where the research and review take place
• Provide qualifications of key investigators, including details of their previous experience with outbreak-relevant research
• Indicate if the protocol is part of a multicenter trial. If so, describe the status of ethics approval for the master protocol or the ethics approval from the sponsoring country

The G-CTEmergncy indicates that the NREB will also use the following guidelines to ensure compliance during health emergencies:

• Establish surge capacity for protocol reviews and implement systems for virtual discussions (via platforms like Zoom)
• Identify core members to handle the majority of the review burden, providing specialized training in outbreak-related research review to ensure high standards without compromising ethical considerations. Additional members can be called upon as demand increases
• Ensure that the Director alerts members and determines whether they are available for emergency review
• Identify subject experts (technical and ethical) within the country and abroad who are willing to serve as ad-hoc or co-opted members during outbreaks, anticipating the need to review multiple studies in a short time
• Establish a quorum consisting of one-third of NREB members, including pre-identified subject matter experts. If a pre-identified member submits their review but cannot attend the meeting, the member will still count towards the quorum

The G-CTEmergncy further states that revised SOPs will be circulated to all review committee members. Meetings may be virtual or electronic to reduce health risks during highly infectious outbreaks (e.g., COVID-19, Ebola). Protocols should be submitted electronically for efficiency, with hard copies to follow, if mandatory. PIs must inform the NREB as early as possible of their intent to submit a high-level overview of their research (e.g., trial of a new medicine or vaccine, observational study, or survey) to prepare the committee for forthcoming protocols. Face-to-face meetings with PIs are not mandatory and may be conducted electronically or virtually, if necessary. Also, protocols will be sent to reviewers within 48 hours of submission. Reviewers should complete their reviews within five (5) days during an outbreak. The PI should receive consolidated reviews with suggestions or approval within 10 working days and should respond to the review within 48 hours. The director of the NREB secretariat will be the primary contact for communication with PIs, and all communications will be documented and archived for future reference.

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.

Note: Per LBR-38, the National Research Ethics Board of Liberia (NREB) has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

National Research Ethics Board of Liberia

As described in the G-NREB, the NREB must charge a minimal fee for the review of each submission type. Submissions include research protocols, re-submissions, amendments, and continuing reviews. The fee structure is based on the following application types: research protocol, behavioral research, investigational product (IP) (clinical trial), non-clinical trial, or waiver/exemption. Fees specifically associated with conducting a clinical trial involving IPs are based on a project’s scope, duration, sample size, and complexity, as well as the types and quantities of IPs, among other criteria. The fees delineated in the G-NREB are as follows:

• Clinical trial: $7,000 USD
• Re-submission: $1,500 USD
• Continuing Review: $1,500 USD
• Amendment: $1,500 USD

Payment Instructions

No information is currently available regarding payment instructions for the NREB.

Atlantic Center for Research and Evaluation Institutional Review Board

As per the G-ACRE-IRB, the ACRE IRB fees for protocol review other than clinical trials are as follows:

• Health, Behavioral and Education Research: $500 USD
• Re-Submission: $500 USD
• Continuing Review: $500 USD
• Amendment: $250 USD
• Foreign Student: $300 USD
• Liberian Student: $100 USD

The fee for non-sponsored research conducted by individual investigators is 50 percent of the sponsored research fee.

Payment Instructions

No information is currently available regarding ACRE IRB payment instructions for protocol review other than clinical trials.

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

There are no applicable regulations or guidance regarding the authorization of ethics committees (ECs) in Liberia. However, per G-NREB, the National Research Ethics Board of Liberia (NREB) is responsible for maintaining a registry of health research ECs and mitigating conflicts among ECs, researchers, and research entities.

Registration, Auditing, and Accreditation

No information is currently available on registration, auditing, and accreditation requirements.

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

In accordance with the LibCTReg and the G-LibClinTrial, the sponsor, the legal representative, the principal investigator (PI), or the sponsor-investigator is required to submit a clinical trial application to the Liberia Medicines and Health Products Regulatory Authority (LMHRA) and obtain written permission from the National Research Ethics Board of Liberia (NREB) to be granted authorization to conduct a clinical trial in Liberia. However, per the G-NREB, the PI must obtain ethics committee (EC) approval. The LibCTReg and the G-LibClinTrial state that the NREB and LMHRA reviews may be conducted in parallel. Per the G-LibClinTrial and the G-NREB, the LMHRA will only issue final approval once NREB approval is obtained.

Regulatory Submission

As indicated in the LibCTReg and the G-LibClinTrial, the sponsor or the representative should submit the application form and associated documents along with the prescribed fee. Also, per the G-LibClinTrial, four (4) sets of the application should be submitted both electronically and as printed copies to the LMHRA. The clinical trial application and any accompanying material must be submitted in English. If the documents are written in another language, a certified translation is required. Per LBR-29, the sponsor's representative must also submit a power of attorney attesting that the representative is a duly appointed agent.

Additionally, per the LibCTReg and the G-LibClinTrial, any substantial amendment to the approved clinical trial documentation, trial arrangements, or the investigational product must be submitted by the applicant to the LMHRA and the NREB, together with the prescribed fee, for the evaluation and authorization related to such amendment. Per the G-LibClinTrial, the submitted amendment(s) must be indicated in a signed cover letter that specifies the clinical trial and the sponsor (applicant), and must describe the possible consequences for clinical trial participants already enrolled in the trial as well as the possible consequences for the evaluation of the results. The amendment(s) must also be described in a completed Clinical Trial Amendment form (Annex 2 of the G-LibClinTrial). The amended documents should include updated version numbers and dates. In addition, the submitted documents should clearly present scientific arguments justifying the classification of the amendment to the LMHRA and the NREB, and, where applicable, supporting information must be included with the submission.

