National Health Surveillance Agency (ANVISA)

As per ResNo9 and ResNo255, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspection of drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of ResNo9 and ResNo255.

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 ResNo255 explain that the goods and products under the agency’s purview include medicines for human use and their active ingredients, immunobiologicals and their active substances, and blood and blood derivatives.

As indicated in LawNo9.782 and ResNo255, ANVISA is headed by a Collegiate Board of Directors composed of up to five (5) members, one (1) of whom serves as the Chief Executive Officer. Among the Collegiate Board’s key responsibilities are its role in defining ANVISA’s strategic guidelines and proposing governmental policies and directives to the Minister in support of the agency’s health surveillance objectives.

LawNo9.782 and ResNo255 further indicate that ANVISA has an Advisory Board. Per ResNo255 and BRA-36, the Advisory Board’s main objectives include requesting information and proposing guidelines and technical recommendations to the Collegiate Board to be addressed by ANVISA, and providing opinions on proposed governmental policies. Refer to LawNo9.782, ResNo255, and BRA-36 for detailed Collegiate Board and Advisory Board responsibilities.

As delineated in ResNo255, ANVISA’s General Management of Medicines and Biological Products (Gerência-Geral de Medicamentos e Produtos Biológicos (GGMED)) coordinates and supervises the organizational units responsible for the regulation of active pharmaceutical ingredients, medicines, and biological products, and manages the implementation of international cooperation activities aimed at regulating active pharmaceutical ingredients, medicines, and clinical research involving human beings. The Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is an administrative unit operating within GGMED that evaluates the processes and petitions related to clinical research on drugs and biological products, and issues technical opinions with the goal of granting approval to initiate clinical research in Brazil. See ResNo255 for detailed information on 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). BRA-73 and BRA-113 indicate that Brazil implemented the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) in 2019.

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-42, the following is ANVISA’s contact information:

ANVISA
Setor de Indústria e Abastecimento (SIA)
Trecho 5
Área Especial 57
CEP: 71.205-050
Brasília - DF

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

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

Per BRA-12, the medicines and biological products contact information is as follows:

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

Per BRA-18, the clinical research 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 delineated in ResNo9 and ResNo255, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications (referred to as Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs))) for drugs to be registered in Brazil. Per ResNo9, the G-DDCMManual, and BRA-8, the DDCM must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the application to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM, also known as Experimental Drug Dossiers. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. Per ResNo9 and BRA-8, while the DDCM may be submitted at any stage of development, Phase IV post-marketing trials are only subject to Clinical Trial Notification by ANVISA after obtaining ethical approvals. See ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products in Brazil (i.e., medicines for human use that are based on genes, tissues, or cells).

In addition, ResNo205 repealed the ResNo9 requirement that the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel. As indicated in ResNo9 and also noted in BRA-2, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))’s approval is required for certain studies (e.g., foreign studies), but ANVISA’s decision to approve the DDCM is not dependent on CONEP. Similarly, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory for all studies, but may be requested, according to BRA-1. However, per ResNo9, the EC (CEP) is required to approve substantial protocol amendments prior to implementation. Refer to the Ethics Committee topic for additional information on the CEP/CONEP System; CLNo038 for the criteria CONEP uses to process protocol amendments; and CLNo24 and CLNo24-Note for general guidelines on conducting clinical trials.

Clinical Trial Review Process

As delineated in ResNo255, 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). ResNo9 and the G-DDCMManual explain that following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all the trials included in the DDCM that are permitted to initiate the clinical study. BRA-8 further explains COPEC experts conduct a preliminary review that includes a benefit-risk assessment based on various criteria such as drug registration status and drug status in other agencies (e.g., fast-track or breakthrough therapy). After this evaluation, the reviewer may release the dossier by the expiration deadline date so that the sponsor (applicant) may proceed with conducting the trial, requesting a meeting, or conducting a more detailed and complete dossier evaluation. See the Timeline of Review section for additional ANVISA timeline information. Also, see BRA-79 for additional information on ANVISA’s clinical trial review and approval framework, and BRA-40 for information on ANVISA drug registration requirements.

