National Health Surveillance Agency (ANVISA)

As delineated in ResNo945 and ResNo705 (amending 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 ResNo705 (amending 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 ResNo705 and ResNo800 (amending 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 ResNo705 (amending 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 ResNo705 (amending ResNo585) for detailed information on GGMED, COPEC, and ANVISA’s organizational structure and administrative units.

Other Considerations

Per BRA-65, Brazil is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ResNo945 indicates that Brazil has formally adopted the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025).

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 Electronic Contact Form (BRA-68) may be used to submit technical questions.

Phone: 0 800 642 9782 (for general inquiries) (BRA-135). Calls can be made to specific administrative offices posted on ANVISA’s Who’s Who website (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 an 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)
2^nd & 3^rd 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 ResNo705 (amending 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 the specific standards of the National Research Ethics Authority.

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

Clinical Trial Review Process

As described in ResNo705 (amending 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, except in cases of 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. See the Timeline of Review section for ANVISA’s petition review timelines. See also BRA-40 for information on ANVISA drug registration requirements.

Pursuant to ResNo945, substantial modifications to the investigational product (IP) refer to changes that potentially have an impact on the quality or safety of the experimental drug, active comparator, or placebo. Per ResNo945 and the G-DDCMManual, substantial IP modifications and substantial protocol amendments 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 normative act regarding IP modifications considered to be substantial and non-substantial. See also the G-DDCMAmdmts for clarifying information on substantial and non-substantial protocol modifications. Refer to the Submission Process and Submission Content sections for IP modification submission process and documentation requirements.

Regarding substantial amendments to the clinical trial protocol, ResNo945 explains that an amendment should be considered substantial when it meets at least one (1) of the following criteria:

• Changes to the clinical trial protocol 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 data produced in the clinical trial

Per ResNo945 and the G-DDCMManual, substantial protocol amendments must also be linked as secondary petitions 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. ANVISA will issue a supplementary normative 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 the approval of DDCM, DEEC, and secondary petitions filed with ANVISA prior to the publication of ResNo945 that are 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 discussed below in this section.

Pursuant to ResNo945, the DDCM or any linked clinical trial or related secondary petitions may at, any time, be cancelled or suspended when ANVISA:

• Deems that the approval conditions have not been met, or if there are reports of safety, quality, or efficacy that significantly affect the trial participants or affect the reliability or robustness of the data obtained in the clinical trial
• Participants are being exposed to significant and unreasonable risks
• The sponsor violates the rules described in ResNo945 or fails to comply with the GCP principles and good manufacturing practice (GMP) requirements of the IP

In order to comply with these provisions, per ResNo945, ANVISA will notify the sponsor about the suspension or cancellation of DDCM or clinical trial and will open an administrative and/or investigative process, in accordance with current legislation, when applicable.

Inspection

In accordance with LawNo14.874, ANVISA is authorized to carry out good clinical practice (GCP) inspections of clinical research centers, sponsors, and contract research organizations (CROs) (clinical research representative organization (CRPO) in Brazil). ResNo945 further specifies that ANVISA may carry out GCP inspections of clinical trial centers, sponsors, CROs, laboratories, and other institutions involved in the development of the IP to verify the degree of adherence to current Brazilian legislation and compliance with GCP, in addition to ensuring the rights and duties that concern the scientific community and Brazil. In addition to specific GCP inspection standards issued by ANVISA, GCP inspections will follow the harmonized guidelines of the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates which Brazil has formally adopted. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025). 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 requires all clinical trial inspections to be conducted in accordance with BRA-28. GuideNo35-2020 and GuideNo36-2020 further explain that GCP inspections of sponsors and CRO representatives and in clinical trial centers may be carried out before, during, or after a clinical trial has been conducted and will be classified as either a routine inspection or complaint/suspected irregularity, per RegNo122. In addition, per GuideNo35-2020 and GuideNo36-2020, the inspections will involve at least two (2) ANVISA inspectors, one (1) of whom will be the lead inspector and the focal point for communication with either the clinical trial center or the sponsor/CRO(s). The inspections for both entities will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.

Priority Submissions

In addition to the previously stated DDCM requirements, ResNo204 establishes a priority category to register, amend previously registered, or request prior approval for drug submissions. ResNo204 states that the priority submission may be submitted as a DDCM or a DEEC. A priority DDCM submission is required to meet one (1) or more of the following criteria: new drug trial in any phase to be carried out in Brazil, the drug is part of the Ministry of Health (MOH)’s National Immunization Program, or the product is determined to be of strategic public health interest and included under the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53). A priority DEEC submission is required to comply with the following: the drug will be used for neglected, emerging, or reemerging diseases, health emergencies, or serious debilitating conditions for which there is no alternative; the trial will be conducted exclusively with the pediatric population; or the drug will be used in a Phase I trial only to be manufactured in Brazil. The sponsor should specify at the time of submission that the new or amended protocol is a priority category request. If not confirmed prior to the technical review phase, the request for approval may be denied. ANVISA is required to first issue a written opinion letter within 45 calendar days from the first business day following protocol submission, a final opinion in 120 days for new drug registration requests, and a final opinion 60 days for post-registration petitions. See the Timeline of Review section for detailed timeline information. Refer to ResNo204, ResNo811 (which partially amends ResNo204), and BRA-14 for detailed information on priority submission requirements. See also BRA-82 for additional information on priority submissions.

New Drugs for Rare Diseases Submissions

ResNo205 sets forth specific approval procedures for clinical trials to be conducted to register new drugs to treat, diagnose, or prevent rare diseases. The applications may be submitted as an initial DDCM, a secondary petition linked to the original DDCM, or a DEEC either linked to the original DDCM or for a new process. The sponsor must delineate at the time of submitting a new drug submission (DDCM), an amended DDCM (secondary petition), or DEEC, whether the DDCM is pertaining to a rare disease drug. If not confirmed prior to the technical review phase, the request for approval may be denied.

In addition, per ResNo763, which modifies ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, and if the sponsor deems it necessary, then ANVISA will hold the meeting within 60 days following this request. Refer to ResNo205 and ResNo811 (which partially amends ResNo205) for additional submission documentation requirements.

Optimized Analysis Procedure Reviews

As delineated in ResNo945 and ResNo741, ANVISA has adopted a technical evaluation mechanism known as the “optimized analysis procedure” which uses the technical analysis or supporting documentation issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) as a sole or complementary reference, for its decisions. AREEs have regulatory practices aligned with those of ANVISA and are therefore considered to be in a practice of regulatory trust (referred to as Reliance). ANVISA designates a specific list of approved AREEs for each type of authorization request (see below for the AREE lists based on request type).

ResNo741 provides general criteria for the admissibility of the AREE regulatory documentation, which includes reports, opinions, or technical/legal documents, used to issue an opinion. Among other requirements, in order for ANVISA to adopt the optimized analysis procedure, the health surveillance process covered in the AREE’s documentation must meet all the requirements, criteria, and specifications established by ANVISA for the corresponding health surveillance process. ResNo945 also explains that the documents required for the instruction of each type of petition or process submitted, may be partially or fully exempted from technical analysis using 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 based on Reliance.

Drug & Biological Product Registration/Post-Registration

In accordance with ResNo741, ANVISA approved RegNo289, which establishes specific criteria and procedures for ANVISA’s application of the optimized analysis procedure in which one (1) or more AREE assessments are used to analyze registration and post-registration authorization requests for medicines, vaccines, biological products, and their active substances that are already approved in the reference country. ANVISA will issue a Letter of Adequacy of Active Pharmaceutical Ingredient Dossier (Carta de Adequação de Dossiê de Insumo Farmacêutico Ativo (CADIFA)) to certify the AREE has regulatory trust practices aligned with those of ANVISA and has ensured that products authorized for distribution have been adequately evaluated and meet recognized standards of quality, safety, and effectiveness.

Pursuant to RegNo289, ANVISA has designated the following foreign agencies as AREEs to review registration and post-registration authorization requests of medicines, vaccines, biological products and their active substances:

• European Medicines Agency (EMA)
• Health Canada
• European Directorate for the Quality of Medicines & HealthCare (EDQM)
• Swiss Agency for Therapeutic Products (Swissmedic)
• Medicines and Healthcare products Regulatory Agency (MHRA), United Kingdom
• US Food and Drug Administration (FDA)
• Therapeutic Goods Administration (TGA), Australia

Refer to RegNo289 for detailed requirements on submitting a request for ANVISA authorization via the optimized analysis procedure. See ResNo741 for additional information on the optimized analysis procedure and AREE related requirements. See also the Manufacturing & Import section for AREE manufacturing and inspection criteria and procedures and Good Manufacturing Practices Certification via the optimized analysis procedure as delineated in RegNo292.

DDCMs, DEECs, Substantial IP Modifications & Substantial Protocol Amendments by Reliance

As per ResNo945, RegNo338, and BRA-122, the optimized analysis procedure based on Reliance is also applicable to primary DDCM and DEEC petitions, and secondary petitions for substantial modifications to the IP and substantial amendments to the clinical trial protocol. 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:

• EMA and its member countries
• Health Canada
• Swissmedic
• MHRA
• 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 and RegNo345 (amending RegNo338) following its evaluation, 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 does not comply with the criteria for applying the optimized analysis procedure by Reliance, 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 by 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 ResNo204 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 details.

DDCM & IP Substantial Modifications by Risk Assessment

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 process may be partially or fully exempted from technical analysis, through the optimized analysis procedure, according to the 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, and/or the active comparator is identical to the registered drug, ANVISA’s evaluation of the documents present in the IMPD or DPI may also be analyzed by the optimized procedure by 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.

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

According to 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 bearing on other clinical trials which is of significance 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. Also, the LMHRA must ensure that the list of approved and rejected clinical trial applications as well as summary of evaluation reports and 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 indicating 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 written consent of the applicant or in accordance with the directive of the LMHRA Board of Directors.

Per the LibCTReg and 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 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. In the case of trials involving human participants, per the G-LibClinTrial, 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.

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 as determined by the LMHRA in the corresponding 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 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. The LMRHA may reject or accept the changes, 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. However, in order to allow the LMHRA to exercise its clinical trial oversight function, the sponsor should ensure that the LMRHA is aware of a non-substantial amendment(s) as soon as possible. For example, progress reports including safety data as well as annual updates of the investigator's brochure (IB) are not considered amendments per se, and therefore, do not have to be notified as substantial amendments to the LMHRA. However, the sponsor has to verify whether the data presented requires a change to the documentation submitted with the request for clinical trial authorization. If this amendment is substantial, the rules for notification of substantial amendments apply to these changes. 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, or
• In the case of trials involving human participants, the documentation requirements (see Section 1 (4) 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 Chapter II (Sections 1-2) of LibCTReg) are no longer fulfilled

The LibCTReg indicates that in a clinical trial of an IP consisting of a genetically modified organism, consisting of a combination of genetically modified organisms, or containing such 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 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 a clinical trial authorization must be suspended by the LMHRA for a limited period of time if at least one (1) of the following 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 Chapter II (Section 5 (3)) 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 a decision is taken, 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 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 may also:

• Request additional information
• Inspect any resources that are deemed by the LMHRA to be related to the clinical trial and that may be located at the trial site, the sponsor´s and/or CRO’s facilities, or other establishments deemed appropriate by the LMHRA
• Suspend or stop a clinical
• Withdraw the authorization to conduct a clinical trial, if the LMHRA is of the opinion that the safety of the trial participants may be compromised, that the scientific reasons for conducting the trial have changed, or if 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 (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). As per ResNo857 and BRA-47, once the sponsor has completed the process of submitting a 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 and LBR-39, 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

Payment Instructions

No information is available regarding payment instructions.

Overview

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos). The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) which must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

CEP/CONEP System

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 National Health Council (Conselho Nacional de Saúde (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 participants 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 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)

National Research Ethics Authority

LawNo14.874 specifies that the EC (CEP) should be composed of a collegiate, interdisciplinary team in the medical, scientific, and non-scientific areas, to ensure that the members 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)).

National Research Ethics Commission (CONEP)

As per OMREC, the EC (CEP) is required to be composed of a minimum of seven (7) members having proven expertise in research. ResNo706, in turn, states the EC (CEP) must be composed of at least nine (9) members with at least two (2) 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 is 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 Research Ethics Authority

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

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

As described in LawNo14.874, the deliberation on the ethical adequacy of the research will take place in a previously scheduled meeting, which must have a minimum quorum, as defined in the EC’s (CEP's) internal regulations. Only active EC (CEP) members are permitted to issue opinions and deliberate on the ethical adequacy of submitted research. EC (CEP) members may invite external experts and representatives of vulnerable groups to give their opinion on specific issues related to research projects, but they will not have the right to vote. Once duly accredited or certified, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP.

In addition, LawNo14.874 explains that depending on the degree of risk involved in the research, the role of the research ethics review body will be exercised by one (1) of the following:

• An EC (CEP) accredited or certified by the National Research Ethics Authority, in the case of low or moderate risk research
• An EC (CEP) accredited by the National Research Ethics Authority, in the case of high-risk research

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. Once duly accredited or certified, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP. The EC (CEP) 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. 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’s (CEP)’s activities are subject to inspection and monitoring by the National Research Ethics Authority. Failure by the EC (CEP) to comply with the provisions of LawNo14.874 will result in its de-accreditation by the National Research Ethics Authority, in accordance with regulations.

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

National Research Ethics Commission (CONEP)

As set forth in OMREC, 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’s (CEP’s) SOPs. As per ResNo706, the term of office of EC (CEP) members is valid for four (4) years, with the possibility of reappointment, at the discretion of the CEP. At the end of the term of office, an EC (CEP) member may remain in this role up to 90 days, until a replacement or reappointment takes place.

See OMREC for detailed EC (CEP) procedures and information on other administrative processes. See CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up EC (CEP) accreditation and renewal processes and maintain regular functioning of ECs (CEPs), and CLNo25 for guidance on conducting virtual CEP/CONEP system meetings.

Overview

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)).

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. According to LBR-38, only the NREB has the sole responsibility to review all clinical trial protocols. 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 protect their rights, privacy, and confidentiality
• Evaluating the potential risks and benefits of research projects and ensure that they 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 review of research for health protocols for use by other review boards
• Giving 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 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 finished research/study reports

Atlantic Center for Research and Evaluation Institutional Review Board

As noted in the G-ACRE-IRB, the ACRE IRB is mandated by the Board of Directors of the ACRE Africa Center. According to LBR-28, the ACRE IRB has the expertise to review clinical research, and some members of the ACRE IRB also serve on the NREB and provide expertise in the review of clinical trial protocols. However, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical research protocols submitted to the ACRE IRB are referred to the NREB.

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 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 membership must include both scientists and non-scientists from diverse backgrounds to undertake an impartial and adequate review of research proposals. The ACRE IRB membership must include the following:

• 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 recruitment of ad-hoc reviewers. There must be adequate representation by age, gender, community, etc., on the board 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 relevant 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 issues, as long as 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 number of applications meet the threshold. 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.

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 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.

Refer to the G-ACRE-IRB for detailed information on ACRE IRB administrative processes.

Overview

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos). The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available.) See also BRA-117 for additional information.

National Research Ethics Authority

According to LawNo14.874, the primary scope of information reviewed by ECs (CEPs) relates to protecting the dignity, safety, and well-being of research participants throughout the conduct of a clinical trial. The ECs (CEPs) are responsible for acting independently and autonomously before and during the trial through their analysis, review, and ethical approval of research protocols and their amendments, as well as through their evaluation of the methods and materials used to obtain and document the free and informed consent of research participants.

As part of their ethical review and analysis, LawNo14.874 indicates that the ECs (CEPs) are also responsible for requesting the provision of additional information to research participants when deemed essential to protect their rights, safety, and well-being; ensuring the research project and other documents adequately address relevant ethical issues and satisfy applicable regulatory requirements, including those related to good clinical practice (GCP); and, ensuring adequate means are provided for obtaining consent from the research participant or the legal representative, among others. The ECs (CEPs) must also pay special attention to protecting the welfare of participants deemed to be vulnerable (See the Vulnerable Populations and Pregnant Women, Fetuses & Neonates sections for additional information about these populations).

As part of the National System of Ethics in Research with Human Beings, per LawNo14.874, the ECs (CEPs) are guided by the following principles:

• Protection of the dignity, safety, and well-being of the research participant
• Encouragement of technical and scientific development
• Independence, transparency, and publicity
• Equality in the application of criteria and procedures for analyzing research projects, according to the risk-benefit relationship inferred from their protocols
• Efficiency and agility in the analysis and issuing of opinions
• Multidisciplinary focus
• Social control, with the participation of research participant representative(s)
• Respect for GCP

National Research Ethics Commission (CONEP)

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 a clinical trial.

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). ResNo304 further establishes specific ethical requirements for research studies involving indigenous populations. Detailed information on documentation and consent requirements for studies involving indigenous populations is available in the Documentation Requirements, Vulnerable Populations, and Consent for Specimen sections.

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

CONEP-Designated Protocol Reviews

Per ResNo580, the Ministry of Health (MOH)’s Secretary of Science, Technology and Strategic Inputs refers protocols to CONEP that are determined to be of strategic public health interest for the Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53). ResNo580 recognizes strategic research protocols as those studies that may contribute to public health, justice, reduction of social inequalities and technological dependencies, and those that address public health emergencies. Refer to the Oversight of Ethics Committees section for additional information on CONEP’s review requirements for this type of protocol. A working group was also created to support the MOH’s assessment of research involving human beings when carried out in the SUS sphere, per OrdNo552. The interagency working group includes National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), CONEP, and the National Health Council (Conselho Nacional de Saúde (CNS)), and is coordinated by an MOH representative.

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

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

EC analysis varies according to the type of research and modulation factors (i.e., consent process, confidentiality, and/or research methods), and requires the reviewer to verify the documentation the investigator submits in Plataforma Brasil (BRA-34). Per BRA-93, Plataforma Brasil is a national and unified database of human subjects research records that represents the entire CEP/CONEP System. The platform is also used to track research applications from submission to final approval by the EC (CEP), and when necessary, by CONEP. See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.

There are four (4) ways of processing protocols in the CEP/CONEP System: express, simplified, collegiate, and special collegiate; the modulation factors per Annex II of ResNo674 provides additional characteristics to further modify the protocol processing method to be used. See ResNo674 and BRA-4 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures. (Note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor Plataforma Brasil (BRA-34) for any developments.)

Role in Clinical Trial Approval Process

National Research Ethics Authority

As delineated in ResNo945, ANVISA and the EC (CEP) must approve a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) before a trial is permitted to commence. Research involving human beings must be subject to prior ethical analysis by ECs (CEPs) according to National Research Ethics Authority legislation and regulations. Clinical trial applications can be submitted in parallel, however, a drug clinical trial may only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

In addition, as indicated in ResNo945, the EC (CEP) must 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.