Per the G-LibClinTrial, the signed cover letter and clinical trial application dossier should be sent to the following:

The Managing Director
Liberia Medicine and Health products Regulatory Authority (LMHRA)
2^nd & 3^rd Floors Clay Building
Sekou Toure Avenue
Mamba Point
Monrovia, Liberia

Ethics Review Submission

Note: Per LBR-38, the NREB has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

National Research Ethics Board of Liberia

As delineated in the LibCTReg, application submissions to the NREB must include all of the information and documents as required for the board’s opinion. According to the G-NREB, PIs must submit typed, dated, and signed submissions electronically and in hard copy to the NREB. The documents should be formatted in standard 12-point font, double-spaced, with the pages printed on one (1) side only. The NREB requires 15 comb-bound copies of the complete research protocol, along with the attachments listed in the G-NREB, and where applicable, an email version that includes the protocol title and the PI’s name. All protocols must also be numbered appropriately and separately from all other supporting documentation (e.g., letters, participant information sheets and consent forms, questionnaires, curriculum vitae(s) (CVs), etc.). Supporting documents should also be numbered separately. Refer to LBR-32 for the NREB Research Protocol Template.

In addition to protocol submission requirements, the G-NREB also specifies that the PI should submit the complete application for ethical review and approval of a proposed health research study to the NREB Secretariat three (3) weeks prior to the next NREB meeting. Applications submitted by a PI and researchers from foreign institutions must also include a local (resident) Liberian researcher on the research team as well as support letters and CV(s). See the G-NREB for detailed application submission requirements.

Per the G-NREB, NREB submissions should be submitted to the following address:

Director
National Research Ethics Board of Liberia (NREB)
First Floor West, John F. Kennedy Medical Center
Monrovia, Liberia
Email: nreb.liberia.gov@gmail.com

As delineated in the G-CTEmergncy, during a public health emergency in Liberia or in a neighboring country, the NREB requires protocols to be written in English and include, at a minimum, the proposed study, the corresponding ethics approval, consent or assent forms, and data collection tools and forms. In addition, along with the standard documents for review (protocols, CVs, Human Subject Protection Certificates, Good Clinical Practice, etc.), the following must be submitted:

• A collaboration letter (in the form of an MOU) with sponsor institutions and research funders, including declarations of interest, when possible
• A monitoring and safety management plan for the project provided by the PI and the study sponsor
• Data-sharing and material transfer agreements for data and biological materials, especially if samples will be exported out of the country, to ensure compliance with the Laws of Liberia (a draft version may be submitted initially)
• Clear procedures for dissemination, publication, co-authorship, co-presentation, and intellectual property rights
• Plans to disseminate findings to the affected community, to ensure continued engagement and trust, especially among research participants
• Depending on the type of research, a local insurance policy for trials and interventions may be required

Atlantic Center for Research and Evaluation Institutional Review Board

As indicated in the G-ACRE-IRB, PIs are required to submit the research protocol as part of an application packet that includes the documentation specified by the ACRE IRB submission form (see Article XXV in the G-ACRE-IRB). According to LBR-28, the ACRE IRB has not reinstated the requirement for PIs to submit eight (8) hard copies of the protocol. Applications should be submitted electronically. See the Submission Content section for additional documentation requirements.

Per the G-ACRE-IRB, all research proposals are to be submitted (either via electronic mail or in person) to:

The IRB Coordinator
Atlantic Center for Research and Evaluation (ACRE)
Ground Floor, Graduate School Building
University of Liberia
Capitol Hill
Monrovia, Liberia

Per LBR-28, proposals submitted electronically should be sent to ulpireirb@gmail.com and smithedwardg@yahoo.com, in copy.

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 set forth in the LibCTReg and the G-LibClinTrial, the sponsor, the legal representative, the principal investigator (PI), or the sponsor-investigator is required to submit the following documentation to the Liberia Medicines and Health Products Regulatory Authority (LMHRA) (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Cover letter (signed, witnessed, and notarized) including list of documents submitted and their version numbers and date
• Clinical trial application form, including cover page
• Clinical trial protocol (see below for detailed protocol requirements)
• A list of the planned clinical trial sites and the planned number of study participants to be recruited at the sites located in Liberia
• Details of the site(s) where the trial is to be conducted, and a duly justified written statement on the suitability of the clinical trial sites adapted to the nature and use of the investigational product (IP) and including a description of the suitability of facilities, equipment, human resources, and description of expertise, issued by the head of the clinic/institution at the trial site or by some other responsible person
• Participant information sheet, informed consent form(s) (ICF(s)) or video(s), or assent form(s) in case of minor(s) or persons under legal disability who are to participate in the trial, and informed consent procedures for clinical trials in humans
• Product information for registered IPs (e.g., summary of product characteristics, patient information leaflet/package insert, and labelling)
• Investigator’s Brochure (IB) containing relevant chemical, pharmaceutical, pre-clinical pharmacological and toxicological data, and where applicable, human or animal pharmacological and safety and efficacy clinical data about the IP
• If applicable, synopsis of previous trials with the IP(s)
• If applicable, electronic copies of key, peer-reviewed publications following the International Committee of Medical Journal Editors (ICMJE) recommendations to support the application
• Copies of recruitment advertisement(s), if applicable, and questionnaires
• Investigational medicinal product (IMP) dossier, if applicable
• Product information and certificate of analysis (CoA) for concomitant and rescue medications
• Good Manufacturing Practice (GMP) certificate issued from the national regulatory authority of the country where the IP is manufactured, translated into English
• CoA of the IP(s)
• Certificate(s) of accreditation for the central laboratories
• Workload forms for investigators
• Signed declaration by the applicant (including a commitment to adhere to the ethical principles outlined in the Declaration of Helsinki (LBR-27) and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (LBR-8))
• Signed declaration by the national PI
• Signed curriculum vitae (CV) for all key staff participating in the conduct of the clinical trial (e.g., PI and/or co-investigators, study coordinator, regional and local monitor, contract research affiliate, etc.)
• Signed declaration(s) by each investigator(s)
• Signed joint financial declaration between the sponsor and the PI
• Signed declaration by the sub-investigators and key staff participating in the trial
• Signed declaration by the regional clinical trial monitor(s)
• Signed declaration by the sponsor/sponsor-investigator
• Proof of registration with the Pan African Clinical Trials Registry (PACTR) (LBR-36) or another World Health Organization (WHO) Primary Registry (LBR-35)
• Active clinical trial insurance for Phase I, II, and III trials
• Evidence of insurance coverage for prospective participants
• Proof of sponsor indemnification for investigators and trial site
• Good Clinical Practice (GCP) certificates for the investigators
• Proof of registration of the key investigators with a professional statutory body, if applicable
• Proof of residence in Liberia for the PI
• Proof of professional indemnity (i.e., malpractice insurance)
• Study budget
• In case of parallel submission, proof of submission of the clinical trial application to the National Research Ethics Board of Liberia (NREB)
• The written permission of the NREB in case of sequential submission, and in case of parallel submission, the updated versions of documents or information as requested by the NREB, for the conduct of the clinical trial, if applicable
• Information on the composition of the Data and Safety Monitoring Board (DSMB)—including the list, terms of reference, and CVs for its members—justifying their expertise as members of the DSMB
• Summary of product characteristics or other professional information for all registered medicines used in the trial, or the international equivalent if the medicines are not registered in Liberia
• Registered IPs should include the registered indication or registered dosage regimen
• Recruitment arrangements
• Request for authorization of export of biological samples out of Liberia as well as the respective material transfer agreement (MTA), if applicable
• Summary of the clinical trial (100-150 words) to be made publicly available on the LMHRA website
• Proof of payment of the appropriate application fee