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

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

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

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

See also BRA-19 and BRA-90 for guidance on scheduling pre-submission meetings with COPEC to discuss the clinical development of a drug (e.g., DDCM, an amended 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.

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 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 is to be used for neglected, emerging, or reemerging diseases, health emergencies, or serious debilitating conditions for which there is no alternative; the trial is to be conducted exclusively with the pediatric population; or the drug will be used in a Phase I trial only to be manufactured in Brazil. The sponsor should specify at the time of submission that the new or amended protocol is a priority category request. If not confirmed prior to the technical review phase, the request for approval may be denied. ANVISA is required to 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 detailed timeline information. Refer to ResNo204, ResNo811 (which partially amends ResNo204), and BRA-14 for detailed information on priority submission requirements.

See also BRA-2, BRA-1, and BRA-42 for additional information on priority submission.

New Drugs for Rare Diseases

ResNo205 sets forth specific approval procedures for clinical trials to be conducted to register new drugs to treat, diagnose, or prevent rare diseases. 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, 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. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.

Equivalent Foreign Regulatory Authority Submissions

ResNo741 provides general criteria for the admissibility of the Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) regulatory documentation that ANVISA requires to conduct a technical evaluation using the “optimized analysis procedure”. ANVISA defines the optimized analysis procedure as a technical evaluation mechanism that uses the AREE’s documentation, which includes reports, opinions, or technical/legal documents used to issue an opinion, as a sole or complementary reference. The optimized analysis procedure is facilitated by regulatory trust practices that are based on collaborative work and recognition, mutual or unilateral, among regulatory authorities or international entities. Among other requirements, in order for ANVISA to adopt the optimized analysis procedure, the health product covered in the AREE’s documentation must be essentially identical to the one submitted for ANVISA’s evaluation; and the products authorized for distribution should also have been adequately evaluated, and meet recognized standards of quality, safety, and efficacy. The specific criteria and procedures for defining the AREEs will be established in normative acts in a phased approach, according to each type of health surveillance process or product category. RegNo289 and RegNo292 are the initial normative acts adopted by ANVISA to define these processes/categories.

In accordance with ResNo741, ANVISA approved RegNo289, which establishes the criteria and procedures for ANVISA’s technical evaluation, known as the optimized analysis procedure, of one (1) or more AREE assessments 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 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. Additionally, RegNo289 also provides procedures for regulatory authorities to be designated as AREEs and a list of the currently approved AREEs.

Pursuant to RegNo289, ANVISA has designated the following foreign agencies as AREEs:

• European Medicines Agency (EMA)
• Health Canada
• European Directorate for the Quality of Medicines & HealthCare (EDQM)
• Swiss Agency for Therapeutic Products (Swissmedic)
• MHRA, UK
• 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 also BRA-26 for additional background information on RegNo289. See ResNo741 for additional information on the optimized analysis procedure and AREE related requirements. See also the Manufacturing & Import section for additional information on RegNo292.

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 ResNo9 and 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 DDCM request (“petition” in Portuguese), 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, BRA-69 for information on the TFVS fee, and BRA-10 for additional information on TFVS requirements. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

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 BRA-11, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval. BRA-8 further notes that ANVISA charges a fee for substantial amendments to the clinical protocol. Additionally, 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 information.

Payment Instructions

As described in ResNo857, the TFVS fee must be paid by 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 explained in BRA-115, PagTesouro (BRA-114) is programmed to allow the payment of all fees related to ANVISA petitions in the Solicita system (BRA-56). 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