As stated in LawNo14.874, the EC (CEP) research ethics analysis process will be instructed with the information and documents established in specific regulations. All documents requested by the EC (CEP) must be provided for in an act of the MOH, in a regulation, or in the rules of the EC (CEP) itself and be relevant to the matter analyzed.

Per LawNo14.874, the EC (CEP) will issue an opinion following acceptance or denial of the all the submitted research documents. Before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor, or request that adjustments be made to the research documentation. The EC’s (CEP’s) review will be suspended during this time, and the investigator will be given time to meet the EC’s (CEP’s) demands. However, the EC (CEP) study analysis process may be canceled in case of non-compliance with the deadline. At the discretion of the EC (CEP), the investigator may participate in the collegiate meeting to provide clarifications about the research, but the investigator is prohibited from attending the meeting while the final decision is being made. Upon completion of its review, 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 decision contained in the EC’s (CEP's) opinion may be initially appealed to the EC (CEP) that issued the opinion and, subsequently, the opinion may be appealed one (1) final time to the National Research Ethics Authority. All those involved in conducting, monitoring, evaluating, or approving the research who have direct access to its records, to verify compliance with the procedures and applicable legislation and the validity or integrity of the data, must ensure the preservation of the confidentiality of the data and the anonymity of the research participant, in accordance with current legislation.

After the start of the research, per LawNo14.874, if there is a need for a change that interferes with the risk-benefit relationship or the approved documentation, the coordinating investigator will submit, in writing, an amendment to the research project, duly justified, for analysis and opinion by the EC (CEP) that analyzed the research. 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.

LawNo14.874 also notes that the ethical analysis of research involving more than one (1) research center in the country will be carried out by a single EC (CEP), preferably the one linked to the research coordinating center, which will issue the opinion and notify the ECs (CEPs) of the other participating centers of its decision. Additionally, 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 given priority in ethical analysis and will be subject to special analysis procedures, including deadlines. See the Timeline of Review section for detailed timeline information.

In addition, research conducted with human beings that does not comply with the provisions of LawNo14.874 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 CRO is affiliated, without prejudice to applicable civil and criminal sanctions. For the purposes of applying the disciplinary sanctions, the EC (CEP) or the National Research Ethics Authority 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.

National Research Ethics Commission (CONEP)

As per ResNo466 and OSNo001, ANVISA and the EC (CEP) (and CONEP, if applicable) must approve a clinical trial application before a trial is permitted to commence. Per OSNo001, the EC (CEP) must also review and approve any protocol amendments prior to those changes being 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 the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via BRA-34. CLNo24 and CLNo24-Note for CONEP’s general guidelines for investigators and ECs (CEPs) on conducting clinical trials.

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. In this case, the EC (CEP) will analyze the IB together with the other documents pertaining to the amendment, and, if necessary, the required amendments and/or clarifications will be requested.

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 to CONEP itself. From an analysis of the resources submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal, the processing of the appeal is terminated, the research protocol is archived, and no other appeal requests will be permitted. 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.

Foreign Research

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

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

Multicenter Research

Per ResNo346, for multicenter research protocols, the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. Per OSNo001, the principal investigator is also required to submit a list of the participating institutions and associated protocols, the coordinating center, and the EC (CEP) designated to monitor the study’s progress as part of the research protocol package sent to the EC (CEP) for review. ResNo346 further notes that CONEP will only evaluate the first protocol submitted and then send its final opinion to the original EC (CEP) and the other participating institutions. ResNo674 similarly explains that the initial analysis of the research protocol using the research classification procedure will occur at the EC (CEP) of the coordinating center or the accredited EC (CEP), when applicable, and will be subsequently forwarded for analysis by the EC (CEP) of the other co-participating centers and/or institutions, after approval.

See ResNo346 for additional multicenter protocol processing information.

Exemption from Review

Pursuant to Article 26 of ResNo674, CLNo12 provides further guidance on research that is exempt from ethical assessment by the CEP/CONEP system. Research that is exempt includes protocols that fall exclusively into the following categories: public opinion surveys with unidentifiable participants; research that uses publicly accessible information; research that uses public domain information; census research carried out by government agencies; research carried out exclusively with information or data already available in aggregate form, without the possibility of individual identification; research carried out exclusively with scientific texts to review the scientific literature; research that aims at the theoretical deepening of situations that emerge spontaneously and contingently in professional practice, as long as it does not reveal data that can identify the individuals; activity carried out with the sole purpose of education, teaching, extension or training, without the purpose of scientific research, of undergraduate students, technical course, or professionals in specialization; market research; scientific research carried out with cells, tissues, organs, and organisms of nonhuman origin, including their biological products, provided there is no interaction with research participants or imply the collection or use of human biological material to obtain them; and, activity whose purpose is to describe or analyze the productive or administrative process exclusively for organizational development purposes.

Overview

According to the G-ACRE-IRB and the G-NREB, 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 clinical trial. According to the NatResHlthPlcy, 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)).

The G-ACRE-IRB and the G-NREB also state that the ECs are responsible for ensuring independent, timely, and competent reviews of all ethical aspects of the clinical trial 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. As per the G-ACRE-IRB, the ACRE IRB must pay special attention to reviewing informed consent and protecting the welfare of certain classes of participants deemed to be vulnerable, including children.

See the G-ACRE-IRB and the G-NREB for detailed ethical review guidelines.

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 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 is in possession of information bearing on other clinical trials which is of significance 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.

National Research Ethics Board of Liberia

Per the G-LibClinTrial and the G-NREB, ethical clearance by the NREB is required as part of the LMHRA clinical trial approval process. 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 the application for a clinical trial in line with its written standard operating procedures (SOPs). According to LBR-20, upon receiving the research proposals, the NREB conducts a preliminary screening to ensure that all required documents and information are included and that the proposals meet the submission requirements. Incomplete or insufficient proposals may be returned to researchers with instructions for revisions or additional information. 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, and the 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 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 make revisions to their proposals, provide additional information, or address specific ethical issues before final approval is granted. The LibCTReg also notes that a written permission from the NREB 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, including the trial protocol, the investigator’s brochure, the modalities for selecting trial participants, and informed consent/assent, do not correspond to the current state of scientific knowledge, and especially, 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 Chapter II (Section 1) of LibCTReg) are not fulfilled.

Per the G-NREB, a principal investigator (PI) will be contacted by written communication (letter or email) if the NREB determines that additional materials are required to complete its review. PIs may also be asked to be available for presentations and/or contacted during the meetings. The G-NREB also explains that 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 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, 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. If the NREB has not reviewed and approved a study’s request by the current expiration date, study activities should cease until the board determines whether continuing the research is in the best interest of all previously enrolled participants. The NREB will also review continuing review submissions prior to the expected expiration date of NREB approval for requests to extend the ethical approval to continue implementation of the research project. 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 written permission must be withdrawn if the NREB subsequently becomes aware that grounds for a refusal as referred to in the clinical trial authorization procedures (see Chapter II (Section 5 (1)) of LibCTReg) existed at the time the authorization was issued. The authorization must be withdrawn if the NREB becomes aware of the fact that subsequently 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 Chapter II (Sections 1-2) of LibCTReg) are no longer fulfilled. The NREB shall inform the LMHRA through a 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 due to 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 the 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 protocols or ethical concerns that arise 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. In certain cases, the site visits may 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 and 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 reviews and systems for virtual discussions (via platforms like Zoom)
• Identify core members who will 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
• The Director will alert members and determine 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 about 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.

Atlantic Center for Research and Evaluation Institutional Review Board

Per G-ACRE-IRB, the ACRE IRB’s purpose is to review and certify the ethical acceptability of all research involving human participants conducted in Liberia. However, per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.

Per G-ACRE-IRB, all studies submitted to the ACRE must be approved by the ACRE IRB. This includes all studies conducted by ACRE investigators as well as all research conducted by outside investigators or students and faculty of universities in Liberia. The G-ACRE-IRB is intended to ensure 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.

According to G-ACRE-IRB, on receipt of a proposal for review, the ACRE IRB Secretariat will preliminarily assess the completeness of the submission. If the submission is incomplete, the Secretariat will inform the PI accordingly and request the additional materials. Once the submission is deemed complete, the Secretariat will notify the PI and distribute the materials to the assigned ACRE IRB members. Exempt studies will be reviewed by all board members; expedited studies will be reviewed by all board members; full review studies will be sent to the entire ACRE IRB membership for review. An expedited study is defined as one which does not require review by a convened ACRE IRB quorum because it has been determined that participants are subject to low risk. Additional information about the various review types can be found in the G-ACRE-IRB. The PI must check the level at which the protocol will be reviewed and confirm the required documents before submitting it for review. Please refer to the G-ACRE-IRB for additional information on the administrative processes relating to proposal submission.

As specified in the G-ACRE-IRB, the ACRE IRB approval will commence on the day the study is approved and will expire within a defined time period based on the 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 also states that the ACRE IRB must review and approve any protocol amendments prior to those changes being implemented. The protocol submission is reviewed either via expedited procedures (for minor changes) or via full ACRE IRB review (for all other changes). The criteria for approval are the same as for initial review. In addition, the ACRE IRB has a continuing responsibility to monitor the approved trial(s) to ensure ethical compliance throughout the study duration. A continuing review is conducted to review progress of an ongoing study, and not just changes made in the study, in order to ensure continued protection of the rights and welfare of research participants. Refer to the G-ACRE-IRB for protocol amendment and continuing review documentation submission and procedural requirements.

Additionally, per the G-ACRE-IRB, a protocol may be selected to undergo post-approval monitoring due to reported complaints and/or requests by the convened EC. Other reasons for post-approval monitoring may include:

• From continuing review or reports from other sources, it is revealed that material changes may have occurred without ACRE IRB approval
• Where an investigator conducting a project has previous records of noncompliance
• Projects involving vulnerable populations that raise cause for concern
• Complex projects involving unusual levels or types of risks to participants
• Upon request by the investigator
• In response to inquiries from external regulatory agencies

The G-ACRE-IRB further notes that if the monitoring reveals serious or continuing noncompliance, the EC Secretariat or EC designee will compile the information regarding the allegation, complaint, or report and submit the information to the EC for further review and processing as needed. See the G-ACRE-IRB for additional information on monitoring procedures, reporting of monitoring results, and noncompliance.

As described in the G-ACRE-IRB, the ACRE IRB is also authorized to suspend or terminate an approved research study for a variety of reasons, including but not limited to:

• Failure to obtain appropriate consent or keep appropriate study-related paperwork
• Conduct of research activities without prior ACRE IRB approval
• Serious adverse event(s)
• Detrimental change in the risk-benefit ratio of the study
• Failure of investigators to complete required training

The convened board is specifically authorized to suspend or terminate approval of research protocols that are not being conducted in accordance with the ACRE IRB’s requirements or that has been associated with serious harm to the participants. The ACRE IRB Chair, or the designee, is authorized to suspend research protocols in emergency situations, such as when the rights, safety, or welfare of research participants are at immediate risk. Refer to the G-ACRE-IRB for detailed information on the board’s process for study suspension/termination, notification of the investigator, the consequences of study suspension/termination, and ACRE IRB requirements for permitting study reinstatement.

National Research Ethics Authority

No information is currently available regarding research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) fees.

National Research Ethics Commission (CONEP)

According to ResNo466, OMREC, and ResNo706, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit 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.

National Research Ethics Board of Liberia

As described in the G-NREB, the National Research Ethics Board of Liberia (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 is 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 available regarding payment instructions for the NREB.

Atlantic Center for Research and Evaluation Institutional Review Board

As per the G-ACRE-IRB, the Atlantic Center for Research and Evaluation Institutional Review Board (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 available regarding payment instructions for the ACRE IRB.

Overview

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos). The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

National Research Ethics Authority

Per LawNo14.874, the National Research Ethics Authority, an interdisciplinary and independent collegiate body that is part of the MOH, is responsible for the following:

• Issuing regulatory standards on ethics research
• Evaluating the effectiveness of the National System of Ethics in Research with Human Beings
• Accrediting and certifying the ECs (CEPs) so that they are able to perform the function of ethical analysis in research, according to the degree of risk involved
• Monitoring, supporting, and supervising the ECs (CEPs) in relation to the analysis of research protocols and compliance with the pertinent standards
• Promoting and supporting the training of EC (CEP) members, with special emphasis on ethical and methodological aspects
• Acting as an appeals court for decisions made by ECs (CEPs)

National Research Ethics Commission (CONEP)

As per ResNo466, OSNo001, and ResNo446, CONEP is the central statutory body responsible for the registration, audit, and accreditation of ECs (CEPs). CONEP was created by the MOH to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. CONEP reports to the CNS, the advisory body to the MOH.

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

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

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

Registration, Auditing, and Accreditation

National Research Ethics Authority

As stated in LawNo14.874, the National Research Ethics Authority is responsible for accrediting and certifying the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)) so that they are able to perform ethical research reviews according to the degree of risk involved.

National Research Ethics Commission (CONEP)

As per ResNo466, SP006REC, OSNo001, ResNo446, and ResNo706, all ECs (CEPs) must be registered and accredited by CONEP. CONEP’s Executive Secretariat who performs a documentation review to ensure compliance with the requirements delineated in ResNo446 carries out accreditation. ResNo706 further states that CEP registration and accreditation may only be requested by health, teaching, or research institutions headquartered in Brazil, without potential conflict of interest, and in good standing with competent bodies. The granting of EC (CEP) registration and accreditation is prohibited to research centers maintained or linked to Representative Clinical Research Representative Organizations (Organização Representativa de Pesquisa Clínica (ORPCs)) and professional category associations.

CNSResNo506 states that accreditation is valid for three (3) years. ResNo706, in turn, indicates that the term of validity of EC (CEP) accreditation is four (4) years.

ResNo706 specifies that registration and accreditation of the EC (CEP), as well as its renewal, will be carried out upon submission of the following documents:

• Application sent by the supporting institution, signed by its legal representative, containing the description of this institution and the commitment to ensure the minimum operating conditions of the EC (CEP)
• Proof of the minimum operating requirements of the supporting institution, in accordance with specific standards
• Request form, according to the model provided by CONEP
• Letters of appointment of Research Participant Representatives (RPPs), in accordance with the specific resolution
• Act of designation of the EC (CEP)
• EC (CEP) internal regulations

Additionally, per ResNo706, to begin activities, the EC (CEP) must, within 90 days after the announcement of registration and accreditation approval, prove the adequate training of its members. The approval of registration and accreditation of the EC (CEP) that does not begin its activities will be revoked within 120 days after approval of its registration. The renewal of the EC (CEP) accreditation must be initiated 90 days before the expiration date of its validity and be completed before it expires. An extension of the deadline for renewal may be requested once for a maximum period of 90 days when justified.

CNSResNo506, by comparison, states that to apply for accreditation, as well as renewal, an EC (CEP) is required to submit the following documentation along with a proposal for accreditation:

• Formal application justifying the EC (CEP)'s accreditation request
• Current EC (CEP) internal regulations
• Description of the EC (CEP)’s current functioning and infrastructure
• Proposal of the minimum number of high-risk protocols of other institutions that the EC (CEP) undertakes to evaluate on an individual basis, after obtaining the accreditation certificate
• Report of EC (CEP) activities for the three (3) years prior to the publication date of the public call

See CNSResNo506 for additional documentation requirements.

As noted in CNSResNo506 and SP006REC, the renewal application must be submitted within the window of 60 days before to 60 days after the accreditation’s expiration date. Once the deadline has elapsed, and no renewal has been requested, the accreditation certificate will be canceled automatically. Additionally, per CNSResNo506, the accreditation certificate may be canceled, at any time, at the request of the EC (CEP), upon presentation in writing, without prejudice to the loss of its registration. In the absence of compliance with current CNS norms, CONEP will cancel the accreditation certificate, consubstantiating its decision in opinion. In case of cancellation of the accreditation by CONEP, the EC (CEP) may appeal. During the review period, the accredited CEP will maintain the rights conferred by the accreditation certificate. SP006REC also notes that if communication with CONEP during the pending renewal process is interrupted by the EC (CEP) for more than 60 days, the EC (CEP) registration will be automatically cancelled and the EC (CEP) will be notified by official letter.

See SP006REC, CNSResNo506, and ResNo706 for additional details on CONEP’s accreditation process. See CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up EC (CEP) accreditation and renewal processes and maintain regular functioning of ECs (CEPs).

High-Risk Research Protocols

In addition to being accredited by CONEP per the earlier stated requirements, CNSResNo506 explains that ECs (CEPs) may also be certified for their role in the ethical analysis of high-risk research protocols. As per ResNo674, the CNS has published protocol risk classification and processing guidelines to be used in the CEP/CONEP System to provide criteria to assess the risk level of research protocols.

Per CNSResNo506, until ResNo674 becomes operational, CONEP has determined that protocols falling within the special thematic areas of human genetics, human reproduction, indigenous populations, genetically modified organisms, and the establishment and operation of biobanks must be considered high risk. Refer to ResNo466, ResNo446, and ResNo340 for a complete listing of the special thematic areas. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., including protocols on the constitution and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically; and CLNo26 for information on submitting research protocols with human bodies and/or anatomical parts.

CNSResNo506 further states that at the time of obtaining accreditation, the EC (CEP) should submit a statement signed by the EC coordinator that commits the EC (CEP) to evaluating high-risk protocols at least equal to the protocol submitted to CONEP. This process also supports CONEP’s plan to decentralize the CEP/CONEP System and delegate more high-risk protocol reviews to certified ECs (CEPs). If the number of high-risk protocols exceeds the EC’s (CEP’s) operational capacity to review, then CONEP will evaluate the outstanding protocols. BRA-2 also provides helpful information on this process.

Additionally, ResNo674 notes CONEP will be solely responsible for the registration of biobank development protocols, and the research classification and modulation factors used to further characterize the protocols in BRA-34 will not be applicable. (Note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor Plataforma Brasil (BRA-34) for any developments.)

Suspension and Cancellation of Accreditation

As indicated in ResNo706, an EC (CEP) or the supporting institution may request suspension of the EC’s (CEP’s) accreditation for a maximum period of 90 days, upon reasoned justification, and the suspension may be extended once, for an additional 90-day period.

Per ResNo706, the suspension of EC (CEP) accreditation consists of the temporary interruption of the receipt of new research protocols for ethical assessment. The suspended EC (CEP) must maintain monitoring of the protocols under its responsibility, whether approved or in progress, while the suspension remains. New protocols, submitted for consideration by the suspended EC (CEP), will be directed to another EC (CEP), as indicated by CONEP. CONEP’s decision to suspend the EC (CEP)'s accreditation may be appealed to CONEP within 30 days. An extension of the deadline for appeal may be requested, once, for a maximum period of 30 days, upon justification.