Refer to the LibCTReg and the G-LibClinTrial for detailed application requirements and expedited application documentation requirements.

The LibCTReg also notes that in the case of emergency situations, the LMHRA may also make exemptions to the documentation requirements for the submission of clinical trial applications. Refer to 2.3 of the G-LibClinTrial for additional information on how to submit an expedited clinical trial application package.

Ethics Committee Requirements

Note: Per LBR-38, the NREB has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

National Research Ethics Board of Liberia

As indicated in the G-NREB, for clinical trials and biomedical/epidemiological study submissions, the following documents may be included, but are not limited to:

• Full protocol and executive summary (refer to LBR-32 for research protocol template)
• Sponsor’s protocol, if applicable (per LBR-32)
• Signed agreement between sponsors and PI, where applicable
• A statement that the researcher(s) agree to comply with ethical principles set out in relevant guidelines
• IB
• MTA for shipment of specimen(s)/biological material(s) outside of Liberia, where applicable (See also Specimen Import & Export and Consent for Specimen sections)
• Data Sharing Agreement, where applicable
• Administrative information on study sponsors
• Signatory page of key persons from the collaborative institutions involved in the study (i.e., Sponsor Signatory Approval Page duly signed, with date, where applicable)
• Written ICF with dates and version number and translations into the local language, where necessary
• Written parental consent form for children under 17 years of age (if study involves minors)
• Written parental consent form and assent form for children under 18 years of age (15-17 years) (if study involves adolescents)
• All forms, documents, and community engagement advertisements to be used in the recruitment of potential participants
• All data collection forms to be used in the research including, but not limited to, case report forms, questionnaires, interview schedules, etc., clearly indicated and dated
• Referral forms for treatment, where applicable
• Study budget
• Study timeline
• Any other information deemed necessary to facilitate the review process
• Current CV(s) of PI and co-investigator(s), if not submitted to the NREB in the preceding 12 months
• Profile on previous study (i.e., Phase I & Phase II studies, where applicable)
• Investigator Agreement (PI’s responsibility), page duly signed with name and date, and current Certificate of Training in GCP for PI(s)
• DSMB membership and charter of work/current member CVs
• Insurance coverage for study participants
• Scientific review approval
• LMHRA approval letter for use of the IPs/devices and clinical trial approval (this should be submitted after the NREB approval)

Atlantic Center for Research and Evaluation Institutional Review Board

Per the G-ACRE-IRB, the following documentation must be submitted along with the application for an initial application review of a protocol for clinical research other than a clinical trial:

• Cover letter
• Protocol summary (Article XXV (Section 25.02) in the G-ACRE-IRB)
• Protocol and/or amendments (including data collection instruments, surveys, tests, questionnaires, debriefing information, etc.)
• IB, where applicable
• Evidence of submission and/or approval from other ECs, where applicable
• Proof of research ethics training (i.e., certificate in human subject protection) by research team members
• ICFs, where applicable
• Questionnaires and other study instruments, where applicable (including interview schedules, recruitment and interview scripts, and recruitment materials (Article XXV (Section 25.02) in the G-ACRE-IRB)
• DSMB and Institutional Biosafety Committee (IBC) records, if applicable
• MTA, if applicable (See also Specimen Import & Export and Consent for Specimen sections)
• Status report for ongoing study (applicable for continuing review)
• Letter of collaboration or support with collaborating entity/researcher(s), if applicable
• Capacity building plan for collaborating agency/researcher, if applicable
• Investigator(s) CVs
• Social corporate responsibility plan for communities, if applicable
• Letter from an appropriate official permitting research activities on their premises, if the research/recruitment will take place in or through schools, businesses, care facilities, or other organizations
• Budget

Clinical Protocol

Liberia Medicines and Health Products Regulatory Authority

Per the G-LibClinTrial, the contents and format of the clinical trial protocol should follow the requirements laid down in LBR-8. Refer to LBR-8 for detailed protocol guidelines.

In addition, as indicated in the G-LibClinTrial, the protocol should contain a statement indicating that the trial will be conducted in compliance with the protocol, GCP, and the applicable regulatory requirements, and signed and dated by both the sponsor/sponsor’s representative and the PI to document the their agreement to the protocol. If the protocol is not signed and dated by both parties, a corresponding declaration that is signed and dated by both must be submitted to the LMHRA with the application.

National Research Ethics Board of Liberia

The LBR-32 requires the following elements to be included in the research protocol template submission:

• Specific aims
• Background and significance of research
• Research locations and collaborating sites
• Study team
• Study design
• Recruitment methods
• Consent process
• HIPAA privacy protections
• Vulnerable populations
• Risks
• Benefits
• Participant privacy
• Data confidentiality
• Data/statistical analysis plan
• Costs and compensation
• Sharing study results
• Research related injuries
• Reportable events
• Regulatory compliance
• Data or specimen banking (repositories)
• Clinical trials
• Device, if applicable
• Drug/biologic

National Research Ethics Board of Liberia/Atlantic Center for Research and Evaluation Institutional Review Board

Per the NatResHlthPlcy, Liberian ECs including the NREB and the ACRE IRB, should structure the research protocol according to the follow format:

• Title
• Investigators’/researchers’ information including contact addresses
• Abstract/summary
• Background/Introduction
• Aims and objectives
• Study design and methods
• Data collection, management, and analysis
• Study administration and ethical issues
• Resource requirements
• Study plan
• Supervision
• Dissemination and outcome

For more details, see Annex 2 of the NatResHlthPlcy.