As per ResNo466, ResNo446, and OSNo001, Brazil has a centralized registration process for research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) and requires institutional level EC (CEP) approval for each trial site. The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs (CEPs), and for registering and accrediting the ECs (CEPs). ResNo466, ResNo446, and OSNo001 state that CONEP is a collegiate advisory body directly linked to the National Health Council (Conselho Nacional de Saúde (CNS)), a permanent body within the Ministry of Health (MOH)’s Unified 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 particular 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, BRA-16, 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. The members represent a balanced gender composition; eight (8) members must equally represent various segments of the CNS. In addition, according to BRA-16, five (5) members must have a background in ethical research and health, and eight (8) members must represent the theological, legal, health management, and other related professions. Per ResNo446, CONEP also has an Executive Secretary appointed by the MOH’s Secretariat for Science, Technology and Strategic Inputs and an Assistant Secretary appointed by the CNS to coordinate CONEP’s work and to manage the technical and operational work to be carried out by the Executive Secretary. See ResNo466, OSNo001, ResNo446, and BRA-16 for detailed information on CONEP composition and responsibilities. See also BRA-50 for useful information on CONEP.

Research Ethics Committees (CEPs)

As per the PANDRH-GCPs, an institutional EC (CEP) must have at least five (5) members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. By comparison, the OMREC requires the EC (CEP) to be composed of a minimum of seven (7) members having proven expertise in research. ResNo706, in turn, states the EC (CEP) must be composed of at least nine (9) members with at least two (2) Research Participant Representatives (Representantes de Participante de Pesquisa (RPPs)).

The PANDRH-GCPs, the OSNo001, OMREC, and ResNo706 also indicate that the EC (CEP) should be multidisciplinary, represent a balanced gender and age composition, and consist of members embodying community interests and concerns. The OMREC and ResNo706 further state that not more than half of its members should belong to the same professional category. ResNo706 also notes that at least half of members must demonstrate experience in research. In addition, as per the PANDRH-GCPs, in communities where minority ethnic populations predominantly reside, the EC (CEP) should include a member, alternate, or consultant from that group. The EC (CEP) may also designate alternate members whose functions are delineated in the EC’s (CEP’s) standard operating procedures (SOPs). Per ResNo706, any changes to the infrastructure, composition of members or administrative employees must be communicated to CONEP. When there is a change in CEP member composition, at least one third of the members of the previous composition must be maintained. Changes in 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 3.2 of the PANDRH-GCPs and Section 2 of OMREC.

ResNo647 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

As set forth in the PANDRH-GCPs and OMREC, each EC (CEP) must have written SOPs, including a process for conducting reviews. The SOPs should include information on EC (CEP) composition, meeting schedules, frequency of reviews, requirements for initial and ongoing evaluation of the research study, and requirements for notifying the investigator and the institution of results related to the study’s initial and ongoing evaluation. 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

Also, as noted in ResNo706, 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 the PANDRH-GCPs, 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.

The PANDRH-GCPs also state that the EC (CEP) must retain all relevant records (e.g., SOPs, member lists, member affiliations and occupations, documents presented, meeting minutes, and correspondence) for three (3) years after the study’s conclusion, and make them available to the regulatory authorities upon request.

For detailed EC (CEP) procedures and information on other administrative processes, see Sections 3.3 and 3.4 of the PANDRH-GCPs and the OMREC. Also, see CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up 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

As set forth in ResNo466, the PANDRH-GCPs, ResNo251, and the G-ClinProtocols-FAQs, the primary scope of information assessed by research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), jointly known as the CEP/CONEP System, relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial.

Per ResNo466, the PANDRH-GCPs, ResNo251, and OSNo001, the CEP/CONEP System 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, the PANDRH-GCPs, and OSNo001. It must act in the interests of the potential research participants and the communities involved, evaluating the possible risks and expected benefits to participants, confirming the suitability of the investigator(s), facilities, and methods, and verifying the adequacy of confidentiality and privacy safeguards. Refer to ResNo466, the PANDRH-GCPs, and OSNo001 for detailed ethical review guidelines that govern the CEP/CONEP System.

National Research Ethics Commission (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).

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, BRA-4, and BRA-5 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures. (Please 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 the Plataforma Brasil webpage for any developments.)