ResNo706 further explains that the cancellation of EC (CEP) accreditation consists of revoking the registration and removing the EC (CEP) in the CEP/CONEP System. If cancelled, CONEP will transfer the protocols to another EC (CEP) for due monitoring. Cancellation, at the request of the supporting institution, will be assessed by means of a request addressed to the CONEP Coordination, containing the reasons for the request. The cancellation decision may be appealed to CONEP within 30 days. An extension of the deadline for appeal may be requested once, for a maximum period of 30 days, upon justification. In case of cancellation, requests for new registration by the supporting institution within a period of 12 months are prohibited. See ResNo706 for detailed information on EC (CEP) accreditation suspensions and cancellations.

Overview

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 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 approval for a clinical trial application (Clinical Drug Development Dossier (Dossier 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).

According to LawNo14.874 and ResNo945, research involving human beings must be subject to 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 drug clinical trial may only be initiated after approval is obtained by both the EC (CEP) and ANVISA.

According to National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) regulations and guidelines as delineated in ResNo466 and OSNo001, the principal investigator (PI) must obtain approval from the EC (CEP). Applications with coordination or sponsorship originating outside of Brazil require additional EC (CEP) review by CONEP unless the co-sponsor is the Brazilian Government.

Note: Regulatory requirements for both the National Research Ethics Authority and CONEP will be included in the profile until the CONEP system has fully transitioned to the new national system enacted by LawNo14.874.

Regulatory Submission

Primary Petitions

As per ResNo945, the 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 the 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 defined as a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) in the DDCM. DEECs must be filed in the form of individual processes for each clinical trial and linked to the respective DDCM. Per the G-DDCMManual, DEECs must be submitted as primary petitions and, therefore, will have a case number, with specific subjects for each clinical trial that is to be carried out in Brazil and that have not yet been submitted to ANVISA. Also, only DEECs from clinical trials to be carried out in Brazil should be submitted. ResNo945 further indicates that the sponsor, CRO, or sponsor-investigator may link new DEECs to the submitted DDCM at any time following the initial submission.

ResNo945 provides the following additional DDCM submission requirements:

• The person responsible for submitting the DDCM to ANVISA must be the same for all subsequent petition submissions related to it
• Submissions by the CRO may only be made when 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
• In cases where a sponsoring investigator wishes to conduct a clinical trial with a drug that already has an approved DDCM, the sponsoring investigator, with the initial DDCM owner’s permission, may use the information previously sent, without having to resubmit all the documentation. When an authorization from the initial DDCM owner is not provided, the sponsoring investigator must submit to ANVISA all the required information through updated and indexed literature that supports the proposed development rationale

In addition, per ResNo903, when a sponsor or CRO transfers responsibility for submitting a DDCM petition and the linked specific clinical trial processes for an 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 respective specific processes. When a secondary petition is related to a DDCM, it must be filed together with the Petition Consent Form (BRA-21). Some 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 DEECs must be linked to the respective clinical trial processes. Some 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.

A stated in ResNo945 and the G-DDCMManual, for substantial protocol modifications of the investigational product (IP), the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM. ResNo945 also indicates that 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 report (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 for DDCM modifications. See also BRA-127 for the Substantial Modification of the Investigational Product form. Refer to the Submission Content section for substantial IP modification 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.

ResNo204 and BRA-14 further note that DEECs may be submitted as priority requests to ANVISA to register, amend previously registered, or request prior consent for drug submissions. However, as described in the G-DDCMManual, in cases where the DDCM or DEEC has been prioritized, under the terms of ResNo204, ResNo205, and ResNo811 (which partially amends ResNo205), prioritization does not automatically extend to secondary petitions. The company must request the prioritization of analysis at the time of petitioning each secondary petition, if applicable. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections.

See ResNo742, ResNo931 and ResNo942 (amending ResNo742), BRA-6, and BRA-7 for requirements associated with submitting DEECs linked to DDCMs for comparative bioavailability/bioequivalence studies and comparative pharmacokinetic studies with biosimilar products.

In addition, for the purposes of regulatory submission, the G-SUSARs indicates that Drug Development Safety Reports (DSURs) must be submitted as secondary electronic petitions linked to the DDCM process. The subject of petition 10825 – CLINICAL TRIALS – Safety Update Report of the Development of the Investigational Drug should be used.

As delineated in ResNo945, RegNo338, the G-DDCMManual, and BRA-122, the sponsor may also submit a request for technical analysis by the optimized procedure based on regulatory trust practices (Reliance) or by risk or complexity criteria of the clinical trial or the IP at any time, by means of a secondary petition, before ANVISA begins its technical evaluation of the corresponding DDCM petition. 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 Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) recognized by ANVISA. The AREE approved documents must also be the same versions as those presented to ANVISA.

The G-DDCMManual further explains that the optimization procedure concerns the documentation that may be exempted from technical analysis when the criteria for each of the specific situations are met. However, all documents required for the instruction of each type of petition or process must be submitted.

In accordance with ResNo945 and RegNo338, the G-DDCMManual and BRA-122 indicate that the applicant must file a secondary petition to request the optimized analysis procedure by Reliance using one (1) of the subject codes listed below:

• 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

BRA-122 also explains that only a single subject code (12102) is used to submit a request to ANVISA to apply the optimized analysis procedure by Reliance for the DEEC. Additionally, per the G-DDCMManual and BRA-122, the petitioning system does not allow a secondary petition to be linked to another secondary petition. Since requests for the application of the optimized analysis procedure must be made through secondary petitions, and petitions for substantial IP modifications and clinical protocol amendments are also secondary petitions, requests referring to these petitions must be linked to the DDCM and DEEC by subject codes 11634 and 12103, respectively. Therefore, in the case of a DDCM petition and linked DEECs, for both petitions to be analyzed according to the optimized procedure, a company must make the request in parallel and individually for each of the petitions (codes 12102 and 12104), including for each related secondary petition, if applicable. 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 based on 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).”
• 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)) should be submitted electronically. ResNo947 also notes that documents to be filed with ANVISA must be submitted exclusively electronically 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, and BRA-58 explain that when the DDCM has been submitted, the sponsor is then required to electronically file all the documents corresponding to the initial DDCM petition’s subject code checklist. As described in BRA-75, the sponsor must electronically attach all the documents required in the related DDCM checklist (accessed online via BRA-56) that corresponds to one (1) of the following related subject codes: 10748, 10749, 10750, 10751, 10752, 10753, 10754, and 10755. ResNo945 also specifies that the documentation presented must allow for textual searches, copying, and contain bookmarks and hyperlinks that facilitate navigation. Refer to BRA-47 and BRA-59 for instructions for submitting the DDCM checklist documents via BRA-56. Additionally, per the G-DDCMManual, for DEEC petition electronic submissions, one (1) file needs to be attached for each item contained on the corresponding checklist. DEECs can be submitted to ANVISA using one (1) of the following subject codes: 10482, 10479, 10476, 10773, 10483, 10478, 10477, 10774. See the G-DDCMManual and BRA-47 for additional DEEC petition submission instructions. See also ResNo947 for 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)) fees. ResNo857 explains that petitions subject to TFVS will only be eligible for filing after confirmation of full corresponding payment. Once the full TFVS payment is confirmed, the electronic petitions will be automatically filed. (See the Regulatory Fees section for detailed information on the payment process.)

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

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

BRA-59 explains that once the fee is paid, a reference (transaction) number is generated that will be required for the subsequent submission of the associated checklist documents. The processing of this request can take up to two (2) days, which is the time given to the banking network to clear the payment. Refer to BRA-59 for additional instructions. See also BRA-47 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition 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 investigator’s brochure) 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.

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

In addition, per ResNo763, which modifies ResNo205, ANVISA has suspended the requirement for the sponsor to hold a pre-submission meeting to present a rare disease DDCM or amended DDCM. The pre-submission meeting is optional, if the sponsor deems necessary, and ANVISA should hold the meeting within 60 days following this request. Refer to ResNo205 and ResNo811 (which partially amends ResNo205) for additional submission documentation requirements.

Ethics Review Submission

National Research Ethics Authority

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, including any amendments.

National Research Ethics Commission (CONEP)

Per ResNo466 and OSNo001, the PI must obtain approval from the EC (CEP). The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional EC (CEP) 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.

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

Overview

In accordance with the LibCTReg and the G-LibClinTrial, the sponsor, the legal representative, the principal investigator (PI), or the sponsor-investigator is responsible for submitting 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). 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, and 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 identifying the clinical trial, the sponsor (applicant) and must include 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), and the new version of the documents identified should include an updated version number and date. Also, the submitted document should clearly present scientific arguments justifying classification of an 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

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 by hard copy to the NREB. The documents should be formatted in standard font size 12, double-spaced, with the pages printed on one (1) side only. The NREB requires 15 comb-bound copies of the full 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. In addition, all protocols must 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 complete application for ethical review and approval of a proposed health research study should be submitted by a PI to the NREB Secretariat. Applicants should submit the application 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, corresponding ethics approval, consent or assent forms, and data collection tools and forms. In addition, along with the usual documents for review (protocols, CVs, Human Subject Certificates, Good Clinical Practice, etc.), the following must be submitted:

• A collaboration letter (in the form of a memorandum of understanding) 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 study sponsor
• Data-sharing and material transfer agreements for data and biological materials, especially if samples will be exported out of the country, ensuring 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, ensuring 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 Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) submission form (see Article XXV in the G-ACRE-IRB). (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.) 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

Proposals submitted electronically should be sent to jktegli@yahoo.com and ulpireirb@gmail.com.

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 (Dossier 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)
• Declaration of commitment to distribute to clinical trial centers and use investigational products (IPs) only after authorization from the corresponding DDCM and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)), when import is authorized prior to publication of the approval/rejection in the Official Gazette of the Union (Diário Oficial da União (DOU))
• 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 authorization from DDCM and corresponding initial and subsequent DEEC(s). This document should only be attached to the DDCM if the sponsor is interested in receiving the Import Document (DI) prior to the DDCM's analysis and approval. If the company has attached this to the DDCM, the DI will be issued for early importation both for the initial DEECs submitted together with the DDCM, and for the clinical trials submitted after the approval of the DDCM.

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 the linked specific clinical trial processes for an 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. 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)

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 (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025)
• Statistical analysis plan (PAE), at least in draft version, in the case of phase 3 clinical trials and adaptive clinical trials
• Opinion of any country/region's scientific advisory board, if any, on the clinical trial
• Pediatric investigation plan of any country/region, if any
• Sample investigational drug label
• Proof of registration of the clinical trial, in the same version of the clinical protocol submitted to ANVISA, in the registration database of 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.); and, if proof of registration is not available at the time of DEEC submission, it must be submitted together with the notification of commencement of the clinical trial.)

Substantial IP Modifications

Per ResNo945 and the G-DDCMManual, for substantial modifications of the IP, the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM. ResNo945 states that the petition for substantial IP modification must contain a copy of the previously approved IMPD or Investigational Product Dossier (DPI), containing the proposed modifications highlighted (track-changes format) and a table comparing the current situation with the proposed changes, the justifications for each change, and the assessment of the impacts of the modifications on clinical development. ResNo945 and the G-DDCMManual also indicate that if there is a GMP certificate or equivalent document for the IP, it must be attached to the petition for substantial IP modification. In addition, the Petition Form for Substantial Modification to the Product under investigation (BRA-127) and other information in accordance with each proposed modification must be attached to the petition. See the G-DDCMAmdmts for detailed submission instructions.

ResNo945 also indicates that 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 report (DSUR), whichever occurs first.

Substantial Protocol Amendments

As per ResNo945 and the G-DDCMManual, petitions for substantial amendments to clinical trial protocols must also be filed electronically as a secondary petition linked to the corresponding DEEC. ResNo945 further indicates that the petition must contain a 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, the justifications for each change and the assessment of the impacts on clinical development. In addition, clean and track changes versions of the updated Clinical Trial Submission Form (FAEC) (BRA-22) must be attached to the petition, along with the new clean version of the clinical protocol. See the G-DDCMAmdmts for detailed submission instructions for protocol amendments. See also BRA-125 for the Substantial Amendment to Clinical Trial Protocol form.

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 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.

Optimized Analysis Procedure (Reliance) Submissions

Pursuant to ResNo945, to comply with the documentation requirements for the optimized analysis procedure by Reliance, the sponsor must present official proof issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) regarding the clinical protocol approval or clinical protocol amendment, or, official proof of the DDCM or substantial IP modification of the IMPD or Investigational Product Dossier (DPI). In the absence of this official document, a declaration signed by the sponsor's legal and technical representatives 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. Among the documents required for the instruction of each type of petition, the optimized analysis procedure based on risk assessment may be applied to the documents listed below:

• IB, when dealing with the risk categories defined in the low-risk clinical trial categories for medicine used as registered in Brazil or by an AREE, without substantial modifications; and fixed-dose combinations with registered active pharmaceutical ingredients 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, when dealing with low-risk clinical trial categories and moderate risk clinical trial categories for new therapeutic indication, and/or target population, and/or dosage regimen

RegNo338 further indicates that ANVISA will review the following documents based on the optimized analysis procedure by Reliance:

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

See also BRA-124 for the Form for Declaration of Compliance with the Requirements for the Admissibility of the Optimized Analysis Procedure by Regulatory Trust (Reliance) to be completed by the sponsor’s legal representative or technical manager.

See also BRA-42 for additional information on ANVISA protocol filing requirements.

Ethics Committee Requirements

National Research Ethics Authority

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 EC (CEP)/National Research Ethics Authority submission documentation requirements.

National Research Ethics Commission (CONEP)

As per OMREC and OSNo001, the CONEP requires sponsors to submit the following documentation online via BRA-34 (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

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

As per the LibCTReg and the G-LibClinTrial, the following documentation must be submitted to the 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 procedure for clinical trials in humans
• Product information if the IP is registered (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
• Copy or copies of recruitment advertisement(s), if applicable, and questionnaires
• Investigational medicinal product (IMP) dossier, if applicable
• Product information and certificate of analysis (CoA) for the 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 language
• CoA of the IP(s)
• Certificate(s) of accreditation for the central laboratories
• Workload forms for investigators
• Signed declaration by the applicant (includes 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 (Phase I, II, and III)
• 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 thereof if the medicines are not registered in Liberia
• Registered IPs should include 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, 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

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
• Material Transfer Agreement (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 sponsors of the study
• 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 (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• 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. Accordingly, LBR-8 requires the following protocol contents:

• General information (protocol title, identifying number, and date; contact information for the sponsor, medical expert, investigator(s), trial site(s), qualified physician(s), and laboratory and/or institutions involved in the study)
• Background information
• Objectives and purpose
• Trial design
• Selection, withdrawal, and treatment of participants
• Assessment of efficacy
• Assessment of safety
• A description of the statistical methods to be used in the trial
• Direct access to source data and documents
• Quality control and quality assurance
• Ethical considerations
• Data handling and recordkeeping
• Publication policy

In addition, as indicated in the G-LibClinTrial, the protocol should contain a statement 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 PI to document the investigator’s and sponsor’s 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 provided 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 can 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’s analysis of the primary petitions for clinical trials with human beings (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento de Medicamentos Clínicos (DDCMs))) must be completed within 90 business days. If no response is provided after regular receipt of the primary DDCM petition, clinical development may be initiated, provided that it contains the relevant ethical approvals. ResNo945 further specifies that upon receipt of the primary DDCM and the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions, ANVISA has 90 business days, counting from the date of issuance of the DEEC document, to evaluate the application. If the agency fails to issue a response within 90 days of receipt, the DDCM and respective DEEC will be released after the deadline, and clinical development can begin after the relevant ethical approvals have been obtained. The 90-day deadline also applies to primary petitions for new DEECs subsequently linked to the DDCM, and to secondary petitions for substantial modifications to the investigational product (IP) and substantial amendments to the clinical protocol. See Scope of Assessment section for detailed DDCM and DEEC submission requirements.

Additionally, per ResNo945, ANVISA’s analysis of the DDCM will only occur after the filing of at least one (1) DEEC, which must be carried out within 15 business days from the DDCM’s issue date. The absence of the DEEC, after the 15-day deadline, will result in the rejection of the DDCM without technical analysis, except in cases of clinical trials involving more than one (1) investigational product (IP), whose DEEC has already been linked to one of the DDCMs of these drugs.

LawNo14.874 and ResNo945 further explain that ANVISA may request, one (1) time only, by means of a technical requirement, additional clarifications and documents during the analysis of primary DDCM and DEEC petitions and secondary petitions for substantial IP modification or substantial clinical protocol amendment. ANVISA’s technical requirement will result in the suspension of the analysis deadlines, and its interruption is prohibited. ResNo945 also notes that the deadline for the sponsor’s compliance with this technical requirement is 30 business days, counting from the date of confirmation of receipt by ANVISA.

In addition, per BRA-122, petitions submitted to request an ANVISA evaluation using the optimized analysis procedure based on regulatory trust practices (Reliance) that have not been analyzed within ANVISA’s 90-day deadline, will be released due to the expiration of the term in accordance with ResNo945 and LawNo14.874. The petitions will have their status 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.

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

Priority Submissions

As delineated in ResNo204, ANVISA is required to issue a final decision on applications for registration and post-registration of drugs classified as a priority within 120 days for new drug registration requests and in 60 days for post-registration petitions. The deadlines will be counted from the date of submission, and any requests for clarification or additional technical requirements will result in suspending the counting of deadlines until the requests have been met. See also BRA-40 for additional information on ANVISA drug registration requirements.

In addition, per ResNo204, ANVISA must first issue a written opinion letter within 45 calendar days from the first working day following protocol submission for priority petitions in the following categories:

• Prior consent petitions in the clinical development dossier process
• Prior consent petitions in the drug research process
• Secondary petitions referring to the prioritized primary process

Refer to ResNo204 and ResNo811 (which partially amends ResNo204) for detailed information on DEEC submissions.

In addition, as set forth in ResNo205, for a clinical trial with medicines for rare diseases to be conducted in Brazil, ANVISA must evaluate a DDCM, DEEC, or substantial modification due to inclusion of a clinical trial protocol within 30 days after submission, 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 also ResNo811 (which partially amends ResNo205) and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.

Ethics Committee Approval

New National System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings. The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the ECs (CEPs), which must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

National Research Ethics Authority

As set forth in LawNo14.874, the EC (CEP) must conduct a research ethics review and issue an opinion within 30 business days from the date of acceptance of all research documents. The EC (CEP) must accept or deny these documents within 10 business days from the date of submission. Additionally, before issuing the opinion, the EC (CEP) may request additional information or documents from the investigator or research sponsor or make adjustments to the research documentation, for up to 20 business days. The investigator will have 10 working days, extendable for an additional 10 working days upon justification, to meet the demands requested by the EC (CEP), and the study analysis process may be canceled in case of non-compliance with the deadline.