Atlantic Center for Research and Evaluation Institutional Review Board

According to the G-ACRE-IRB, the clinical research protocol should contain the elements included in the ACRE IRB submission form (see Article XXV in the G-ACRE-IRB). The initial protocol submission should also contain:

• Original protocol (including cover sheet, abstract, and research section including the Human Subjects Section)
• Application letter
• ICF and/or assent form
• Sample questions survey
• Investigator(s) CVs
• Qualification of study site(s)
• Protocol budget
• Copy of ACRE IRB approval, if available
• Study design
• Study participation, including informed consent procedures and content/language and participant information sheet content (See also the Documentation Requirements section)

Note: Per the G-ACRE-IRB, for regular renewal or interim modification reviews of a protocol, PIs should attach current consent document(s) and include instruments ONLY if changes are being proposed (Article XXV (Section 25.02) in the G-ACRE-IRB).

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

According to the LibCTReg and the G-LibClinTrial, the National Research Ethics Board of Liberia (NREB) and the Liberia Medicines and Health Products Regulatory Authority (LMHRA) reviews may be conducted in parallel. However, per the G-LibClinTrial and the G-NREB, the LMHRA will only issue final approval once NREB approval is obtained.

Regulatory Authority Approval

The LibCTReg and the G-LibClinTrial state that the LMHRA must inform an applicant in writing about the outcome of an assessment of a clinical trial application within a maximum of 45 working days for pharmaceutical investigational products (IPs); 60 working days for biological and biotechnology IPs; and 90 working days for genetically modified organisms. However, the G-LibClinTrial also indicates that the LMHRA must inform the applicant within a maximum of 60 working days.

As indicated in the LibCTReg and the G-LibClinTrial, upon receipt of a clinical trial application, the LMHRA screens the application package for completeness and must inform the applicant in writing about the validity of the application or the formal grounds for non-acceptance of the application within 10 working days of application receipt. If applicable, the applicant, in turn, must address formal grounds for non-acceptance within 10 working days. These timelines exclude time taken for the applicant to respond to queries from the LMHRA during the review and decision process. If changes are required and the applicant fails to modify the application within a maximum of 30 working days, the application will be rejected.

Additionally, the G-LibClinTrial further notes that if the LMHRA requires changes to the application, and the applicant fails to modify the application within a maximum of 90 days, the application will be rejected.

As explained in the G-LibClinTrial, upon approval of the application, the LMHRA must issue a clinical trial certificate to the applicant that includes the LMHRA clinical trial number. The clinical trial certificate may contain conditions required by the LMHRA with respect to the conduct or reporting of the trial. If the application is rejected, the applicant can submit a written appeal to the LMHRA’s Managing Director within 60 days of receipt of the rejection notice.

Per the G-LibClinTrial, in the case of expedited clinical trial application reviews, the LMHRA will review the application within no more than 14 working days for approved products and within 21 days for new products.

Additionally, per the G-LibClinTrial, the LMHRA must respond to any substantial clinical trial amendment within 20 calendar days upon receipt of the written decision from the NREB.

Ethics Committee Approval

Note: Per LBR-38, the NREB has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

National Research Ethics Board of Liberia

Pursuant to the G-NREB, principal investigators (PIs) are required to submit new research protocols no later than one (1) month prior to the next bi-monthly board meeting. The NREB should notify PIs in writing of its decision within two (2) weeks following a board meeting, where applicable, following a complete review of the protocols. The G-NREB does not specify an approval expiration date.

The G-NREB explains that for protocol amendments, the NREB Secretariat, in consultation with the Chair, will make a determination regarding the type of review (full board review or expedited based on the risk) and will notify the investigator within three (3) weeks upon submission per the board’s decision. Expedited reviews must take no more than three (3) weeks, and if any committee member raises a concern about a protocol that was expedited, the protocol must undergo a full board review.

Refer to the G-NREB for additional information on the various submission types that may be submitted to the board and their corresponding review and approval processes.

Atlantic Center for Research and Evaluation Institutional Review Board

As specified in the G-ACRE-IRB, PIs are required to submit all application materials to the ACRE IRB four (4) weeks in advance of the date that a decision is requested. In the case of full review studies, submission is required four (4) weeks prior to the next scheduled ACRE IRB meeting. The ACRE IRB will convene a special meeting, if necessary, to accommodate the PI’s compliance with an external funding deadline; however, submission is required four (4) weeks prior to the special meeting date.

No timeline of review is specified for the ACRE IRB’s review. However, the G-ACRE-IRB states that the clinical research protocol and accompanying documents are approved as they are submitted. Approval will commence on the day the study is approved and will expire within a defined time period based on a risk assessment and regulations. If specific conditions are stipulated in the approval letter, those conditions must be met by the designated date or approval may be withdrawn.

The G-ACRE-IRB states that the ACRE IRB must also review and approve any clinical research protocol amendments prior to those changes being implemented. The clinical research protocol submission is reviewed either via expedited procedures (for minor changes) or via full board review (for all other changes). Refer to the G-ACRE-IRB for clinical research protocol amendment documentation submission and procedural requirements.

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 the LMHRA-Act, the LibCTReg, and the G-LibClinTrial, a clinical trial can only commence after the sponsor or the representative receives authorization from the Liberia Medicines and Health Products Regulatory Authority (LMHRA). The LibCTReg and the G-LibClinTrial further state that the sponsor, the legal representative, the principal investigator (PI), or the sponsor-investigator must obtain written permission from the National Research Ethics Board of Liberia (NREB). In addition, per the G-LibClinTrial, the appointed PI must provide proof of residency in Liberia in the clinical trial application submission package.

As per the G-LibClinTrial, the sponsor or the representative is required to obtain LMHRA approval for the clinical trial before the import of an investigational product (IP) to be used in the trial is authorized. However, parallel submission is permitted for approval of the clinical trial and the IP import permit if the import permit application is included in the clinical trial application submission package.