Role in Clinical Trial Approval Process

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

In addition, as indicated in ResNo9, and also noted in BRA-2, CONEP’s approval is not a requirement for ANVISA to approve the DDCM. However, the PANDRH-GCPs, ResNo9, and OSNo001 state that the EC (CEP) must review and approve any protocol amendments prior to those changes being implemented. According to BRA-1, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory, but may be requested. In these cases, only the EC (CEP) is required to approve the amended protocol prior to implementation and ANVISA should be notified. Per ResNo9, the EC (CEP) is required to approve substantial protocol amendments prior to implementation. See ResNo9 and the G-DDCMManual for additional information on preparing DDCMs, and 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. Also see the Timeline of Review section for additional EC timeline information. There is no stated expiration date for an EC (CEP) approval in ResNo466, the PANDRH-GCPs, ResNo9, or OSNo001. However, in the event that an EC (CEP) revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator and ANVISA.

Per CLNo29, in the case of an appeal, only the researcher 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 researcher 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 researcher, 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.

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

• EC (CEP) member profiles (names and addresses)
• Documented approval of EC (CEP)’s favorable opinion
• Copy of EC (CEP) recommendations in case it has based its approval on change(s) in any aspect of the study (e.g., protocol modifications, written informed consent form, (ICF) or any other written information or other procedures)

Per the PANDRH-GCPs, the sponsor should also obtain documentation and dates relating to any EC (CEP) re-evaluations, re-approvals, withdrawals, or suspensions of approval from the investigator. (See the Submission Content section for additional details on the EC review process).

Additionally, CONEP has published a number of circular letters to clarify protocol review and processing procedures, submission instructions, and investigator responsibilities related to the following:

• Classifying protocol thematic areas requiring CONEP review (CLNo172)
• Processing protocol amendments (CLNo038)
• Providing general clinical trial guidelines (CLNo24 and CLNo24-Note)
• Presenting documentation required for CONEP analysis (CLNo062)
• Conducting virtual CEP/CONEP System meetings (CLNo25)
• Updating the informed consent form (ICF) (CLNo17)
• Additional clarifications on ICF text (CLNo51)
• Obtaining consent for human specimens (CLNo041)
• Using medical records data for research purposes (CLNo039)
• Submitting requests for research center inclusion/exclusion (CLNo046)
• Processing biobank development protocols electronically (CLNo34)
• Linking investigator/institutions to the responsible EC in submissions (CLNo183)
• Standardizing consent and electronic assent for research participants and biobanks (CLNo23)
• Submitting research protocols with human bodies and/or anatomical parts (CLNo26)
• Processing adverse events for Brazil and abroad (CLNo13)
• Submitting the Serious Adverse Event (SAE) form and instructions (CLNo008)
• CEP protocol processing timeline and responsibility to researchers/research participants in the event of a temporary strike or institutional recess (CLNo10)
• Submitting appeals to the CEP/CONEP System (CLNo29)
• Obtaining consent from research participants under 18 years old and people with “absence of autonomy” (CLNo11)

The above circulars are described in more detail where appropriate across the Brazil profile.

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

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

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 Commission (CONEP)

According to ResNo466, OMREC, and ResNo706, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit research ethics committees (ECs) (Comitês de Ética em Pesquisas (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

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

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

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

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

LawNo14.874, which comes into force on August 27, 2024, establishes the National System of Ethics in Research with Human Beings (Sistema Nacional de Ética em Pesquisa com Seres Humanos), which consists of a national research ethics body and an ethical analysis research body, represented by the ECs (CEPs). The national research ethics body, 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)

The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

Registration, Auditing, and Accreditation

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 guardian, 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 date of publication 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 the Plataforma Brasil webpage 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 ResNo9, the G-DDCMManual, and BRA-8, the sponsor, the designated contract research organization (CRO), or the sponsor-investigator must apply to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to obtain approval for a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) for a drug to be registered in Brazil that will have all or part of its development in Brazil. Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside of Brazil require additional EC review by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. ResNo205 repealed the ResNo9 requirement that EC (CEP) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel.