LawNo14.874 further explains that the decision contained in the EC (CEP)’s opinion may be appealed, in the first instance, within 30 business days, to the EC (CEP) itself that issued the opinion, and in the second and final instance, within 30 business days, to the National Research Ethics Authority. The appeals provided will be decided by the National Research Ethics Authority 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, the EC (CEP) opinion regarding research of strategic interest to the Ministry of Health (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 research documents.

National Research Ethics Commission (CONEP)

As delineated in OSNo001 and BRA-91, the institutional EC (CEP) is required to issue an initial report in 30 days from the date the principal investigator (PI) submits an application for review. The CEP’s review of the protocol documentation for completeness should be accomplished within 10 days following submission. Per BRA-91, the review period must be counted from the date the project entered “Ethical Assessment” (i.e., after going through the validation of documents which takes around 10 days and when the Certificate of Presentation for Ethical Assessment (Certificado de Apresentação de Apreciação Ética) (CAAE)) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment. If these deadlines have expired, BRA-91 further suggests that the investigator responsible for the research project, contact the CEP to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation. 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 to CONEP itself. From an analysis of the resources submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal, the processing of the appeal is terminated, the research protocol is archived, and no other appeal requests will be permitted.

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 indicate that 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.

The LibCTReg and the G-LibClinTrial further explain that after validation of a complete clinical trial application, the LMHRA must inform the applicant in writing about the outcome of the scientific assessment of the application within a maximum of 60 working days, or according to the following timeline for the different types of investigational products (IPs), unless otherwise specified by the LMHRA on a case-by-case basis:

• Pharmaceutical IPs: 45 working days
• Biological and biotechnology IPs: 60 working days
• Genetically modified organism IPs: 90 working days

As indicated in the LibCTReg and the G-LibClinTrial, 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. Per the G-LibClinTrial, during the clinical trial scientific assessment process, the LMHRA may 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, 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, the LMHRA must issue a clinical trial certificate indicating 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 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 in 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

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 given 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 Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) four (4) weeks in advance of the date that a decision is requested. (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.) 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.

As specified in the G-ACRE-IRB, the ACRE IRB 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. 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.

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

New National Ethics System of Ethics in Research with Human Beings

LawNo14.874 introduces the National System of Ethics in Research with Human Beings. The system consists of the Ministry of Health (MOH)’s National Research Ethics Authority and the research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). The ECs (CEPs) must be accredited by the National Research Ethics Authority. In this framework, the ECs (CEPs) are solely responsible for the ethical review of clinical trial protocols involving human participants. During the transition to the new system, the current National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) system will continue to be implemented and described in this profile. The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

In accordance with ResNo945 and the G-DDCMManual, a clinical trial can only commence after the sponsor, the designated contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or the sponsor-investigator receives clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). According to LawNo14.874, ResNo945, ResNo466, and OSNo001, research involving human beings is also subject to prior ethical analysis by research ethics committees (ECs) (Comitês de Ética em Pesquisa (CEPs)). ResNo945 states that a drug clinical trial may only be initiated after approval is obtained by both the EC (CEP) and 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 National Research Ethics Authority 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).

Per BRA-65, Brazil is a member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). ResNo945 indicates that Brazil has formally adopted the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025.) ResNo945 and the G-DDCMManual also specify that clinical trials should be conducted in compliance with 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 forms indicating the start and end date of the clinical trial in Brazil must be filed as a secondary petition to the corresponding Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) process, within 30 business days after each start and end date. (See Clinical Trial Start Date Form in Brazil (BRA-25)).

Clinical Trial Agreement

As per LawNo14.874, the sponsor is responsible for establishing the contract between the parties involved in the research. Prior to initiating the trial, as described in BRA-28, the sponsor must sign an agreement between all involved parties, including between the investigators, the institution, the EC (CEP), and the CRO, to ensure full compliance with the regulatory requirements. In addition, the sponsor should obtain the investigator’s/institution's agreement:

• To conduct the trial in compliance with GCP, with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC (CEP)
• To comply with procedures for data recording and reporting
• To permit monitoring, auditing, and inspection
• To retain the trial-related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement. 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 has developed a clinical trials search tool to obtain detailed information about scientific/academic research or clinical trials authorized by the agency to support the registration of medicines since 2015. The Clinical Trials (Ensaios Clínicos) tool may be accessed via ANVISA’s Consultation System webpage (BRA-44), which 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.

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, in turn, 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 for approval of the clinical trial and the permit to import the IP is possible 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 signed 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, the AESafetyManual, and CLNo13, the following definitions provide a basis for a common understanding of Brazil’s safety reporting requirements (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Adverse Event/Experience (AE) – Any adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
• Adverse Drug Reaction or Adverse Reaction (ADR) – 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 investigational product (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 to the sponsor, the health authority, the research ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)), and the National Research Ethics Authority all serious or unexpected AEs. ResNo945, the G-SUSARs, and the AESafetyManual 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 the 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 communicating to the sponsor the occurrence of all AEs. 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. The AESafetyManual further states the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the EC (CEP) with any additional requested information (e.g., autopsy reports and terminal medical reports).

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.

Sponsor Responsibilities

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

• Promptly notifying the investigator, the institution, the competent ethical review entities, and 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 investigator’s brochure (IB), amendments, reports, or early termination of the clinical trial. The G-SUSARs further notes that, as a joint action to submit SUSAR notifications, 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. While the IB is not updated, it is necessary to notify additional occurrences (follow-ups) of SUSARs to ANVISA. (See Quality Requirements section for detailed IB requirements)

ResNo945 and the G-SUSARs also state that if there is a possibility that an event may be a SUSAR, the sponsor must break the blinding for notification to ANVISA, and the break must only be in relation to the designation of the participant who was affected by the SUSAR. Where possible, the blinding should be preserved to 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 in question and 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 states 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 (referred to as fatal or life-threatening SAEs/SADRs by the AESafetyManual) 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 and the AESafetyManual, 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.

Per the AESafetyManual, AEs/ADRs and SAEs/SADRs do not need to be reported to ANVISA under the above timelines when they occur outside of Brazil or are defined in the protocol as a primary or secondary outcome. Additionally, SAEs/SADRs that are categorized as Unlikely, Conditional/Unclassified, or Unassessable/Unclassifiable do not need to be reported under the above timelines. The sponsor should classify all AEs/ADRs and SAEs/SADRs according to the World Health Organization’s Uppsala Monitoring Centre (WHO-UMC)’s standardized causality assessment system (BRA-31). The recommended criterion to categorize each event is as follows: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and Unassessable/Unclassifiable.

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. ResNo945 explains that safety information originating from other countries where clinical development is taking place must be communicated to the 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. The G-SUSARs also notes that information about the late AEs can become part of the IP safety profile. See ResNo945 and the G-SUSARs for additional safety monitoring requirements.

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.

Ethics Committee Responsibilities

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

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

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

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

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

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

Other Safety Reports

As described in ResNo945, the G-SUSARs, and the AESafetyManual, Drug Development Safety Reports (DSURs) must be sent annually to ANVISA, until the end of the clinical development of the IP in Brazil. The DSURs must be filed within a maximum of 60 calendar days of the yearly anniversary of the date that ANVISA approves the clinical trial application (DDCM), or the date determined in the international development. 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 at any time, 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.

Per BRA-37, sponsors of clinical trials that have not yet been registered with VigiMed 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-85 for VigiMed Frequently Asked Questions (FAQs).

Safety Reporting Definitions

According to the LibCTReg, the G-LibPV, and the G-ACRE-IRB, 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, 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 National Research Ethics Board of Liberia (NREB). Per the G-LibClinTrial, in the case of multicenter trials involving clinical trial sites (in 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.

The G-LibPV provides the following scale by which to assess the severity of AEs/ADRs: Mild, Moderate, Severe, or Fatal. For more details, see Table 2 in G-LibPV. The G-LibPV also provides criteria for determining the link between the intervention and the AEs/ADRs as either certain, probably/likely, possible, unlikely, conditional/unclassified, or un-assessable/unclassified. For more details, see Table 3 in G-LibPV.

Investigator Responsibilities

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

As indicated in the G-ACRE-IRB, for studies using the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB), the investigator must promptly report any unanticipated problems to the ACRE IRB in accordance with the following guidelines (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• 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

In addition, per the G-ACRE-IRB, when making a report to the ACRE IRB, the investigator should include the following information:

• The appropriate identifying information for the research protocol, such as the title, the investigator’s name, and the ethics committee (EC) project number
• A detailed description of the AE, incident, experience, or outcome; however, to maintain confidentiality, participants’ names and identifiable information should not be included in the report
• An explanation of the basis for determining that the AE, incident, experience, or outcome represents an unanticipated problem
• A description of any changes to the protocol or other corrective actions that have been taken or are proposed in response to the unanticipated problem

Other Safety Reports

As explained in the G-ACRE-IRB, for studies using the ACRE IRB, the ACRE IRB Executive Committee conducts the initial review of unanticipated problems. This committee is authorized to take the following actions in response to any incident report:

• Conduct an administrative review of the report, including assessing whether the incident constitutes an unanticipated problem
• If a convened ACRE IRB review is needed, the Chair assigns the incident report for review at the next available regularly scheduled ACRE IRB meeting
• Alternately, the ACRE IRB Executive Committee may convene an emergency meeting of the ACRE IRB to review the report
• If the ACRE IRB Executive Committee finds that the rights, safety, and welfare of the participants are jeopardized by the research, the Chair may suspend the research until such time when the full ACRE IRB can convene to review the report. When reviewing a particular incident, experience, or outcome reported as an unanticipated problem by the investigator, the board may determine that the incident, experience, or outcome does not meet the criteria for an unanticipated problem

Following a review of the unanticipated problem report, per the G-ACRE-IRB, the ACRE IRB may require the following actions, in order to protect the ongoing safety of the research participants:

• Modification of participant inclusion or exclusion criteria to mitigate the newly identified risks
• Implementation of additional procedures for monitoring participants
• Modification of informed consent documents to include a description of newly recognized risks
• Addition of provisions about newly recognized risks to previously enrolled participants
• Suspension of enrollment of new participants
• Suspension of research procedures in currently enrolled participants
• Suspension of the entire study
• Termination of approval for the entire study

Per the G-ACRE-IRB, if the solution to an unanticipated problem is to amend the research protocol and/or informed consent forms, then an amendment request must be made to the ACRE IRB. If the changes are minor, they may be reviewed by expedited review procedures. If the changes are major, they must be reviewed and approved by the convened board. Changes made in response to an unanticipated problem must be reviewed and approved by the ACRE IRB before being implemented, except where implementation is necessary to eliminate immediate hazards to research participants.

Form Completion & Delivery Requirements

Liberia Medicines and Health Products Regulatory Authority

As per the G-LibPV, all SAEs/SADRs and SUSARs must be reported on the LMHRA’s Suspected Adverse Drug Reaction Reporting Form (Annex 3 in the G-LibClinTrial).

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.

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.

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 National Research Ethics Board of Liberia (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). As part of the country’s compliance with LBR-8, the investigator should submit written summaries of the trial status to the NREB annually, or more frequently, if requested by the board. The investigator should also promptly provide written reports to the sponsor, the NREB, and where applicable, the institution on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

Atlantic Center for Research and Evaluation Institutional Review Board

For clinical research studies using the Atlantic Center for Research and Evaluation Institutional Review Board (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. (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.)

As indicated in the G-ACRE-IRB, the following list provides the required documentation to submit a continuing review to the ACRE IRB:

• A completed Continuing Review form
• A copy of the current informed consent document(s) or any newly proposed consent document(s) if enrollment is ongoing
• A copy of current recruitment material(s) or any newly proposed recruitment material(s) if enrollment is ongoing
• A summary of adverse events and any unanticipated problems involving risks to participants
• Numbers of and reason for withdrawal of participants from the research
• A summary of any relevant information about risks associated with the research
• Number and demographics of participants enrolled
• Changes in the principal and/or associate investigator(s)
• A summary description of participant experiences
• Research results obtained thus far
• A current risk-benefit assessment based on the study results
• Any new information since the ACRE IRB’s last review

After the Secretary and the Coordinator have determined that the continuing review submission is complete, the documentation must be submitted to the ACRE IRB and reviewed by the convened board, or by the expedited reviewer(s), if necessary, for an expedited review.

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 adverse events reported by the PIs.

Per LBR-8, the investigator, where applicable, should inform the institution; the investigator/institution should provide the ethics committee with a summary of the trial’s outcome, and the regulatory authority (LMHRA) with any reports required.

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 adverse events 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 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 for submitting 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 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 LBR-8 and the 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.

LBR-8 and the LibCTReg also define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed. 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. LBR-8 further explains that although a sponsor may transfer responsibility for any or all of the sponsor’s obligations to a CRO, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. The sponsor should also ensure oversight of any trial-related duties and functions carried out on its behalf, including trial-related duties and functions that are subcontracted to another party by the sponsor’s CRO. Any trial-related responsibilities transferred to a CRO should be specified in writing. The CRO should implement quality assurance and quality control.

Overview

As set forth LawNo14.874 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the sponsor is responsible for selecting the investigator(s) and the institution(s) for a clinical trial. The sponsor must also ensure that the investigator(s) are qualified by education, training, and experience to assume responsibility for the proper conduct of the trial. BRA-28 also notes that the investigator(s) should provide evidence of all the qualifications specified by the applicable regulatory requirements through up-to-date curriculum vitae(s) (CVs) and/or other relevant documentation requested by the sponsor, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), and/or the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)).

As delineated in BRA-28, prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. See the Submission Content section for additional information on clinical trial application requirements. See also CLNo046 for the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidance on submitting requests for inclusion/exclusion of research center(s).

Foreign Sponsor Responsibilities

As specified in the 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

BRA-28 indicates that for multicenter trials, the sponsor should ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and, if required, by ANVISA, and given approval/favorable opinion by the EC (CEP)
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites. For investigators collecting additional data, supplemental CRFs should also be provided that are designed to capture the additional data
• The responsibilities of coordinating investigator(s) and the other participating investigators are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards for the assessment of clinical and laboratory findings, and completing the CRFs
• Communication between investigators is facilitated

Per BRA-28, the sponsor must also organize a coordinating committee or select coordinating investigators.

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. Per LBR-8, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial. Each investigator should be qualified by training and experience and should have adequate resources to properly conduct the trial for which the investigator is selected. LBR-8 also explains that the sponsor should utilize appropriately qualified individuals to supervise the overall conduct of the trial, to handle the data, to verify the data, to conduct the statistical analyses, and to prepare the trial reports.

As indicated in LBR-8, the investigator(s) should be qualified by education, training, and experience to assume responsibility for the proper conduct of the trial, should meet all the qualifications specified by the applicable regulatory requirement(s), and should provide evidence of such qualifications through up-to-date curriculum vitae (CV) and/or other relevant documentation requested by the sponsor, the ethics committee (EC), and/or the regulatory authority(ies) (see section 4 in LBR-8 for detailed investigator requirements).

As stated in the G-LibClinTrial, all investigators must be trained in good clinical practices (GCP) documented by the provision of training certificates not older than three (3) years 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 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 also 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 and 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.

Furthermore, per LBR-8, the sponsor should obtain the investigator's/institution's agreement to:

• Conduct the trial in compliance with GCP, the applicable regulatory requirement(s), and the approved protocol
• Comply with procedures for data recording/reporting
• Permit monitoring, auditing, and inspection
• Retain the trial related essential documents until the sponsor informs the investigator/institution these documents are no longer needed

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement.

Foreign Sponsor Responsibilities

No information is 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.

LBR-8 further indicates that the sponsor may consider establishing a DSMB (also known as an independent data monitoring committee (IDMC)) to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial. The DSMB should have written operating procedures and maintain written records of all its meetings.

Multicenter Studies

As delineated in LBR-8, in the event of a multicenter clinical trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor and are given EC approval
• The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
• Investigator responsibilities are documented prior to the start of the trial
• All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
• Communication among investigators is facilitated

Further, per LBR-8, if the organization of a coordinating committee and/or selection of coordinating investigator(s) are to be used in multicenter trials, their organization and/or selection are the sponsor's responsibility.

Insurance

As set forth in the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the sponsor is responsible for providing insurance or should indemnify the investigator/institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

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 research, 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 with regard to 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 prior material provision
• Other types of compensation required, depending on the research project

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

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

Post-Trial Access

Pursuant to LawNo14.874, before the start of the clinical trial, the sponsor and the investigator must submit a post-study access plan to the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), presenting and justifying the need or otherwise to provide free access to the investigational product (IP) after the trial’s completion. If there is a need to supply post-trial access to the IP, a post-study supply program must be prepared, in accordance with the regulations. In order to guarantee the receipt of the IP after the end of the clinical trial, the post-study supply program must ensure the continuity of the participant's safety monitoring. The program should only be initiated after regulatory approval, the request for which must be submitted in a timely manner so that the research participant can transition to the post-study period without prejudice to the continuity of treatment.

Additionally, per LawNo14.874, at the end of the clinical trial, the investigator, after hearing from the sponsor and the research participant, must carry out an assessment on an individual basis to determine the need to continue the IP for each participant. The free provision of the IP after the trial must be implemented whenever it is considered the best therapy or treatment for the participant’s clinical condition and presents a more favorable risk-benefit ratio in comparison with other available treatments. The assessment of the need for continued supply of the IP 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-study 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
• 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.

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

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. ResNo311, which amends 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-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (CNS)). The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Study Medicine Supply Programs (see 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-study 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 protecting the LMHRA from liability related to an injury or an adverse event which may be sustained by a person, directly or indirectly, as a result of the conduct of the trial and which occurs or reveals itself at the time of the trial or subsequently.

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.

Per LBR-29, both clinical trial insurance and indemnification certificates must be included in the clinical trial application dossier in accordance with the African Vaccine Regulatory Forum (AVAREF)’s Clinical Trial Application Checklist (LBR-1). According to LBR-4, the AVAREF was established by the World Health Organization (WHO) in 2006 to promote the harmonization of ethics and regulatory processes in Africa.

In addition, per the G-LibClinTrial, under certain circumstances, the Liberia Medicines and Health Products Regulatory Authority (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. LBR-8 states that if required by the applicable regulatory requirement(s), the sponsor should provide insurance or should indemnify (legal and financial coverage) the investigator/the institution against claims arising from the trial, except for claims that arise from malpractice and/or negligence.

Compensation

Injury or Death

Per LBR-8, the sponsor or the representative is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries or death.

LBR-8 states that the sponsor's policies and procedures should address the treatment costs of trial participants in the event of trial-related injuries, and when trial participants receive compensation, the method and manner of compensation should comply with applicable regulatory requirement(s). According to LBR-29, the LMHRA does not have a compensation committee.