In addition, per the LibCTReg, the applicant must inform the LMHRA in writing of the exact clinical trial commencement date (i.e., first patient first visit). If the trial does not begin within 90 calendar days from issuance of the clinical trial certificate, the applicant must show cause for the failure to commence as scheduled and solicit issuance of a new clinical trial certificate. Pursuant to Part VIII of the LMHRA-Act, the LibCTReg delineates that failure to inform the LMHRA of the commencement, or not starting the clinical trial within this period, will have regulatory implications including, but not limited to, the payment of administrative charges for the re-issuance of the clinical trial certificate on its expiration.

The LibCTReg also states that the sponsor, the investigator, and all of the persons involved in the clinical trial must fulfill the requirements of good clinical practice in accordance with the International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (LBR-8) and the World Health Organization (WHO)'s Guidelines for Good Clinical Practice (GCP) for Trials on Pharmaceutical Products (LBR-25), as determined by the LMHRA. The G-LibClinTrial further specifies that the LMHRA has adopted LBR-8 for use along with the LMHRA guidelines.

Clinical Trial Agreement

While a formal clinical trial agreement is not an official requirement, the G-LibClinTrial states that the protocol should contain a statement that the trial will be conducted in compliance with the protocol, LBR-8, and the applicable regulatory requirements. The protocol should also be signed and dated by both the sponsor or the representative and the PI to document the investigator’s and the sponsor’s agreement to the protocol. If the protocol is not signed and dated by both parties, a corresponding declaration, signed and dated by both, must be provided to the LMHRA with the application.

Clinical Trial Registration

As delineated in the LibCTReg, the sponsor or the sponsor-investigator must register all clinical trials with a public international database. The G-LibClinTrial further specifies that the LMHRA requires the sponsor or the representative to provide proof of registration with the Pan African Clinical Trials Registry (PACTR) (LBR-36) or another WHO Primary Registry (LBR-35).

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.

Note: Per LBR-38, the National Research Ethics Board of Liberia (NREB) has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

Safety Reporting Definitions

According to the LibCTReg, the LibPVReg, and the G-LibPVSys, the following definitions provide a basis for a common understanding of Liberia’s safety reporting requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event (or Adverse Experience) (AE) – Any untoward medical occurrence in a participant to whom a medicinal product has been administered, including occurrences which are not necessarily caused by or related to that product, or any abnormal sign (e.g., any abnormal physical exam or laboratory finding), symptom, or disease, that is temporally associated with the participant’s involvement in the research; AEs encompass both physical and psychological harms
• Adverse Drug Reaction (ADR) – Any noxious and unintended responses in a participant to an investigational medicinal product which is related to any dose administered to that participant. A causal relationship between a medicinal product and an adverse event is at least a reasonable possibility (i.e., the relationship cannot be ruled out)
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any untoward medical occurrence that at any dose: results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability/incapacity, is a congenital anomaly/birth defect, or may jeopardize the participant’s health and may require medical or surgical intervention based upon appropriate medical judgment (e.g., the development of drug dependency or drug abuse). A causal relationship between a medicinal product and an adverse event is at least a reasonable possibility, i.e., the relationship cannot be ruled out
• Unexpected Adverse Drug Reaction – An adverse reaction where the nature or severity is inconsistent with the applicable product information (e.g., Investigator's Brochure for an unapproved investigational product (IP) or package insert/summary of product characteristics for an approved product)

Safety Reporting Requirements

Per the LibCTReg and the G-LibClinTrial, the principal investigator (PI) or the sponsor should report any SAEs/SADRs suspected to be related to the IP immediately, and in any event, no later than three (3) calendar days after becoming aware of the event, to the Liberia Medicines and Health Products Regulatory Authority (LMHRA) and the NREB. However, per the LibCTReg, in the case of death, all SAEs must be reported within 24 hours. Per the G-LibClinTrial, in the case of multicenter trials involving clinical trial sites both within and outside of Liberia, the PI or sponsor must submit all SAEs/SADRs deemed to be related to the IP within 15 calendar days to the LMHRA and the NREB. The PI or the sponsor is also required to indicate the timelines allocated for related investigations.

In addition, the LibPVReg provides the following serious adverse reaction reporting timelines:

• All serious adverse reactions associated with the use of a product must be reported on an expedited basis as soon as possible, but not later than 15 calendar days of initial receipt of the minimum required information. If all the information needed is not available within 15 days, the applicant should submit an initial report containing at least the minimum required data elements (i.e., patient details, suspected product details, reaction details, and the reporter details) in order to meet the expedited reporting timeframes. A follow-up report containing more detailed information should be submitted later as soon as this becomes available
• Every serious suspected adverse reaction occurring in all post-marketing studies of which the manufacturer is aware must be reported to the LMHRA on an expedited basis

However, the LibPVReg also states that the reporting of SAEs and serious unexpected adverse drug reactions (SUSARs) occurring during clinical trials must comply with the requirements stipulated under the LibCTReg.

The G-LibPVSys also notes that all SUSARs occurring in Liberian post-authorization safety studies, of which the local representative or marketing authorization holder (MAH) is aware and includes the design and conduct of company-sponsored, post-marketing surveillance studies (i.e., Phase IV clinical trials), should be reported within seven (7) days.

Investigator Responsibilities

Pursuant to the LibPVReg, for fatal or life-threatening, unexpected events during clinical development, the PI is required to alert the LMHRA as soon as possible but not later than seven (7) calendar days after first knowledge. If a case qualifies, the PI should subsequently submit a complete report as soon as possible within eight (8) additional calendar days.

The G-NREB indicates that investigators are required to submit a report to the NREB for all AEs, except those resulting in death, within seven (7) calendar days. Investigator(s) must report all deaths that are possibly, probably, or definitely related to the study within 24 hours to the NREB.