In addition, per the LibCTReg, any person(s), institution(s), corporate entity(ies), their designees, or legal representative(s) who does not provide insurance coverage for prospective participants as required, and in the course of the research bodily injury or substantial harm results, the person(s), institution(s), corporate entity(ies), their designees, or legal representative(s) commits a first degree misdemeanor consistent with the PenalLaw. The PenalLaw states a person commits a misdemeanor of the first degree if the person recklessly engages in conduct which creates a substantial risk of death or serious bodily injury to another.

Pursuant to Part VIII of the LMHRA-Act, the LibCTReg also specifies that the principal investigator 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 that results in the death of a participant during the conduct of a clinical trial must constitute negligent homicide consistent with the PenalLaw which states that a person is guilty of negligent homicide if the person causes the death of another human being negligently; negligent homicide is a felony of the third degree.

Trial Participation

Per LBR-8, the participant should be provided with information regarding any anticipated prorated payment, if any, for participating in the trial.

Quality Assurance/Quality Control

As set forth in LawNo14.874 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil adopted per ResNo945, the sponsor is responsible for the implementation and maintenance of quality assurance (QA) and quality control (QC) systems, based on standard operating procedures (SOPs), in order 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, with a view to ensuring its reliability and correct processing; 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). Per BRA-28, the CRO should also implement a QA/QC plan.

As delineated in BRA-28, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

• During protocol development, identifying risks to critical trial processes and data
• Identifying risks to critical trial processes and data
• Evaluating the identified risks against existing risk controls
• Deciding which risks to reduce and/or which risks to accept
• Documenting quality management activities and communicating to those involved in or affected by these activities
• Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• Describing in the clinical study report, the quality management approach implemented in the trial and summarizing important deviations from the predefined quality tolerance limits and remedial actions taken

In addition, BRA-28 states that the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. See the Initiation, Agreements & Registration section for additional information on sponsor agreements with investigator(s), institution(s), and any other parties.

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 quality assurance and monitoring.

Monitoring Requirements

As part of its QA system, BRA-28 notes that the sponsor or the CRO should ensure the trial is adequately monitored and determine the appropriate extent and nature of monitoring, based on considerations such as the objective, purpose, design, complexity, blinding, size, and endpoints of the trial. Monitors, which are appointed by the sponsor, should be appropriately trained, and have the scientific and/or clinical knowledge needed to monitor the trial adequately. A monitor’s qualifications should be documented.

BRA-28 also explains that if or when the sponsor performs audits as part of implementing QA, the following should be considered:

• The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, GCP, and other applicable regulatory requirements
• The sponsor should appoint auditors to review the clinical trial who are independent of the clinical trial/data collection system(s)
• The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented
• Auditing procedures that ensure the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written SOPs
• The auditor’s observations and findings should be documented

LawNo14.874 also 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, and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)); allowing the sponsor to monitor and audit the research; and allowing ANVISA, the National Research Ethics Authority, and the EC (CEP) to conduct inspections.

BRA-28 does not provide a specific timeframe for the audit process. Regulatory authorities may seek access to an audit report on a case-by-case basis when evidence of serious GCP noncompliance exists, or in the course of legal proceedings. Additionally, noncompliance with the protocol, SOPs, GCP, and/or applicable regulatory requirement(s) by an investigator/institution or member(s) of the sponsor’s staff should lead to prompt action by the sponsor to secure compliance. If the monitoring and/or auditing identify serious and/or persistent noncompliance on the part of an investigator/institution, the sponsor should terminate the investigator’s/ institution’s participation in the trial. When an investigator’s/institution’s participation is terminated because of noncompliance, the sponsor should notify the regulatory authorities promptly. Refer to BRA-28 for detailed audit requirements.

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.

ANVISA has also published GuideNo35-2020 and GuideNo36-2020 to provide guidance on the procedures for conducting GCP inspections in clinical trial centers, and provide guidance for sponsors and CROs respectively for clinical trials involving medicines and biological products. Both guides describe ANVISA’s compliance with the GCP inspection requirements set forth in RegNo122 with the goal of guiding those involved in the inspection procedures to ensure a unified standard and the safety of all involved parties.

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.

Premature Study Termination/Suspension

Pursuant to LawNo14.874, the sponsor is responsible for promptly communicating to the investigators involved, the executing institution, and ANVISA regarding the reasons for the suspension or premature termination of the research, where applicable. ResNo945 further explains that, at any time, the sponsor may 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 clinical trial has 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. If a DDCM or clinical trial is canceled for safety reasons, the sponsor must describe the reasons for the cancellation and present the measures to minimize/mitigate risk to the clinical trial participants in compliance with the requirements detailed in the AESafetyManual. 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, 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 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.

BRA-28 also explains that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigators/institutions, and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The EC (CEP) should be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). Additionally, if the investigator terminates or suspends a trial without the sponsor’s prior agreement, the investigator should inform the institution where applicable, and the investigator/institution should promptly inform the sponsor and the EC, and should provide the sponsor and the EC a detailed written explanation of the termination or suspension.

Quality Assurance/Quality Control

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. Per LBR-8, sponsors are responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol.

Per LBR-8, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:

• During protocol development, identifying processes and data that are critical to ensure participant protection and the reliability of trial results
• Identifying risks to critical trial processes and data
• Evaluating the identified risks against existing risk controls
• Deciding which risks to reduce and/or which risks to accept
• Documenting quality management activities and communicate to those involved in or affected by these activities
• Periodically reviewing risk control measures to ascertain whether the implemented quality management activities are effective and relevant
• In the clinical study report, describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken (Refer to the ICH’s Structure and Content of Clinical Study Reports (E3) guidelines (LBR-37))

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.

Monitoring Requirements

Per LBR-8, if or when sponsors perform audits as part of implementing quality assurance, they should consider the following:

• The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, good clinical practice (GCP), and applicable regulatory requirements
• The selection and qualification of auditors who are independent of clinical trials/systems to conduct audits; the sponsors should ensure the auditors are qualified by training and experience to conduct audits properly and have appropriate qualifications that should be documented
• Auditing procedures that ensure the auditing of clinical trials/systems is conducted in accordance with the sponsor’s written procedures on what to audit, how to audit, the frequency of audits, and the form and content of audit reports

In addition, per LBR-8, the sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).

Refer to LBR-8 additional audit procedure details.

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. LBR-8 further explains that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigator(s)/institution(s) and the regulatory authority(ies) of the termination or suspension and the reason(s) for the termination or suspension. The ethics committee (EC) should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor or by the investigator/institution, as specified by the applicable regulatory requirement(s). Additionally, according to LBR-8, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the sponsor should promptly inform the EC and provide the reason(s) for the termination or suspension.

Electronic Data Processing System

As set forth in the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, when using electronic trial data processing systems, the sponsor must ensure that the system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human participant protection and reliability of trial results. In addition, the sponsor must maintain standard operation procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. The responsibilities of the sponsor, investigator, and other parties should be clear, and the system users should be provided with training. Refer to BRA-28 for additional information.

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. ResNo945 and BRA-28 also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, or a marketing application receives the last approval. Per BRA-28, the sponsor should also inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

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

Electronic Data Processing System

As 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.

As per LBR-8, when using electronic trial data processing systems, the sponsor must ensure that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. Sponsors should base their approach to validate such systems on a risk assessment that takes into consideration the intended use and the potential of the system to affect participant protection and reliability of trial results. In addition, sponsors should maintain standard operation procedures (SOPs) for the systems that cover system setup, installation, and use. The responsibilities of the sponsor, investigator, and other parties should be clear, and the system users should be provided with training in their use. Refer to LBR-8 for additional information.

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.

As set forth in LBR-8, the sponsor should inform the investigator(s)/institution(s) in writing of the need for record retention and should notify the investigator(s)/institution(s) in writing when the trial related records are no longer needed. Sponsor-specific essential documents should be retained for at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the investigational product’s clinical development. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

In addition, LBR-8 states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial. Per LBR-8, the sponsor should ensure the protocol or other written agreement specify that the investigator(s)/institution(s) provide direct access to source data/documents for trial related monitoring, audits, ethics committee review, and regulatory inspection.

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 Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB), the ACRE IRB must retain all relevant records (e.g., study documents specific to board activities and administrative documents related to ACRE IRB internal operations) per the following timelines (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the National Research Ethics Board of Liberia (NREB) and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• All records regarding a research application (regardless of whether it is approved) must be retained for at least three (3) years
• All records regarding all applications that are approved, and the research initiated must be retained for at least three (3) years after completion of the research
• Denied applications will be treated as terminated files and records must be retained for three (3) years after the denial of the research

The G-ACRE-IRB further explains the 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 of 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

For the purposes of data protection requirements, the LGPD delineates that the sponsor acts as the “controller” who is responsible for decisions regarding the processing of personal or sensitive personal research data. Within this context, the controller (sponsor) may carry out studies as a research body, guaranteeing, whenever possible, the anonymization of personal data.

Per CD-ANPD-No18, which regulates the performance of the person responsible for processing data, the person in charge is appointed by the controller and operator to act as a communication channel between the controller, data subjects, and the National Data Protection Authority (Autoridade Nacional de Proteção de Dados (ANPD)). The person in charge may be a natural person, member of the organizational structure of the processing agent or external to it, or a legal entity, and must be able to communicate with the holders and with the ANPD, clearly, 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. See also BRA-116 and BRA-119 for additional information.

Data Protection

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

Pursuant to the LGPD, the controller may implement a privacy governance program that, at a minimum:

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

See the LGPD and BRA-76 for detailed information on data protection requirements in Brazil.

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

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

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

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

In the event of a security incident, per CD-ANPD-No15, the controller must communicate to the ANPD and the data holder the occurrence of a security incident that could cause significant risk or damage to the holders in compliance with Article 48 of the LGPD. CD-ANPD-No15, which defines a security incident as any confirmed adverse event, related to the violation of the confidentiality, integrity, availability, and authenticity properties of personal data security, 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, establishes the procedures and rules applicable to international data transfer operations for countries or international organizations that provide a level of personal data protection adequate to that provided for in the LGPD, upon recognition of adequacy by the ANPD; or, when the controller verifies compliance with the principles, rights of the holder, and the data protection regime in the form of specific contractual clauses for a given transfer; standard contractual clauses; or global corporate standards as provided for in the LGPD and CD-ANPD-No19. Refer to Chapter V of the LGPD, CD-ANPD-No19, and BRA-118 for detailed international data transfer requirements.

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 the 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 available related to responsible parties for personal data protection.

Data Protection

No information is available related to data protection.

Consent for Processing Personal Data

As stated in the LibCTReg, the clinical trial participant must be informed of the purpose and scope of the collection and use of personal data, especially medical data. The trial participant must be informed especially of the fact that where necessary, the collected data should be:

• Kept available for inspection by the Liberia Medicines and Health Products Regulatory Authority (LMHRA) or for monitoring or auditing by the sponsor in order to verify the proper conduct of the clinical trial
• Be passed on to the sponsor and the LMHRA without disclosing the identity of the trial participant

Obtaining Consent

In all Brazilian clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in LawNo14.874 and ResNo466. Per LawNo14.874 and OMREC, the informed consent form (ICF) is known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.

As per LawNo14.874, the ResNo466, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by a research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). CLNo51 further clarifies that the ICF should be written as an invitation rather than as a statement as this may reduce the participant’s autonomy. Refer to CLNo51 for detailed information. See the Required Elements section for details on contents to be included in the form.

LawNo14.874, OMREC, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, state that the investigator, or their designated representative, must fully inform the participant or the legal representative/guardian of the relevant aspects of the research, including the EC’s (CEP)’s approval. As delineated in LawNo14.874, ResNo466, OMREC, the G-ClinProtocols-FAQs, and BRA-28, the ICF content should be presented in clear and objective language that is easy to understand to ensure the participant or the legal representative(s)/guardian(s) completely understands the research. Per BRA-28, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. Further, per LawNo14.874 and BRA-28, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive their legal rights, or, per BRA-28, that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. Per LawNo14.874, the research participant or their legal representative/guardian may withdraw their consent at any time, regardless of justification, without any burden or loss being incurred. ResNo466 further notes that the investigator must bear in mind that the prospective participant’s ability to understand the information required to give consent depends on their maturity, ethics, intelligence, education, and cultural beliefs. Per LawNo14.874, the G-ClinProtocols-FAQs, and BRA-28, the information should be in both written and oral form. Also, per the G-ClinProtocols-FAQs and BRA-28, the participant and the legal representative/guardian should also be given adequate time to consider whether to participate. See BRA-29 for additional information on informed consent.

Re-Consent

According to LawNo14.874 and BRA-28, the ICF must be updated and submitted for EC (CEP) consideration whenever new relevant information arises that could alter the research participant’s decision regarding their participation. CLNo17 also notes that the EC (CEP) should approve any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits before such changes are implemented. Per BRA-28 and CLNo51, the investigator must ensure that the participant or legal representative/guardian sign the revised ICF and any other updated information. CLNo17 further notes that changes made to the ICF through separate documents are not considered acceptable. The update requires the investigator to generate a single and complete version of the new document, free of addenda and/or other documents associated with it. The investigator or their delegated representative should also emphasize the changes contained in the updated ICF. The clarifications delineated in CLNo17 also apply to assent forms.

Language Requirements

As earlier stated, LawNo14.874, ResNo466, the G-ClinProtocols-FAQs, and BRA-28 require the ICF to be presented orally and in writing at a level that the participant is able to understand. The G-ClinProtocols-FAQs further notes that the ICF must be adequately adapted and be fully revised in Portuguese to ensure that the document is properly translated.

Documenting Consent

LawNo14.874, BRA-28, and OMREC state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. In addition, LawNo14.874 and BRA-28 explain that if the participant or legal representative/guardian is illiterate, an impartial witness should be present throughout the informed consent process. At this time, the participant or legal representative/guardian will give verbal, and, if possible, written consent, and the witness should sign and date the form, certifying that the written information was explained accurately and understood.

Before participating in the study, per OMREC, the participant should receive a copy of the signed and dated ICF, and any other written information provided during the informed consent process. ResNo466 and the G-ClinProtocols-FAQs specify that two (2) original copies of the ICF should be prepared with all pages initialed and signed by the participant or legal representative/guardian, and the investigator(s) or person(s) overseeing the consent process.

Waiver of Consent

No information is available on consent waivers for research participants. See the Consent for Specimen section for information on waivers pertaining to a participant’s stored genetic materials.

Obtaining Consent

In accordance with 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 the LMHRA guidelines. Per LBR-8, a freely given informed consent must be obtained from every study participant prior to clinical trial participation. According to the G-ACRE-IRB, the G-NREB, and LBR-8, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an ethics committee (EC).

As delineated in the LibCTReg, the trial participant should be informed of the nature, significance, and implications of the clinical trial and have given a voluntary written informed consent. The trial participant or witness, if applicable, must be informed by an investigator, who is a healthcare professional or a person designated by the investigator, and who is knowledgeable about the nature, significance, risks, and implications of the clinical trial as well as about the participant’s right to withdraw from the clinical trial at any time. A generally comprehensible information sheet is to be handed out to the participant. The trial participant is also to be given the opportunity to have a counseling session with an investigator or a person designated by the investigator about the other conditions surrounding the conduct of the clinical trial.

The LibCTReg further notes that a declaration of consent to participate in a clinical trial can be revoked at any time in the presence of the investigator or a member of the investigating team, orally or in writing, without disadvantage to the trial participant. In the case of a revocation of consent, the study participant must decide whether their stored data may continue to be used.

Per the G-ACRE-IRB, the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) must assess the study to ensure the voluntary, non-coercive recruitment of research participants. The board must ensure that they have adequately considered the following in the protocol (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the National Research Ethics Board of Liberia (NREB) and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• Procedures for obtaining informed consent
• Content of the participant information sheet
• Content and language of the informed consent document
• Translation of the informed consent document into the local language
• The language used in the documents should be simple relative to the general public’s level of understanding
• Contact persons with their addresses and telephone numbers (for both the study team and the EC)
• Privacy and confidentiality
• Risks (physical, mental, social)
• Benefits to participants and to others
• Compensation (reasonable/unreasonable)
• Involvement of vulnerable participants
• Provision for medical/psychosocial support
• Treatment for study-related injuries
• Use of biological materials

Per the G-ACRE-IRB, if the informed consent procedures and consent document(s) are reviewed by the ACRE IRB Secretariat and found to be complete, the documentation is then submitted to the board for review. If the documentation qualifies for expedited review, the chairperson or a designated expedited reviewer will evaluate the materials. After the investigator makes the required changes suggested by the ACRE IRB, the application may be approved by the chair.

(See the Required Elements section for details on what should be included in the ACRE IRB and NREB forms. Refer to LBR-33 for the NREB Exempt Human Research Consent Script Form and LBR-34 for the NREB Short Consent Form.)

LBR-8 states that the investigator or the designated representative must provide detailed research study information to the participant or legal representative/guardian. LBR-8 further specifies that the oral and written information concerning the trial, including the ICF, should be easy to understand and presented without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant or legal representative/guardian, should also be given adequate time to consider whether to participate.

Further, per LBR-8, none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or the legal representative/guardian to waive or to appear to waive the legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence.

Re-Consent

According to LBR-8, the LMHRA and an EC should approve any change in the ICF due to a protocol modification before such changes are implemented. The participant or legal representative/guardian should be informed in a timely manner if new information becomes available that might be relevant to the participant’s willingness to continue participation in the trial. The participant or legal representative/guardian will also be required to re-sign the revised ICF and receive a copy of any amended documentation.

In addition, per the G-ACRE-IRB, in the case that ACRE IRB approval is reinstated, the ACRE IRB may require previously enrolled participants to re-consent.

Language Requirements

As stated in the G-LibClinTrial, all clinical trial application documentation must be submitted in English. If documents are written in another language, a certified translation is required.

Documenting Consent

The LibCTReg states that if the trial participant is unable to read or write English, the informed consent should be obtained in the language the participant understands and in the presence of at least one (1) witness. The witness, who should be able to read and write English and understand the local language in which the trial participant is informed, should not be a member of the investigating team. The consent given by the trial participant must be documented in writing, dated, and signed by the witness and thumb printed by the trial participant.

Per LBR-8, before participating in the study, the participant or legal representative/guardian should receive a copy of the signed and dated ICF. The participant or legal representative/guardian should also receive a copy of the signed and dated consent form updates and a copy of any amendments to the written information provided to the participants.

LBR-34 also provides a sample NREB ICF for adults capable of consent. A witness must also be present during the consent process and the witness must sign and date the ICF. The number of copies to be signed and distributed is not specified.

Per LBR-8, if a participant is unable to read or if a legally acceptable representative is unable to read, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:

• The written ICF and any other written information provided to the participant is read and explained to the participant and legal representative/guardian
• The participant and legal representative/guardian, have orally consented to the participant’s involvement in the trial, and has personally signed and dated the ICF, if capable of doing so

Waiver of Consent

As specified in the G-ACRE-IRB, to obtain a waiver or alteration of informed consent, the investigator must include the request (and provide justification for the waiver or alteration) in the protocol submission to the ACRE IRB. The request for waiver or alteration will be reviewed by the convened board, the ACRE IRB Chair, or the designated expedited reviewer. The ACRE IRB reviewer (Chair or designee) may approve the waiver or alteration of informed consent, if the board reviewer can establish that the research is to be conducted by or subject to the approval of state or local government officials and is designed to study, evaluate, or otherwise examine:

• Public benefit or service programs
• Procedures for obtaining benefits or services under those programs
• Possible changes in or alternatives to those programs or procedures, or
• Possible changes in methods or levels of payment for benefits or services under those programs

The ACRE IRB reviewer should also be able to ascertain that the research could not practicably be carried out without the waiver or alteration.

Additionally, per the G-ACRE-IRB, the ACRE IRB reviewer may approve the waiver or alteration of informed consent, if the reviewer determines the following:

• The research involves no more than minimal risk to the participants
• The research could not practicably be conducted without the requested waiver or alteration
• If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format
• The waiver or alteration will not adversely affect the rights and welfare of the participants, and
• Whenever appropriate, the participants or legal representative/guardian will be provided with additional pertinent information after participation. The ACRE IRB reviewer will document the findings for waiver or alteration of informed consent. An alteration to informed consent may apply when conducting a study where there is deception or an incomplete disclosure (for example, studies that require deception because the study would be compromised if participants were told the true purpose)

In addition, the G-ACRE-IRB explains that a waiver of a signed ICF may be appropriate for some research studies such as survey or interview studies containing highly sensitive questions (e.g., health status, sexual practices, criminal behavior, etc.), or surveys containing non-sensitive information. To obtain a waiver of documented (signed) informed consent, the investigator must include the request (and provide justification for the waiver or alteration) in the protocol submission process. The request for waiver or alteration will be reviewed by the convened ACRE IRB, the Chair, or the designated expedited reviewer. The ACRE IRB reviewer will consider the investigator’s request and review the request to determine if:

• The only record linking the participant and the research would be the consent document, and the principal risk would be potential harm resulting from a breach of confidentiality
• The research presents no more than minimal risk of harm to participants and involves no procedures for which written consent is normally required outside of the research context
• The participants or legal representative/guardian are members of a distinct cultural group or community in which signing forms is not the norm, that the research presents no more than minimal risk of harm to participants, and provided that there is an appropriate alternative mechanism for documenting that informed consent was obtained. In cases where the documentation requirement is waived, the ACRE IRB may require the investigator to provide participants with a written statement regarding the research, such as an information sheet, instead of an informed consent document

Based on ResNo466, OMREC, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

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

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

Liberia Medicines and Health Products Regulatory Authority

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's Guideline for Good Clinical Practice E6(R2) (LBR-8) to comply with informed consent requirements for use along with the LMHRA guidelines.

LBR-8 states that the informed consent form (ICF) should include the following statements or descriptions, as applicable:

• The study involves research and an explanation of its purpose
• Trial treatment(s) and the probability for random assignment to each treatment
• Trial procedures to be followed, including all invasive procedures
• The participant’s responsibilities in participating in the trial
• Experimental aspects of the study
• Any foreseeable risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Alternative procedures or treatment that may be available to the participant, and if any, which might be advantageous to the participant
• Compensation and/or medical treatment available to the participant or the participant’s family or dependents in the event of a trial-related injury
• Any expected benefits or prorated payment to the participant for participating in the trial
• Any additional costs to the participant that may result from participation in the research
• Participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled
• The LMHRA, the monitor(s), the auditor(s), and the ethics committee (EC) will be granted direct access to the participant’s original medical records to verify clinical trial procedures and/or data without violating the participant’s confidentiality
• A statement describing the extent to which, if any, confidentiality of records identifying the participant will be maintained, and if the results of the trial are published, the participant’s identity will remain confidential
• The participant or legal representative/guardian will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue
• The person(s) to contact for further information regarding the trial and the rights of trial participants, and whom to contact in the event of trial-related injury
• Foreseeable circumstances under which the investigator(s) may remove the participant without the participant’s consent
• The expected duration of the participant's participation
• Approximate number of participants involved in the trial

National Research Ethics Board of Liberia

The following elements are to be included in the National Research Ethics Board of Liberia (NREB)’s Exempt Human Research Consent Script Form (LBR-33) and the NREB Short Consent Form (LBR-34) respectively (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Indication that the person is being asked to take part in a research study
• Research study purpose and reason for participant’s eligibility to participate in study
• Duration of research study
• Participation is voluntary and participant may withdraw at any time
• Explanation of study-specific procedures and sample questions provided to participants
• Possible risks associated with participating in study
• Benefits to participant or to others from participating in study
• Appropriate alternative procedures, or courses of treatment, if any
• Explanation of what is experimental vs. routine standard of care
• Statement regarding who will have access to the participant’s personal information
• Participant’s right to decline participating in any part of study for any reason and right to end participation at any time, and refusal to participate will not be held against the participant
• Researcher’s contact information for any questions the participant may have prior to deciding to participate and throughout the participant’s involvement in the study

See LBR-33 and LBR-34 for additional details.

Per LBR-34, if applicable, the following information is also included in the NREB Short Consent Form:

• Whether the participant will get treated or paid if injured
• The possibility of unknown risks
• When the participant may be taken off the research study without the participant’s agreement
• Added costs from taking part in the study
• What will happen if the participant stops taking part
• Steps to safely stop taking part
• What new information will be shared with the participant
• The number of participants expected to take part in the study
• What happens to the participant’s collected data if the participant withdraws from the trial
• An explanation of the ClinicalTrials.gov (LBR-40) website

Atlantic Center for Research and Evaluation Institutional Review Board

The G-ACRE-IRB indicates that the principal investigator (PI) is responsible for preparing the ICF and that the ICF should include the following statements or descriptions (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• The study involves research and an explanation of its purpose
• The expected duration of a participant’s involvement in the research
• A description of the procedures to be followed
• Identification of any experimental study procedures
• Any foreseeable risks or discomforts to the participant
• Any benefits to the subject or to others that may reasonably be expected from the research
• Alternative procedures or treatment that may be available to the participant, and if any, which might be advantageous to the participant
• A statement describing the extent to which, if any, confidentiality of records identifying the participant will be maintained
• A statement noting the possibility that the EC (or its designees) and the study sponsor may inspect the study records, if the research is sponsored by a funding source
• For research involving more than minimal risk, an explanation of compensation and/or medical treatment available to the participant or the family or dependents in the event of a trial-related injury, and if injury occurs, what the medical treatments consist of, or where further information may be obtained
• The person(s) to contact for further information regarding the trial and the rights of research participants, and whom to contact in the event of research-related injury
• Participation is voluntary, the participant may withdraw at any time, and refusal to participate will not involve any penalty or loss of benefits, or reduction in the level of care to which the participant is otherwise entitled

In addition to the required elements listed above, per the G-ACRE-IRB, for research involving the collection of identifiable private information or identifiable biospecimens, one (1) of the following must be included in the informed consent:

• A statement that identifiers will be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies without additional informed consent from the participant or legal representative/guardian
• A statement that the participant's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies

See also the Consent for Specimen section for additional information on informed consent relating to specimens.

Overview

In accordance with LawNo14.874 and ResNo466, Brazil’s ethical standards promote respect for all human beings and safeguard the rights and dignity of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.)

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

The Right to Participate, Abstain, or Withdraw

As set forth in the LawNo14.874, ResNo466, OMREC, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the participant or legal representative/guardian, should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As delineated in the ResNo466, OMREC, and BRA-28, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

As per the ResNo466, OMREC, and BRA-28, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. LawNo14.874 also states that the research must respect the participant’s privacy and the rules of confidentiality of their data, thereby ensuring the preservation of the confidentiality of their identity.

The Right of Inquiry/Appeal

BRA-28 and OMREC explain that the research participant or legal representative/guardian, should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of their rights.

The Right to Safety and Welfare

LawNo14.874 and ResNo466 clearly state that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.

Overview

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's Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with the LMHRA guidelines. The G-ACRE-IRB also complies 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: Per LBR-28, due to a Memorandum of Understanding (MOU) between the National Research Ethics Board of Liberia (NREB) and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.)

As per LBR-8, Liberia’s ethical standards promote respect for all human beings and safeguard the rights of research participants. LBR-8 and the G-ACRE-IRB state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As set forth in the G-ACRE-IRB, LBR-8, LBR-33, and LBR-34, the participant or legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As per the G-ACRE-IRB, LBR-8, LBR-33, and LBR-34, a potential research participant or legal representative/guardian has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study. (See the Required Elements section for a more detailed list.)

The Right to Privacy and Confidentiality

As per LBR-8 and the G-ACRE-IRB, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

The Right of Inquiry/Appeal

The G-ACRE-IRB, LBR-8, LBR-33, and LBR-34, state that the research participant or legal representative/guardian should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries.

The Right to Safety and Welfare

LBR-8 states that the research participant’s rights, safety, and well-being must take precedence over the interests of science and society.

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

As delineated in LawNo14.874, the inclusion of a participant in research in an emergency situation and without their prior consent will follow the provisions of the approved protocol. The research participant or the legal representative/guardian must be notified at the first possible opportunity and the decision regarding their continued participation in the research must be collected.

In addition, according to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible, and the legal representative/guardian is not available, enrolment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), to protect the participant’s rights, safety, and well-being and to ensure compliance with applicable regulatory requirements. The participant or the legal representative/guardian should be informed about the trial as soon as possible. Consent to continue and other consent as appropriate, should be requested. OMREC and ResNo251 similarly state that the EC (CEP) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner about participation in the study.

As set forth in the LibCTReg, in an emergency situation where consent cannot be obtained, treatment which is necessary without delay to save the life of the trial participant can be started immediately. Such situations must be defined by the Liberia Medicines and Health Products Regulatory Authority (LMHRA) and consent for continued participation must be obtained as soon as possible and not later than as defined by the National Research Ethics Board of Liberia (NREB) for a given clinical trial.

The LibCTReg and the G-LibClinTrial further explain that 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. LBR-8 makes provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies in which prior consent from the participant is not possible.

As delineated in LBR-8, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative/guardian should be obtained. If the prior consent of the participant or legal representative/guardian cannot be obtained, the participant’s enrollment should follow measures specified in the protocol, and/or elsewhere, with documented LMHRA approval to protect the rights, safety, and well-being of the participant, and to ensure compliance with ethics committee (EC) and LMHRA requirements. The participant or the participant’s legal representative/guardian should be informed about the trial and provide consent as soon as possible.

Per the G-LibClinTrial, examples of emergency situations are epidemics or other urgent public health interests that require fast utilization of new medicines or health products and/or fast gathering of information on products. Information provided to clinical trial participants about the process of obtaining consent must be included in the documents submitted to the LMHRA. Refer to 2.3 of the G-LibClinTrial for additional information on how to submit an expedited clinical trial application package.

Overview

As set forth in LawNo14.874, in all Brazilian clinical trials, research participants from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Vulnerability is defined as a condition in which a person or group of people has reduced capacity to make decisions and to oppose resistance in the research situation as a result of individual, psychological, economic, cultural, social, or political factors. ResNo466 also defines vulnerability as the state of individuals or groups who, for any reason or motive, have their capacity for self-determination reduced or impeded, or are in any way prevented from resisting, especially with regard to free and informed consent.

According to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, vulnerable participants are characterized as those who may be unduly influenced by the expectation, whether justified or not, of the benefits associated with their involvement in a clinical trial, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. These participants may include those who are members of a group with a hierarchical structure, such as medical, dental, chemistry, pharmacy, biology, and nursing students, subordinate personnel in a hospital or laboratory, employees of the pharmaceutical industry, members of the armed forces, and individuals who are arrested or imprisoned. Some other vulnerable participants may include those with incurable diseases, people in convalescent homes, the unemployed or indigent, patients in emergency situations, ethnic minorities, homeless people, seasonal workers, refugees, minors, and those who cannot give their consent.

Pursuant to LawNo14.874, the inclusion of participants in vulnerable research situations, even if circumstantially, is subject to the following conditions being met:

• An informed consent form (ICF) signed by a legal representative, or one judicially appointed
• The research is essential for the population represented by the participant in a vulnerable situation, and it is not possible to obtain data of comparable validity through the participation of adults capable of giving their consent or through the use of other research methods
• The research participant should be provided with information, when possible and to the extent of their ability to understand, respecting their decision to participate, expressed through an ICF, whenever they are able to evaluate and decide on the information received
• The responsible investigator and the legal representative/guardian of the incapacitated person will co-sign a communication to the Public Prosecutor's Office, informing the schedule for the incapacitated person's participation in the research

LawNo14.874, ResNo466, and BRA-28, specify that the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must pay special attention to protecting participants who are from vulnerable populations. LawNo14.874 also notes that EC (CEP) members may invite external experts and representatives of vulnerable groups to give their opinion on specific issues related to research projects, but these individuals will not have the right to vote. Additionally, per ResNo466, vulnerable individuals or groups should not be included when the desired information can be obtained through participants with full autonomy, unless the research can benefit the health of the vulnerable population represented.

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

Indigenous Peoples

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

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

Overview

The LibCTReg and the G-LibClinTrial explain that 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 the LMHRA guidelines. According to LBR-8, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process.

LBR-8 explains that vulnerable populations include those participants whose willingness to volunteer in a clinical trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate. Examples may include, but are not limited to, members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; employees of the pharmaceutical industry; members of the armed forces; and persons kept in detention. Other vulnerable study participants include patients with incurable diseases, persons in nursing homes, unemployed or impoverished persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.

Persons with Diseases

As indicated in the LibCTReg, in the case of a clinical trial on a person of legal age who is suffering from a disease for which the investigational product (IP) is to be used, one (1) of the following conditions should be applied along with the general clinical trial requirements delineated in the LibCTReg:

• The use of the IP is indicated according to the findings of medical science in order to save the person's life
• The IP must be of direct benefit to the group of patients who are suffering from the same disease as this person

Persons Under Legal Disability

As set forth in the LibCTReg, “persons under legal disability” are defined as being under the same category as a minor in terms of the individual’s ability to grant consent, except that the person under disability may be above the age of consent (18 years), but may be too ill to participate in decisions regarding their own health. In this case, priority is not given to parents or next of kin to petition the Probate Court for Guardianship, but priority is given to any natural person who demonstrates best interest in the welfare of the disabled.

The LibCTReg further explains that a person under legal disability may participate in a trial, if their parents/legal guardians have be informed of the nature, significance, and implications of the clinical trial and have given a written voluntary informed consent. If the informed implication is grave, it may be necessary for the guardian to secure the permission from the Probate Court before granting consent, due to the fact that the Decree of Guardianship has a clause that the Court appointed guardian should not release the disabled person to any other body in which case their welfare will be put at peril. Otherwise, it can be argued that the appointed guardian has breached their fiduciary duty to the Court by releasing the disabled person to peril.

See the Children/Minors and Mentally Impaired sections for additional information about these vulnerable populations.

LawNo8.069 (also known as the Statute of Children and Adolescents) states that a child is a person up to 12 years of age, and a teenager is one between 12 and 18 years of age.

As per ResNo466 and OMREC, when the research participant is a child, the child’s parent/legal guardian must sign the informed consent form. However, per OMREC, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand. The child’s opinion must be considered, even though the child may not be deemed competent to give consent. ResNo466 further notes that in cases where clarification is necessary for research with child and adolescent participants, investigators must provide a clear justification for their choice, specified in the protocol and approved by the EC (CEP), and by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), when applicable. In these cases, the stages of clarification and free and informed consent must be followed, through the legal representatives/guardians of those invited to participate in the research, to preserve their right to information to the extent of their capacity.

In addition, per CLNo11, the CONEP has established guidelines related to the process of obtaining consent from research participants under 18 years of age. The process of consent to participate is essential and should be addressed to those who exercise parental responsibility or guardianship, without prejudice to listening to the participant under 18 years of age. In addition, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, states that when a clinical trial includes minors who can only be enrolled with the consent of the participant’s parent/legal guardian, the participant should be informed about the trial to the extent compatible with the participant’s understanding and, if capable, the participant should sign and personally date the written informed consent.

Per BRA-73, Brazil has also implemented the ICH Harmonised Guideline Addendum to ICH E11: Clinical Investigation of Medicinal Products in the Pediatric Population E11 (R1) (BRA-74).

Assent Requirements

ResNo466 indicates that an assent form should be used to obtain informed consent from minors or those legally incapable of giving their own consent. The form should be prepared in a language that is accessible to minors or those legally incapable of giving their own consent. After the form is explained and the research study is clarified, the child participants should provide their consent to participate in the study, without the influence of their parent or legal guardian.

CLNo11 further specifies that investigators must ensure the assent is made in the form of an invitation without any degree of pressure or coercion, and written in simple, easy-to-understand language to ensure adequate comprehension of the research. The assent process must consider the understanding capacity of the participant under 18 years of age. Pursuant to LawNo8.069 which upholds the principle that the full protection of children and adolescents is the duty of everyone including public authorities and society in general, CLNo11 delineates that seven (7) years is the minimum age for the obligation to obtain the term or registration of consent. The guideline also recommends an assessment of each research participant’s needs, capabilities, and emotional maturity for the presentation of different terms or records of assent according to the age group (from childhood and adolescence), complexity of the research, and for analysis by the CEP/CONEP system. See CLNo11 for additional details.

See the Personal Data Protection section for requirements on processing personal data of children and adolescents.

According to the LibCTReg and the G-NREB, Liberia defines children and minors as those persons under 18 years of age. The G-NREB also defines adolescents as those between the ages of 15 and 17.

The LibCTReg also states that the definition of legal guardian or the “legal representative of a minor” is based on the premise that a minor cannot grant consent or enter into an agreement. According to LibCTReg, the interest of a minor must be firstly protected by the parents (the father if the parents are married or the child is legitimized) or the mother of the child if the parents are not married. Where there is no parent alive, especially the mother if the child is not born out of wedlock or legitimized, any next of kin, preferably the grandparents first, the siblings second, or any person with interest in the welfare of the child, may petition the Probate Court for Decree of Guardianship. A guardian must be authorized to give consent for the minor child. No institution can serve as guardian and give consent for research on the child. A guardian must be a natural person, not an institution.