Other events that must be reported to the NREB include the following:

• Unanticipated problems involving risks to participants or others
• Non-compliance (including major protocol deviations and non-compliance unrelated to a protocol deviation)
• New information that might affect the willingness of participants to enroll or continue to participate in the study

For studies other than clinical trials that use the ACRE IRB, the G-ACRE-IRB states that the investigator must promptly report any unanticipated problems to the ACRE IRB in accordance with the following guidelines:

• Unanticipated problems that are SAEs must be reported to the ACRE IRB within five (5) business days of the investigator becoming aware of the event. The board strongly recommends that a preliminary report be submitted by the investigator within 48 hours of learning of the SAE with a formal follow-up report submitted within the above timeline
• Any other unanticipated problem should be reported to the ACRE IRB within two (2) weeks of the investigator becoming aware of the problem. The board strongly recommends that a preliminary report be submitted by the investigator within five (5) business days of learning of the unanticipated problem with a formal follow-up report submitted within the above timeline

See the G-ACRE-IRB for additional details on the information the investigator should provide.

Sponsor Responsibilities

As explained in the LibPVReg, AEs/ADRs, AEs following Immunization (AEFI) of a vaccine or biological product, fatal or life-threatening AEs of special interest (AESIs), and unexpected ADRs that occur during clinical investigations qualify for very rapid reporting. The sponsor must notify regulatory agencies (e.g., by telephone, facsimile transmission, or in writing) as soon as possible but no later than seven (7) calendar days after first knowledge that a case qualifies, followed by as complete a report as possible within eight (8) additional calendar days. The healthcare facilities, public health programs, manufacturers, MAHs, or any other designated person is required to report AEs/ADRs which include the following to the LMHRA:

• All suspected ADRs resulting from prescription and non-prescription medicinal products
• Unexpected reactions, regardless of their nature or severity, whether or not consistent with product information or labelling
• All ADRs regardless of whether or not the product was used in accordance with the product information provided by the company marketing the product
• All AEs following immunization or use of a biological product
• A serious reaction, whether expected or not
• ADRs in a special field of interest including drug abuse and drug use in pregnancy and during lactation
• ADRs occurring from overdose or medication errors

See the LibPVReg for additional reporting requirements.

Per the LibPVReg, a case initially classified as a non-expedited report, would qualify for expedited reporting upon receipt of follow-up information that indicates the case should be re-classified. The reporting timeframe begins again upon receipt of any medically relevant information for a previously reported case.

Other Safety Reports

Per the LibPVReg, every sponsor and MAH is required to submit an annual Development Safety Update Report (DSUR) to the LMHRA for drugs under development, including marketed drugs under further study. A single DSUR must be prepared for each IP with data pertinent to all dosage forms and strengths, all indications, and all patient populations under study with the IP, wherever feasible. If this is not possible, an explanation should be provided in the introduction section of the DSUR. If more than one sponsor is involved in drug development, a single DSUR can be submitted. The DSUR must provide safety information from all ongoing clinical trials and other studies that the sponsor is conducting or has completed during the review period, including the following:

• Clinical trials using an IP (e.g., human pharmacology, therapeutic exploratory, and therapeutic confirmatory trials (Phase I to III))
• Clinical trials conducted using marketed drugs in approved indications such as therapeutic use trials (Phase IV)
• Therapeutic use of an IP
• Clinical trials conducted to support changes in the manufacturing process of medicinal products
• Any significant other findings pertinent to the safety of the IP

Form Completion & Delivery Requirements

Liberia Medicines and Health Products Regulatory Authority

As per the G-LibClinTrial, all SAEs/SADRs and SUSARs must be reported on the LMHRA’s Suspected Adverse Drug Reaction Reporting Form (Annex 3 in the G-LibClinTrial). In addition, the LibPVReg states that medication errors arising during routine clinical practice must be reported to the LMHRA. The MAHs, healthcare providers, and public health programs must also notify the LMHRA of any reports of unusual failure in efficacy using the Suspected Adverse Drug Reaction Reporting Form. Additionally, patients or consumers may report any suspected ADR/AE associated with the use of a product immediately to the nearest health facility, healthcare provider, or directly to the LMHRA using the Suspected Adverse Drug Reaction Reporting Form.

Atlantic Center for Research and Evaluation Institutional Review Board

Per LBR-28, since all clinical trials protocols submitted to the ACRE IRB are referred to the NREB for review, all AEs/ADRs and SAEs/SADRs are only sent to the NREB. Safety reports for clinical research protocols other than clinical trials should be sent to the ACRE IRB.

National Research Ethics Board of Liberia

No information is available on NREB safety reporting forms and delivery requirements.

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.

Note: Per LBR-38, the National Research Ethics Board of Liberia (NREB) has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

Interim and Annual Progress Reports

Liberia Medicines and Health Products Regulatory Authority

Pursuant to the LibCTReg, the applicant must submit to the Liberia Medicines and Health Products Regulatory Authority (LMHRA) and the NREB progress reports containing safety updates and duly signed and authenticated Data and Safety Monitoring Board (DSMB) reports, as specified in the corresponding clinical trial guidelines. As specified in the G-LibClinTrial, the applicant must provide a progress report at least annually on the clinical trial to the LMHRA, unless otherwise stipulated in the clinical trial certificate. The report should contain recruitment status, safety updates, and DSMB reports, as well as an update on the use and results collected on biological samples exported out of Liberia, if applicable.

National Research Ethics Board of Liberia

As indicated in the G-NREB, for continuing review submissions, PIs must submit review reports to the NREB Secretariat at least eight (8) weeks prior to the approved protocol’s expiration. See LBR-6 for the NREB Continuing Review Form. Additionally, according to LBR-38, the NREB is also using LBR-24 for continuing review, for annual reports, and as a final report to close a study.

Per the G-LibClinTrial and the G-NREB, research in Liberia should comply with the International Council for Harmonisation's (ICH)’s Guideline for Good Clinical Practice E6(R2) (LBR-8). Refer to LBR-8 for additional progress reporting guidance.

Atlantic Center for Research and Evaluation Institutional Review Board

For clinical research studies using the ACRE IRB, the G-ACRE-IRB requires the principal investigator(s) (PIs) to submit progress reports (also referred to as continuing review submissions in Liberia) to the ACRE IRB. If no work was conducted on a study during the last approval period, the PIs should explain why (e.g., too busy with other projects; a delay in funding; or unable to hire a graduate student to work on the project). If the PI(s) are closing the study, a copy of any publications or manuscripts resulting from the study should be attached.