Additionally, per the LibCTReg, a minor may participate in a trial, if their parents/legal guardians have been informed of the nature, significance, and implications of the clinical trial and have given a written voluntary informed consent. If the informed implication is grave, it may be necessary for the guardian to secure the permission from the Probate Court before granting consent, due to the fact that the Decree of Guardianship has a clause that the Court appointed guardian should not release the minor to any other body in which case their welfare will be put at peril. Otherwise, it can be argued that the appointed guardian has breached their fiduciary duty to the Court by releasing the minor or disabled to peril.

Also, as indicated in LibCTReg, in the case of a clinical trial on a minor who suffers or may suffer from a disease for which the investigational product (IP) is to be used, the following conditions should be applied:

• The use of the IP must be indicated according to the findings of medical science in order to save the life of the trial participant, to restore the participant to health, to alleviate suffering, or to prevent a disease
• The clinical trial must be of direct benefit to the group of patients suffering from the same disease as the trial participant
• The research must be absolutely necessary in order to confirm data obtained in clinical trials on other persons or by means of other research methods
• The research must relate to a clinical condition from which the minor concerned is suffering or may suffer
• The research may cause only minimal risk and minimal burden to the trial participant

LBR-34 also provides a sample National Research Ethics Board of Liberia (NREB) informed consent form (ICF) for children that explains the parents’ or guardian’s signatures document their permission for the child to take part in a research study as well as their permission for the use and disclosure of the child’s protected health information. If a second parent’s signature is not obtained, the first parent or guardian needs to choose one (1) of the following options on the form to justify why this is not possible:

• The ethics committee (EC) has determined that the permission of one (1) parent is sufficient (this option is only listed on the form if it has been approved by the EC)
• Second parent is deceased
• Second parent is unknown
• Second parent is incompetent
• Second parent is not reasonably available
• Only one (1) parent has legal responsibility for the care and custody of the child

In addition, an individual may provide permission as a guardian for a child only if that individual can provide a written document indicating that the individual is legally authorized to consent to the child’s general medical care and this documentation must be attached to the signed ICF. LBR-34 indicates that the EC must approve the consent form, a witness must be present during the consent process, and the witness must sign and date the ICF.

LBR-8 further states that when a clinical trial includes minors, the minor should be informed about the trial to the extent compatible with his or her understanding and, if capable, the minor should sign and personally date the written informed consent.

As delineated in the G-ACRE-IRB, the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB) must classify research involving children into one (1) of four (4) categories and document its discussion of the risks and benefits of the research study in order to approve such research. The risk/benefit categories are as follows (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the NREB and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• When the ACRE IRB determines that the risk is no more than minimal to children in a study, it may approve the research only if adequate provisions are made for soliciting the assent of the children and permission of their parents or legal guardians
• When the ACRE IRB determines that more than minimal risk to children is presented by a procedure that indicates the prospect of direct benefit to an individual child, or by a monitoring procedure that is likely to contribute to the child’s well-being, the ACRE IRB may approve the research if it is established that: the risk is justified by the anticipated benefit to the children; the relation of the anticipated benefit to the risk is at least as favorable to the children as that presented by available alternative approaches; and adequate provisions are made for soliciting the assent of the children and permission of their parents or legal guardians
• When the ACRE IRB determines that the study presents more than minimal risk to children and does not hold out the prospect of direct benefit for the individual child, but is likely to contribute generalizable knowledge about the child’s disorder or condition, the board may approve the research if it established that: the risk represents a minor increase over minimal risk; the study intervention or procedure presents experiences to participants that are reasonably commensurate with those inherent in their actual or expected medical, dental, psychological, social, or educational situations; the intervention or procedure is likely to yield generalizable knowledge about the participants’ disorder or condition which is of vital importance for the understanding or improvement of the participants’ disorder or condition; and adequate provisions are made for soliciting the assent of the children and permission of their parents or legal guardians
• When the ACRE IRB determines that the research does not meet the requirements in any of the above three (3) categories, the board may only approve the research if it finds that the study presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children

The G-ACRE-IRB further states that the ACRE IRB should ensure that adequate permissions are made for soliciting the permission of each child’s parent/legal guardian. The following provisions are used depending on the category of research:

• Research not involving greater than minimal risk to children: Where parental permission is to be obtained, the ACRE IRB may suggest that the permission of one (1) parent is sufficient for research not involving greater than minimal risk
• Research involving greater than minimal risk but presenting the prospect of direct benefit to the individual child: Where parental permission is to be obtained, the board may suggest that the permission of one (1) parent is sufficient for research involving greater than minimal risk but presenting the prospect of direct benefit to the individual participants
• Research involving greater than minimal risk and no prospect of direct benefit to the individual child, but likely to yield generalizable knowledge about the child’s disorder or condition: When the research is approved under this category, both parents must give their permission unless one (1) parent is deceased, unknown, incompetent, not reasonably available, or when only one (1) parent has legal responsibility for the care and custody of the child

If the ACRE IRB determines that a research study is designed for a participant population for which approval from the parents and/or legal guardian(s) or representative(s) is not reasonably required to protect the participants (e.g., neglected or abused children), the G-ACRE-IRB indicates that the consent requirements may be waived. In order to protect the rights and welfare of children in a research study, the board should consider the involvement of a court appointed guardian.

Assent Requirements

Per the LibCTReg, an assent form must be signed, and, if possible, dated by the minor. Similarly, per the G-LibClinTrial, when the research participant is a minor, the investigator must obtain assent from the child/minor. The G-NREB also indicates that both written parental consent and assent forms should be completed for children less than 18 years of age. Per LBR-34, the child’s assent should also be attained unless this can be justified by one (1) of the following reasons:

• The EC determined that assent of the child was not a requirement
• The capability of the child is so limited that the child cannot reasonably be consulted

According to LBR-34, the EC must approve the assent form, a witness must be present during the consent process, and the witness must sign and date the ICF.

In addition, the G-ACRE-IRB explains that adequate provisions for the assent of children include the following:

• Children capable of assenting: After the ACRE IRB determines that a child is capable of assenting, the proposed research procedures should be explained to the child in a language that is appropriate to the age, experience, maturity, and condition of the child and should include any discomforts and inconveniences the child may experience if the child agrees to participate in the study
• The option to withdraw: As they are in the developmental stage, children should be asked if they do or do not wish to participate in the research, especially where the research does not involve interventions likely to be of benefit to the participants but that they will be volunteers for the benefit of others
• The signing of assent or consent: When an assent requirement is established, the investigator or the designee and the child (when appropriate) will sign the study consent form. When it is inappropriate for the child to sign the form (due to age or ability), the board requires that the document be signed by the investigator (or the designee) and the parent/legal guardian

Per the G-ACRE-IRB, the ACRE IRB may determine that assent may be waived if the capability of some or all of the children is so limited that they cannot reasonably be consulted; or the intervention or procedure involved in the research has a direct benefit to the health or well-being of the children and is available only in the context of the research. In such instances, a child’s dissent which should normally be respected, may be overruled by the child’s parents at the discretion of the board (for example, when a research study involves providing experimental therapies for life-threatening diseases such as Ebola Virus Disease, severe COVID-19, or cancer, parents may wish to try anything to help their children, even with the likelihood of success being uncertain). If the child is a matured adolescent, the child’s wishes should be respected.

As delineated in LawNo14.874 and ResNo466, research with pregnant women will be preceded by similar research with women outside the gestational period, except when the pregnancy or the unborn child is the fundamental object of the research. Additionally, per LawNo14.874, this research will only be permitted when the foreseeable risk to the health of the pregnant woman or the unborn child is minimal.

ResNo466 also specifies that any Brazilian clinical studies involving women of childbearing age or who are pregnant, require additional safeguards to ensure that the participants are fully aware of the risks and that the research assesses the risks and benefits as well as any potential impact on fertility, pregnancy, the embryo or fetus, labor, lactation, and the newborn. Further, the investigator(s) should also ensure that female participants have the right to participate in the research without the use of compulsory contraceptives, if they have expressly indicated that they are free from the risk of pregnancy and sexual practices, or they are sexually active in a non-reproductive way.

As set forth 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 the LMHRA guidelines.

As stated in the G-ACRE-IRB, for clinical research studies using the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB), pregnant women or fetuses may be involved in research if all the following conditions are met (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the National Research Ethics Board of Liberia (NREB) and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.):

• Where scientifically appropriate, preclinical studies, including studies on pregnant animals, and clinical studies, including studies on non-pregnant women, have been conducted and provide data for assessing potential risks to pregnant women and fetuses
• The risk to the fetus is caused solely by the interventions or procedures considered directly beneficial for the woman or the fetus; or, if there is no such prospect of specific benefit, the risk to the fetus is not greater than minimal and the purpose of the research is for the development of important biomedical knowledge which cannot be obtained by any other means
• Any risk is the least possible for achieving the objectives of the research
• Consent is obtained in accordance with the informed consent provisions in the G-ACRE-IRB if the research holds out the prospect of direct benefit to a pregnant woman; the prospect of a direct benefit both to the pregnant woman and the fetus, or no prospect of benefit for the woman or the fetus when risk to the fetus is not greater than minimal; and the purpose of the research is the development of important biomedical knowledge that cannot be obtained by any other means
• If the research holds the prospect of direct benefit solely to the fetus, then the consent of the pregnant woman and the father is obtained in accordance with the informed consent provisions in the G-ACRE-IRB, except that the father’s consent need not be obtained if he is unable to consent due to unavailability, incompetence, or temporary incapacity, or, the pregnancy resulted from rape or incest (close relationship)
• Each person providing consent is fully informed regarding the foreseeable impact of the research on the fetus and/or resultant child
• For children who are pregnant, assent and permission are obtained in accordance with the provisions for children indicated in this guideline
• No inducements, monetary or otherwise, will be offered to terminate a pregnancy
• Individuals engaged in the research will have no part in any decisions as to the timing, method, or procedures used to terminate a pregnancy
• Individuals engaged in the research will have no part in determining the viability of a fetus

According to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, prisoners are included as an example of a vulnerable population that may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from senior members of a hierarchy in case of refusal to participate.

ResNo466 also states that freedom of consent must be guaranteed to those research participants, including prisoners, who are fully competent but are exposed to specific constraints or have restricted autonomy. These participants must have the freedom to decide whether to participate without any fear of reprisal.

Pursuant to the G-ACRE-IRB, for clinical research studies using the Atlantic Center for Research and Evaluation Institutional Review Board (ACRE IRB), due to the vulnerability of prisoners, research involving prisoners should be reviewed by a fully convened ACRE IRB. (Note: Per LBR-28, due to a Memorandum of Understanding (MOU) between the National Research Ethics Board of Liberia (NREB) and the ACRE IRB in 2022, the ACRE IRB does not review and approve clinical trial protocols. All clinical trial protocols submitted to the ACRE IRB are referred to the NREB.) Per the G-ACRE-IRB, the ACRE IRB may only approve research projects involving prisoners if the research falls under one (1) of the following categories:

• Study of possible causes, effects, and processes of incarceration, and of criminal behavior, provided that the study presents no more than minimal risk or inconvenience to the participant
• Study of prisons as institutional structures or of prisoners as incarcerated persons, provided that the study presents no more than minimal risk and no more than inconvenience to the participants
• Research on conditions particularly affecting prisoners as a class (for example, vaccine trials and other research on Ebola, COVID-19, hepatitis, as well as social and psychological research such as alcoholism, drug addiction, and sexual assaults)
• Research on practices that are intended and have the probability of improving the health or well-being of the participants

In addition, per the G-ACRE-IRB, the ACRE IRB must review research involving prisoners and approve such research only if it finds that:

• The risks involved in the research are commensurate with risks that would be accepted by non-prisoner volunteers
• Procedures for the selection of participants within the prison are fair to all prisoners, and free of arbitrary interference by prison authorities or prisoners. Other than the investigator’s justification to the ACRE IRB, the use of other procedures, and the selection of control participants from the available prisoner population for a particular research study should be randomly done
• The information is presented in a language that is understandable to the participant population
• There is adequate assurance that parole boards will not take into account a prisoner’s participation, withdrawal, or lack of participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that their participation, withdrawal, or lack of participation in the research will have no effect on his or her parole
• The ACRE IRB should ensure that adequate provisions are made where there will be a follow-up examination or care of participants after the end of their participation, considering the variable lengths of individual prisoners’ sentences, and informing participants of this information

According to ResNo466, the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must approve the participation of research participants who are mentally or physically incapable of giving consent, and sufficient justification must be provided for involving this population in a study. In cases where clarification is necessary to obtain adequate consent from participants with mental disorders or diminished decision-making capacity, investigators must provide a clear justification for their choice, specified in the protocol and approved by the EC (CEP), and by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), when applicable. In these cases, the stages of clarification and free and informed consent must be followed, through the legal representatives/guardians of those invited to participate in the research, to preserve their right to information to the extent their capacity.

In addition, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, states that when a clinical trial includes participants who can only be enrolled in the trial with the consent of the legal representative/guardian (e.g., patients with severe dementia), the participant should be informed about the trial to the extent compatible with the participant’s understanding and, if capable, the participant should sign and personally date the written informed consent.

Per CLNo11, CONEP has also established guidelines related to the essential process of obtaining consent from research participants with a "lack of autonomy", permanent or temporary, to consent.

CLNo11 further states researchers must ensure assent is obtained in the form of an invitation without any pressure or coercion, and written in simple, easy-to-understand language to ensure adequate comprehension of the research. See CLNo11 for additional information.

As set forth in the LibCTReg, “persons under legal disability” is defined as being under the same category as a minor in terms of the individual’s ability to grant consent, except that the person under disability may be above the age of consent (18 years) even though the person may lack the mental capacity to reason properly and grant consent. In this case, priority is not given to parents or next of kin to petition the Probate Court for Guardianship, but priority is given to any natural person who demonstrates the best interest in the welfare of the disabled.

The LibCTReg further explains that a person under legal disability may participate in a trial, if their parents/legal guardians have be informed of the nature, significance, and implications of the clinical trial and have given a written voluntary informed consent. If the informed implication is grave, it may be necessary for the guardian to secure the permission from the Probate Court before granting consent, due to the fact that the Decree of Guardianship has a clause that the court-appointed guardian should not release the disabled person to any other body in which case their welfare will be put at peril. Otherwise, it can be argued that the appointed guardian has breached their fiduciary duty to the court by releasing the disabled person to peril.

Also, as indicated in LibCTReg, in the case of a clinical trial on a person of legal age who is incapable of comprehending the nature, significance, and implications of a clinical trial and of determining their will in the light of these facts, and who is also suffering from a disease which is to be treated by the investigational product (IP), the following conditions should be applied:

• The use of the IP must be indicated, according to the findings of medical science, in order to save the life of the trial participant, to restore the participant to health or to alleviate suffering
• The research must relate directly to a life-threatening or highly debilitating clinical condition suffered by the trial participant and the clinical trial may involve as little burden and other foreseeable risks as possible for the trial participant. Both the degree of burden and the risk threshold must be defined specifically in the trial protocol and monitored constantly by the investigator. The clinical trial may only be conducted if there is a justified expectation that the benefits of using the IP for the trial participant outweigh the risks
• Consent should be given by the legal representative/guardian after participant has been duly informed per the general clinical trial requirements in LibCTReg
• The research must be absolutely necessary for the confirmation of data obtained from clinical trials conducted on persons capable of granting informed consent or by means of other research methods
• With the exception of adequate compensation, no advantages may be granted

Additionally, as per 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 the LMHRA guidelines.

LBR-34 provides a sample National Research Ethics Board of Liberia (NREB) informed consent form (ICF) for adults unable to consent, which explains that the signature of the legally authorized representative documents their permission for the participant named in the ICF to take part in this research study, as well as their permission for the use and disclosure of the participant’s protected health information. The participant’s assent should also be attained unless this can be justified by one (1) of the following reasons:

• The EC determined that assent of the participant was not a requirement
• The capability of the participant is so limited that the participant cannot reasonably be consulted

The previously listed options are only available if they have been approved by the EC. A witness must also be present during the consent process and the witness must sign and date the ICF.

As per LawNo14.874, ResNo945, the G-BioIProdManual, and the G-SynthDrugProdManual, an investigational product (IP) is defined as an experimental drug, placebo, active comparator, or any other product to be used in a clinical trial. (Note: Experimental drugs are a subset of IPs, however, the sources and the profile use the two (2) terms interchangeably.)

In addition, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, states that an IP is a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.

Per 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 the LMHRA guidelines.

As delineated in LibCTReg and LBR-8, an investigational product (IP) is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form, when used for an unapproved indication, or when used to gain further information about an approved use. In Liberia, IPs are referred to as investigational medicinal products (IMPs).

Manufacturing

As stated in LawNo14.874 and ResNo945, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the manufacture of investigational products (IPs) in Brazil. ANVISA approves the manufacture of an IP as part of its review and approval of the clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)).

ResNo945 and the G-DDCMManual explain that the sponsor must provide ANVISA with a declaration that the IP and the placebo used in completed or ongoing clinical trials were manufactured in accordance with good manufacturing practice (GMP), as delineated in ResNo658, and that the IP and the placebo to be used in clinical trials in Brazil will also be manufactured in accordance with GMP. If there is a GMP Certificate or equivalent document for the IP, it must be attached to the DDCM or to the petition for substantial modification to the IP, if applicable. Per ResNo945, ANVISA may carry out GMP inspections of the IP produced in order to verify the information and data presented in the DDCM and determine whether the IP is sufficiently safe to be administered to the clinical trial participants. See RegNo136, which provides complementary GMP for IPs to be followed in addition to ResNo658. See the Submission Process and Submission Content sections for DDCM and substantial IP modification submission requirements.

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

Per BRA-73, Brazil has also implemented the ICH Harmonised Tripartite Guideline: Good Manufacturing Practice Guide for Active Pharmaceutical Ingredients (Q7) (BRA-112).

Import

Per LawNo14.874, ResNo945, and the G-DDCMManual, ANVISA is responsible for authorizing the import of IPs. As explained in ResNo945 and the G-DDCMManual, for each DDCM submitted, a single Import Document (DI) will be issued, mentioning all of the clinical trials to be conducted in Brazil. The DI is a document to be used in IP import or export requests, when necessary. The DI lists the IPs to be imported for use in each clinical trial linked to the DDCM. ANVISA will issue the DI within 30 business days from the date of filing of the DEEC petition for the import of IPs necessary for carrying out clinical development, which may be before the approval or rejection of the DDCM and the respective DEEC petitions are published in the Official Gazette of the Union (Diário Oficial da União (DOU)). The import of products before publication in the DOU is at the discretion and responsibility of the sponsor. The G-DDCMManual also notes that the early issuance of the DI applies to the DDCM and DEECs submitted together with the DDCM. Therefore, this measure does not apply to cases in which DEECs are submitted after the approval of the DDCM.