See the G-ACRE-IRB for details on the required documentation to submit a continuing review to the ACRE IRB.

Final Report

Liberia Medicines and Health Products Regulatory Authority

The LibCTReg states that the applicant is required to submit a final clinical trial summary report to the LMHRA. As per the LibCTReg and the G-LibClinTrial, the applicant must notify the LMHRA within 30 business days from the end of a clinical trial. Per the G-LibClinTrial, the end of the trial definition should be documented in the clinical trial protocol.

The LibCTReg and the G-LibClinTrial also indicate that the applicant must submit a closeout report with a copy of the LMHRA-issued disposal certificate to the LMHRA. The G-LibClinTrial specifies this report should be submitted within 90 days from completion of the clinical trial. (See Annex 5 of the G-LibClinTrial for closeout report form).

In addition, per the LibCTReg and the G-LibClinTrial, the applicant must submit a comprehensive end of study report conforming to the ICH’s Structure and Content of Clinical Study Reports (E3) (LBR-37) guidelines, within one (1) year from the trial’s completion.

Per the LibCTReg and the G-LibClinTrial, the end of study report must also contain any AEs reported by the PIs.

National Research Ethics Board

The LibCTReg states that the applicant is required to submit a final clinical trial summary report to the NREB. The applicant must also notify the NREB within 30 business days from the end of a clinical trial.

Additionally, per the LibCTReg, the PI must also inform the NREB of any AEs as part of the end of study report.

The LibCTReg further specifies that the applicant must submit a comprehensive end of study report to the NREB conforming to the LBR-37 guidelines, within one (1) year from the trial’s completion.

According to LBR-38, the NREB is using LBR-24 for continuing review, for annual reports, and as a final report to close a study.

Atlantic Center for Research and Evaluation Institutional Review Board

Per the G-ACRE-IRB, PI(s) should complete Section 12 (Disposition of Project) of the ACRE IRB Submission Form (Section 25.02 in Article XXV of the G-ACRE-IRB) for the final ACRE IRB review. For the board’s purposes, the project has ended when there is no further participant enrollment, intervention(s), or data collection, and the remaining data are either de-identified or maintained with safeguards. The PI(s) should use this section to describe the disposition of the project and its data and to provide a brief summary of their findings.

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 stated in the LibCTReg and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with LMHRA guidelines. Per LibCTReg, the sponsor is defined as an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.

LibCTReg also defines a sponsor-investigator as an individual who both initiates and conducts an investigation, alone or with others, and under whose immediate direction the investigational product is administered or dispensed. The term does not include any person other than an individual. The obligations of a sponsor-investigator include both those of a sponsor and those of an investigator.

In addition, per the LibCTReg, the sponsor may hire a contract research organization (CRO) (commercial, academic, or other) to perform one (1) or more of the sponsor’s trial-related duties and functions. See LBR-8 for additional guidance on sponsor responsibilities.

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

According to the LibCTReg and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with LMHRA guidelines. Refer to LBR-8 for additional guidance on sponsor site/investigator selection requirements.

As stated in the G-LibClinTrial, all investigators must be trained in good clinical practice (GCP), as documented by the provision of training certificates that are no more than three (3) years old at the time of application. Any other training or experience from previous clinical trials and patient care, as needed for the conduct of the trial, must be provided for the investigators to prove their qualifications. The principal investigators (PIs) should have acted as a PI, or at least as an investigator, in at least one (1) prior clinical trial and must provide proof of residency in Liberia in the clinical trial application submission package. The LibCTReg further states that the trial is to be conducted in an appropriate facility by a suitably qualified investigator in a responsible manner and managed by an investigator who can provide evidence of sufficient experience in the conduct of clinical trials, as determined by the LMHRA.

Per the G-NREB, PIs are also required to be able to provide a current Certificate of Training in GCP for PIs, be qualified to undertake the particular study, and be knowledgeable in the values and tenets of ethical and regulatory principles and scientific method applications associated with conducting research in human participants.

In addition, the G-LibClinTrial requires the applicant to provide details of the site(s) where the clinical trial is to be conducted, along with a duly justified written statement on the suitability of the trial sites, adapted to the nature and use of the investigational product in the clinical trial application submission package. The statement should include a description of the suitability of facilities, equipment, human resources, and description of expertise, issued by the head of the clinic/institution at the trial site or by some other responsible person.

See also LBR-8 for information on sponsor agreements with investigators/institutions.

Foreign Sponsor Responsibilities

No information is currently available on foreign sponsor requirements.

Data and Safety Monitoring Board

As per the G-LibClinTrial, the sponsor or the representative should provide information on the composition of the Data and Safety Monitoring Board (DSMB) in the clinical trial application submission package. This information should include the list of members, the terms of reference, and the CVs of its members to justify their expertise as members of the DSMB.

See LBR-8 for additional DSMB guidance.

Multicenter Studies

See LBR-8 for guidance on sponsor requirements for multicenter 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

As set forth in the LibCTReg and the G-LibClinTrial, the applicant should include documentation in the clinical trial application submission package to verify active clinical trial insurance that covers Phases I, II, and III; proof of professional indemnity (malpractice insurance); and proof of sponsor indemnification for investigators and the trial site. The LibCTReg also notes that an indemnity, in the form determined by the Liberia Medicines and Health Products Regulatory Authority (LMHRA), is to be signed by the participant to protect the LMHRA from liability related to an injury or an adverse event that may be sustained by a person, directly or indirectly, as a result of the conduct of the trial and that occurs or reveals itself at the time of the trial or subsequently. The LibCTReg further notes that any person(s), institution(s), corporate entity(ies), their designees, or legal representative(s) who fail to provide insurance coverage for prospective participants as required, and where bodily injury or substantial harm results in the course of the research, commits a first degree misdemeanor.

The G-LibClinTrial also specifies that a study insurance certificate and an indemnity provision should be current and valid for the full duration of the trial and follow-up period. If the validity is shorter, a written renewal commitment for the trial duration is required. The certificate should contain a reference to the clinical trial, the clinical trial protocol number, and the countries to which the insurance cover is extended. The insurance cover should be provided from an internationally recognized company. Additionally, the LibCTReg, requires an insurance policy to be in place to provide benefits in the event that a clinical trial participant suffers injury or death related to the study.

In addition, per the G-LibClinTrial, under certain circumstances, the LMHRA may accept an expedited application and review process for clinical trials (e.g., epidemics or other urgent public health interests requiring fast use of new medicines or health products and/or fast gathering of health product information). In the case of trials involving human participants, the applicant must provide proof of current, relevant, and appropriate study insurance for all participants, or professional indemnity insurance for investigators, as part of the application submission package to be sent to the LMHRA. Furthermore, as specified in the LibCTReg and the G-LibClinTrial, the LMHRA has adopted the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with the LMHRA guidelines. See LBR-8 for additional sponsor insurance requirements.

Compensation

Injury or Death

Pursuant to Part VIII of the LMHRA-Act, the LibCTReg specifies that the principal investigator (PI) or organization is subject to an action of damages for any Serious Adverse Event (SAE)/Serious Adverse Drug Reaction (SADR) that is life-threatening, or results in persistent or significant disability/incapacity or congenital anomaly/birth defect, during the conduct of a clinical trial. Additionally, any SAE/SADR that is life-threatening or results in persistent or significant disability/incapacity, congenital anomaly/birth defect to a participant during the conduct of a clinical trial, subjects the PI or organization to an action of damages.

See LBR-8 for additional sponsor compensation requirements related to trial-related injuries.

Trial Participation

See LBR-8 for guidance on sponsor compensation requirements for trial participants.

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

As specified in the LibCTReg and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) has adopted the International Council for Harmonisation (ICH)'s Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with the LMHRA guidelines. Refer to LBR-8 for guidance on sponsor responsibilities related to quality assurance (QA) and quality control (QC) systems throughout the conduct of the trial.

Monitoring Requirements

See LBR-8 for sponsor monitoring requirements.

Premature Study Termination/Suspension

Pursuant to the LibCTReg, if the trial is suspended or terminated before its purpose is achieved, the applicant must convey the reason(s) in writing to the LMHRA and the National Research Ethics Board of Liberia (NREB) within 10 working days, and all information must be provided as determined by the LMHRA. The G-LibClinTrial also states that the applicant must inform the LMHRA of a clinical trial suspension or premature termination of a clinical trial within 10 working days, and clearly explain the reasons for this decision. See also LBR-8 for additional guidance on sponsor requirements related to premature study terminations/suspensions.

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.

Note: Per LBR-38, the National Research Ethics Board of Liberia (NREB) has sole responsibility to review all clinical trial protocols in Liberia. Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) in 2022, all clinical trial protocols submitted to the ACRE IRB are referred to the NREB. Therefore, the information and requirements from the G-ACRE-IRB described in the ClinRegs Liberia profile only apply to human participants research other than clinical trials.

Electronic Data Processing System

As specified in the LibCTReg and the G-LibClinTrial, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) has adopted the International Council for Harmonisation (ICH)'s Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with the LMHRA guidelines. See LBR-8 for sponsor requirements when using electronic data processing systems.

Records Management

The G-LibClinTrial specifies that the principal investigator (PI) must keep an Investigator Site File (ISF), and the sponsor must keep a Trial Master File (TMF) containing essential documents relating to the clinical trial, which provide verification for the trial conduct and the quality of the data generated, taking into account all trial characteristics. The files must be readily available and directly accessible upon request from the LMHRA. The sponsor and the investigator must archive the contents of the TMF and ISF, respectively, for at least 25 years after the end of the trial including the medical files of study participants.

See also LBR-8 for additional sponsor requirements related to record management.

As per the G-LibClinTrial, data handling and recordkeeping should be conducted in conformity with the World Health Organization's Good Clinical Practice Guidelines (LBR-25) (refer to Section 8 for details).

Per the G-ACRE-IRB, for clinical research studies using the ACRE IRB, research records from a study must be retained by the investigator(s) for a period of no more than five (5) years following the closure date. If other regulations and policies apply to a particular protocol, then the duration of protocol retention is in accordance with the applicable regulations/policies. For detailed ACRE IRB recordkeeping requirements, refer to the G-ACRE-IRB.

The G-ACRE-IRB also specifies that although a research protocol has been closed, the investigator(s) should keep the data they have collected, including identifiable private data, in a manner consistent with the board-approved protocol and participant consent requirements. The investigator(s) must continue to honor any confidentiality protections applicable to the data. Refer to the Informed Consent topic for additional information on documentation requirements and research participant rights during the informed consent process.

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.

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

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

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

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

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

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

In addition, per CD-ANPD-No19, international data transfer may be carried out to countries or international organizations recognized by the ANPD as providing a level of personal data protection equivalent to that provided for under the LGPD. Alternatively, transfers may be based on the controller’s verification of compliance with the LGPD’s principles, data subject rights, and data protection requirements through specific contractual clauses for a given transfer, standard contractual clauses, or global corporate standards as provided for in the LGPD and CD-ANPD-No19. See Chapter V of the LGPD, CD-ANPD-No19, and BRA-118 for detailed international data transfer requirements. See also CD-ANPD-No32 regarding ANPD’s recognition of the European Union (EU) as providing an adequate level of personal data protection for purposes of international data transfers.

CD-ANPD-No19 further explains that if the international data transfer involves sensitive personal data, the parties will apply additional safeguards, including specific security measures proportionate to the risks of the processing activity, the specific nature of the data and the interests, rights, and guarantees to be protected. Also, if international data transfer involves the sensitive personal data of children and adolescents, the parties will apply additional safeguards, including measures to ensure that the processing is carried out in their best interests, in accordance with national legislation and international law. The parties must adopt security measures and provide information on measures taken which consider the nature of the information processed, the specific characteristics and purpose of the processing, the current state of technology, and the risks to the rights of the holders, especially in the case of sensitive personal data and of children and adolescents. The measures may include, among others, the governance and supervision of internal processes, and technical and administrative security measures, including measures to ensure the security of the operations carried out, such as the collection, transmission, and storage of data.

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Children/Adolescents

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

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

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

Responsible Parties

No information is currently available related to responsible parties for personal data protection.