Additionally, as described in ResNo945 and the G-DDCMManual, if a company is interested in importing IP(s) prior to DDCM approval, the sponsor must attach a declaration of commitment along with the DDCM documentation stating that the IP will only be distributed to research centers after the DDCM and DEEC are approved and ANVISA’s authorization is published in the DOU. In the event ANVISA rejects the DDCM, the corresponding DEEC, and prior import of the IP(s) authorization, the sponsor must submit a petition to amend the DDCM process informing ANVISA of the destination or destruction of the IP(s). This document must be submitted to ANVISA within a maximum period of 60 business days from the publication of the DDCM rejection and respective DEEC, and must contain information on the destination given to the IPs including their respective quantities compatible with what was previously imported. ResNo945 further states that changing the import purpose of goods and products is prohibited without ANVISA’s authorization. Any change to the IP information contained in the DI may only be made upon request to ANVISA’s clinical research technical area. Furthermore, the use of any IP imported by means of a DI prior to the approval of the DDCM and DEEC petition published in the DOU, constitutes a health violation 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.

BRA-95 also provides instructions to sponsors or the legal representatives in Brazil on completing the expiration date (or shelf life) information for imported IPs in the Clinical Trial Submission Form (FAEC) (BRA-22). The expiration date (shelf life) is frequently updated, and is therefore often linked to inconsistencies and requests for clarification of requirements by those responsible for importing drugs and products for clinical trials. See BRA-95 for detailed information on stability requirements and instructions on completing BRA-22. Additionally, the updated BRA-22 requires sponsors to complete information on the clinical trial’s type of risk category according to RegNo338. RegNo338 provides criteria for requesting ANVISA review of DDCM, DEEC, or substantial IP modification petitions using the optimized analysis procedure by regulatory trust practices (Reliance) or by risk and complexity of the clinical trial. See RegNo338 for detailed risk category criteria. See also Scope of Assessment and Submission Process sections for ANVISA’s optimized analysis procedure requirements.

Pursuant to ResNo945, imported IPs under investigation for exclusive use in clinical trials are subject to the registration of licenses, permits, certificates, and other documents specified on the Integrated Foreign Trade System (SISCOMEX)’s Single Foreign Trade Portal (BRA-80); are subject to ANVISA inspection; and must comply with ResNo208 (amending ResNo81). ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. ResNo172 specifies that the import of goods and products intended for research involving human beings that have been approved by ANVISA will be analyzed within 48 hours after arriving in Brazil and after compliance with relevant legal requirements. Additionally, imports intended for clinical trials whose objective is to register or alter product registration will be analyzed within five (5) days after protocol approval and compliance with legal requirements. Refer to ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) for detailed import procedures.

As described in ResNo74 and BRA-108, the import petition must be submitted electronically. Per the G-LPCOImprtPetition, the first step in initiating ANVISA’s import protocol process is applying for an import license (Licença de Importação (LI)) via BRA-80. As indicated in BRA-108, the electronic petition must include the documentation specified in ResNo208 (amending ResNo81) and other relevant legislation. ResNo208 (amending ResNo81) explains that the following documentation must be included with the petition:

• Copy of the Special Communication (Comunicação Especial CE)), Specific Special Communication (Comunicado Especial Específico (CEE)), and Document for Importation of Product(s) under Investigation from DDCM
• Knowledge of cargo on board
• Commercial invoice
• In cases of imports carried out by those other than the DDCM holder, document of delegation of import responsibilities

BRA-108 also indicates that in the case of documents already in electronic form, they should be attached as individual files for each LI request in BRA-80. The documents must be attached, preferably, in the order indicated in the checklist of the procedure specified in ResNo208 (amending ResNo81). Refer to BRA-108 for detailed documentation presentation requirements. See also ResNo208 and ResNo81 for detailed import documentation requirements.

Per the G-LPCOImprtPetition, once the LI is registered, the user also must make a request in the Licenses, Permissions, Certificates and Other Documents (Licença, Permissão, Certificado e Outros Documentos (LPCO)) module in SISCOMEX (BRA-80). The G-LPCOImprtPetition explains how the LPCO registration will eventually be integrated with the LI registration, however, at this time, it is necessary for the user to link the LI with the LPCO in order to initiate the import petition protocol in ANVISA’s Solicita Electronic Petition Request System (BRA-56). Refer to the G-LPCOImprtPetition for detailed instructions on registering the LI and the LPCO in BRA-80. See also BRA-106 for additional information on using BRA-80 and obtaining an LI, and See also BRA-109, for additional background on linking imported medicinal products and controlled substances to BRA-80.

As described in BRA-47 and the G-LPCOImprtPetition, users are required to complete the company registration process prior to submitting an import petition via ANVISA’s Solicita Electronic Petition Request System (BRA-56). BRA-47 provides step-by-step instructions on company registration along with the information provided in BRA-105. BRA-107 also provides additional information on registering a company with the National Register of Legal Entities (Cadastro Nacional da Pessoa Jurídica (CNPJ)).

Per ResNo945, imported IPs that are subject to special control as referenced in OrdNo344 (Lists A1, A2, A3, B1, B2, C3, D1, E, and F), must comply with ResNo208 (amending ResNo81) and ResNo659. OrdNo344 defines the substances included in these lists as follows: "A1" and "A2" (permitted narcotics), "A3”, "B1", and "B2" (permitted psychotropics), "C3" (immunosuppressants), "D1" (permitted precursors), "E" (plants that can originate narcotic and/or psychotropic substances), and "F" (substances for prohibited use in Brazil). As indicated in BRA-57, ANVISA has also adopted a protocol for requests for authorization to import medicines and substances subject to special control. See BRA-57 for details. Additionally, the G-ImprtMeds provides information on ANVISA’s Import Authorization Office for Medication (PAFME)) submission requirements for imported IPs subject to special control (e.g., medicines, including advanced therapy products and human cells and tissues for therapeutic purposes). According to the G-ImprtMeds, although these IPs are subject to PAFME approval, imported IPs intended exclusively for clinical trials as well as those being used for expanded access, compassionate use, and post-study IP programs are exempt from ANVISA’s operating authorization (AE) requirements, provided that the company holds an ANVISA import authorization required for the exemption request and for carrying out one of these activities. See the G-ImprtMeds for details.

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

Advanced Therapy Products

Per ResNo506, advanced therapy products refer to medicines for human use that are based on genes, tissues, or cells. As delineated in LawNo14.874, for clinical trial purposes, the export and import of experimental advanced therapy products must be authorized by ANVISA and by regulatory bodies, under specific regulations. Per G-LPCOImprtPetition, applicants may initiate an import petition via ANVISA’s Solicita Electronic Petition Request System (BRA-56) to request an import license for advanced therapy products. The process involves obtaining an LI via the steps discussed earlier in this section followed by making a request through the LPCO module of BRA-80, and linking the LI to the LPCO registration. The user will then be able to initiate an import petition. See G-LPCOImprtPetition for additional information on registering an LI and LPCO for advanced therapy products via BRA-80, and then initiating an import petition via BRA-56. Refer to ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products.

Per ResNo172, ANVISA will analyze and release imported goods and products intended for use in human subjects research within 48 hours after arrival in Brazil, provided that the legal requirements are met and that the purpose of the research is not to register or change the product registration. Also specified in ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172), is the requirement that the investigator and institution submit the imported products through one (1) of the following methods: BRA-80 or Express Shipping. As indicated earlier in this section, the import petition must be submitted electronically and should comply with the documentation submission requirements discussed above and include the information provided in ResNo74 and BRA-108. While each import option has different documentation requirements, they all require the submission of an electronic petition for import, a commercial invoice, a signed statement of responsibility (see ResNo81 (Chapter XXVII) and ResNo172 (Annex I)), research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval, and where applicable, National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) approval. See ResNo172 and ResNo81 for additional information on the required items based on the import method used. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

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

Manufacturing

As set forth in the LMHRA-Act, the Liberia Medicines and Health Products Regulatory Authority (LMHRA) is responsible for issuing licenses or permits for premises and personnel to engage in the manufacture of medicinal products in Liberia. The LibCTReg also states that investigational products (IPs) for clinical trials must be manufactured according to internationally accepted good manufacturing practice (GMP) principles.

Per the LibCTReg and the G-LibClinTrial, the LMHRA has also adopted the International Council for Harmonisation (ICH)'s Guideline for Good Clinical Practice E6(R2) (LBR-8) for use along with the LMHRA guidelines. LBR-8 notes that the sponsor should ensure an IP including the active comparator(s) and placebo, if applicable, is characterized as appropriate to the IP’s stage of development and is manufactured in accordance with applicable GMP. Per LBR-29, the World Health Organization’s (WHO) GMP Guidelines for IPs (LBR-26) and the International Council for Harmonisation (ICH) Harmonised Tripartite GMP Guide for Active Pharmaceutical Ingredients (LBR-9) must also be complied with during the IP manufacturing process.

As explained in G-Inspec-PMS, where pharmaceutical factories have not yet established validated manufacturing processes for pharmaceuticals for use in clinical trials, or have not yet established comprehensive manufacturing control standards, the factories must establish written operational procedures and keep detailed and accurate records for each batch of products manufactured, and each batch of raw material used. Batch manufacturing records must be kept until clinical trials are completed, or until at least two (2) years after the product is completed, whichever period is longer. Additionally, where pharmaceutical factories produce biopharmaceuticals or biotechnology products for use in clinical trials, impurities caused by virus inactivation/removal or other organisms may not exceed the limits imposed on other similar products on the market; where operational procedures for said products have not yet been validated, quality control tests must be performed.

Import

As set forth in the LMHRA-Act, the LMHRA is also responsible for issuing licenses or permits for the import/export of medicinal products in Liberia. Pursuant to the G-Inspec-PMS, authorization must be obtained from the LMHRA for the importation of medicines to be used in clinical trials. Per LBR-30, the Clinical Trials Unit within the LMHRA’s Pharmacovigilance & Clinical Trials Department is responsible for reviewing importation permits for IPs that are required for the conduct of clinical trials. Per LBR-5, the department is also responsible for receiving IP application submissions in Liberia and coordinating with the LMHRA’s Clinical Trial Team to ensure the safety and efficacy of the IPs to be used in clinical trials.

According to LBR-5, the IP dossier documentation requirements for the LMHRA’s approval are as follows:

• Submit typewritten application as per G-LibClinTrial
• Pay the required fee into the LMHRA bank account
• Submit payment slip to the Finance Department to obtain an official LMHRA receipt
• Present the IP dossier(s) along with the official receipt and product samples to the LMHRA

The G-LibClinTrial further explains that if the IP(s), health products, or any auxiliary medicinal product must be imported, the clinical trial must be approved by the LMHRA before the import can be authorized. IPs may only be imported if they are not locally available or if the need for importation is otherwise justified. The justification must be stated in the import permit application letter.

Per the LibCTReg and the G-LibClinTrial, the import permit application must contain the following information and documentation:

• Name and address of the sponsor, the sponsor’s legal representative, or the sponsor-investigator (both physical and postal)
• Principal investigator’s name, address (both physical and postal), and contact details (e.g., phone number and email)
• The clinical trial for which the application is made
• The planned clinical trial sites and the planned number of participants at the sites
• IP(s) description by name or code, strength, and dosage form
• IP(s) unit of issue, total quantity, batch number, manufacture, and expiry dates
• Sample labels of the primary and secondary containers
• Planned return of unused IP(s) to sponsor or destruction at the clinical trial site

The LibCTReg also notes that an application letter should be sent to the LMHRA Managing Director along with the required documentation.

In addition, per G-LibClinTrial, a parallel submission for approval of the clinical trial and the import permit application is possible. In this case, the import permit application can be included in the clinical trial application package.

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.

Investigator's Brochure

In accordance with ResNo945, the G-DDCMManual, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must provide coverage for the following areas (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Physical, chemical, and pharmaceutical properties
• Pharmaceutical aspects
• Pharmacokinetics and metabolism
• Toxicological effects in any animal species tested under a single dose study, a repeated dose study, or a special study
• Results of clinical pharmacokinetic studies
• Information regarding safety, pharmacodynamics, efficacy, adverse events data, and dose responses obtained from prior clinical trials in humans
• For phase 1 clinical trials involving the use of a drug for the first time in humans (First-in-human, FIH), attach reports of toxicity and detailed pharmacokinetic and pharmacodynamic studies, as a complement to the IB as soon as they are available
• Reference Safety Information

Additionally, per ResNo945 and the G-DDCMManual, the sponsor must submit an updated IB to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) in cases where clinical trials aim to support a new therapeutic indication, an expansion of use to a new population, a new dosage regimen, new associations, or any post-registration change that requires clinical data. The updated IB should be submitted with the changes highlighted (track-changes format), or a specific IB, by means of a secondary petition to the clinical trial application (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) using the subject code of “10821 - ENSAIOS CLÍNICOS - Notificação de Atualização de Brochura do Investigador” (10821 - CLINICAL TRIALS - Notification of Update of Investigator's Brochure), per the G-DDCMManual. BRA-28 also notes that the sponsor should update the IB as significant new information becomes available. See ResNo945, the G-DDCMManual, and BRA-28 for detailed IB requirements.

Quality Management

Pursuant to ResNo945 and the G-DDCMManual, the sponsor is responsible for submitting an Investigational Drug Development Plan (PDME) to ANVISA as part of the DDCM. The PDME should contain the following:

• Active pharmaceutical ingredient (API) or active substance name, including IP category (e.g., synthetic, biological, specific, dynamized, medicinal gas, phytotherapeutic or radiopharmaceutical), therapeutic class, pharmaceutical form, concentration and route of administration
• Mechanism of action and indications to be studied
• General objectives and planned duration of clinical development
• A list, in tabular form, of the countries where clinical development has been submitted, including details of the regulatory and ethical approval status, and respective clarifications or justifications in cases of approval under reservation, disapproval, interruption, or cancellation of clinical development in any of the countries where it was submitted
• Scientific advisory opinion of any foreign regulatory authority, if any, on the clinical development
• In cases of linking new Specific Clinical Trial Dossiers (Dossiê Específico de Ensaio Clínico (DEECs)) to the DDCM, and exclusion of protocols cited in the PDME in which the corresponding DEECs were not submitted, the updated version of the PDME must be submitted, by means of a secondary petition to DDCM petition

Refer to the G-DDCMManual and the G-BiolProdManual for detailed PDME submission requirements. See BRA-128 for the Investigational Drug Development Plan (PDME) form.

ResNo945 also specifies that an Investigational Medicinal Product Dossier (IMPD) or Investigational Product Dossier (DPI) must be submitted to ANVISA as part of the clinical trial application (primary DDCM petition). The IMPD or DPI should include the following information on the IP:

• Description of the pharmaceutical form and composition
• Pharmacotechnical development
• Manufacturing process and in-process controls
• Quality control of excipients
• Quality control of the IP
• Standards/reference materials or chemicals
• Packaging material
• Results of stability studies
• Documentation relating to the control of transmissibility of Transmissible Spongiform Encephalopathies (TSE), in accordance with current health regulations or justifications for the exemption of this document

Per ResNo945, the sponsor should also include in the IMPD or DPI the manufacturing and process controls, quality control, and stability study results for the API or active substance; and the manufacturing process and analytical controls, packaging material, and stability study results of the placebo and modified comparator drug. See ResNo945 for additional information. In the event the IP is already registered in Brazil, the IMPD will be waived. However, in cases where there is a substantial change in the quality of the IP in relation to the registered drug, all documentation and information supporting the change(s) must be presented in the DDCM. ANIVSA requires the IMPD or DPI information to be presented following a logical structure that facilitates technical analysis, with the recommended format being Module 3 of the Common Technical Document (CTD) (BRA-133). Per ResNo945 and the G-DDCMManual, ANVISA will also issue a supplementary normative act regarding the quality requirements of the IP, API, or active substance.

In addition to the initial PDME and IMPD submissions, the sponsor must submit to ANVISA any substantial IP modifications which may potentially have an impact on the quality or safety of the IP, active comparator, or placebo, as delineated in ResNo945 and the G-DDCMManual. These submissions must be linked as a secondary petition to the corresponding DDCM. Further, the optimized analysis procedure based on regulatory trust practices (Reliance) is also applicable to secondary petitions for substantial IP modifications. See BRA-127 for the Petition Form for Substantial Modification to the Product under investigation. For detailed information on substantial IP modifications, see the Scope of Assessment, Submission Process, and Submission Content sections.

Per BRA-28, the sponsor must also ensure that the products are manufactured in accordance with Good Manufacturing Practice (GMP) as laid down in ResNo658. ResNo945 and the G-DDCMManual indicate that if there is a GMP certificate or equivalent document for the IP, it must be attached to the DDCM or to the petition for substantial IP modification, if applicable. BRA-28 also states that if significant formulation changes are made in the IP(s) or comparator product(s) during the course of clinical development, the results of any additional studies of the formulated product(s) (e.g., stability, dissolution rate, bioavailability) needed to assess whether these changes would significantly alter the pharmacokinetic profile of the product should be available prior to the use of the new formulation in clinical trials and submitted to ANVISA for review and authorization.

See also the Submission Process and Submission Content sections for DDCM submission instructions and documentation requirements. See also RegNo136, which provides complementary GMP for IPs to be followed in addition to ResNo658.

In addition, per ResNo205, the DDCM submitted to ANVISA to conduct a clinical trial using IPs for rare diseases should also be accompanied by a request for GMP certification. See ResNo205 and ResNo811 (which partially amends ResNo205) for detailed submission information.

International GMP Compliance

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

Furthermore, in accordance with ResNo741, RegNo292 establishes specific criteria and procedures for defining Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) for the purposes of the health inspection and Certification of Good Manufacturing Practices (Certificação de Boas Práticas de Fabricação (CBPF)) of APIs, cannabis products for medicinal purposes, medicines, and biological products. To comply with health inspection and CBPF criteria, AREEs must be regulatory authorities or international entities that are members of the PIC/S and the ICH (See Annex in RegNo292 for list of approved AREEs). See RegNo292 for detailed information on AREEs for the purposes of health inspections and GMP certificates. Also, see BRA-64 for additional information. ResNo945 also notes that the manufacturing process of the API and the IP approved by an AREE must comply with the guidelines and principles described in the current ICH guides, where applicable, according to the clinical development phase. See the Scope of Assessment section for additional information on AREE requirements.

Investigator’s Brochure

Per 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 the LMHRA guidelines. Per the LBR-8, the sponsor should also update the investigator’s brochure (IB) as significant new information becomes available.

As specified in the LBR-8, the IB must provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties
• Pharmaceutical aspects
• Pharmacokinetics and metabolism
• Toxicological effects in any animal species tested under a single dose study, a repeated dose study, or a special study
• Results of clinical pharmacokinetic studies
• Information regarding safety, pharmacodynamics, efficacy, adverse events data, and dose responses obtained from prior clinical trials in humans

See the LBR-8 for additional details regarding the IB.