Regulatory Submission

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

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

For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA, as stated in ResNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial DDCM submission. If the modification has occurred following ANVISA’s issuance of the authorizing document known as a Special Notice (Comunicado Especial (CE)), per BRA-8, ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version. While sponsors are required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, they are only required to submit substantial protocol amendments via a secondary petition whereas non-substantial DDCM protocol amendments should be submitted as part of the annual clinical trial report. Non-substantial amendments that do not impact the protocol should be presented to ANVISA as part of the drug development safety update report. See BRA-13 for updated ANVISA application forms.

See ResNo742, BRA-8, BRA-6, and BRA-7 for requirements associated with submitting DEECs for comparative bioavailability studies and comparative pharmacokinetic studies for biosimilars.

As described in the G-DDCMManual and BRA-8, all DDCM petitions (both initial and secondary) should be submitted electronically to ANVISA via the Solicita Electronic Petition Request System (BRA-56). Per BRA-58, once 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 explained 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. BRA-59 provides detailed instructions for submitting the DDCM checklist documents via BRA-56.

As per ResNo857, BRA-47, and BRA-43, once the sponsor has completed the process of submitting a DDCM request (“petition” in Portuguese), 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 Request Form. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

Per the G-DDCMManual, all of the other documentation associated with the original DDCM including the secondary petitions and the DEEC(s) should be submitted electronically via BRA-56. ResNo204 and BRA-14 further note that DEECs may be submitted as priority requests to ANVISA to register, amend previously registered, or request prior consent for drug submissions. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections. The G-DDCMManual also specifies that for the electronic submission of secondary petitions and DEECs, the sponsor should append at least one (1) PDF file for each item contained in the petition checklist to enable text searching. It is possible to attach up to five (5) files of 750 kb each. BRA-8 also provides an example of an electronic submission in Annex 1.

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

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.

Ethics Review Submission

Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the PI must also 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 review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil 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 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

As delineated in ResNo9 and the G-DDCMManual, to complete the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), the sponsor, the designated contract research organization (CRO), or the sponsor-investigator is required to submit the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s DDCM Petition Request Form (BRA-21) along with the following documentation (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Health Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResNo857 (fee required by individuals and companies engaged in clinical research)
• Drug development plan (known as experimental drug dossier) (See the G-BioIProdManual for instructions on completing a biological products dossier and the G-SynthDrugProdManual for completing a synthetic/semi-synthetic products dossier)
• Certified copy of the clinical agreement (contract or statement) that has been written, dated, and signed by the sponsor or the CRO
• Clinical research protocol
• Investigator’s Brochure (IB)
• Summary of the investigational product (IP)’s safety aspects based on previous research in humans
• Information on any discontinued development or withdrawal of IP
• IP dossier
• Specific dossier for each clinical trial to be conducted in Brazil
• Proof of clinical trial registration in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE) (Note: the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.) Per ResNo449, which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25). Note that per ResNo205, the ResNo9 requirement to include the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval in the initial DDCM or in any protocol amendment submission has been revoked.

Substantial Protocol Modifications

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

While the sponsor is required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, they are only required to submit substantial protocol amendments via a secondary petition whereas non-substantial DDCM protocol amendments should be submitted as part of the annual clinical trial report. Non-substantial amendments that do not impact the protocol should be presented to ANVISA as part of the drug development safety update report. See ResNo9 and the G-DDCMManual for detailed ANVISA application submission requirements, BRA-22 for the clinical trial submission form, and BRA-13 for updated ANVISA application forms. See also BRA-95 for instructions on providing expiration date information for imported IPs to be used during the trial and which the sponsor must include in its submission in BRA-22.

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

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

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

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

Ethics Committee Requirements

As per OMREC and OSNo001, the CONEP requires 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 (BRA-20)
• Clinical research protocol (in Portuguese)
• Background, justification, and registration in the country of origin for drug and device health products
• Description of materials, methods, rationale, expected results, and bibliography
• Critical risk and benefit analysis
• Duration
• Responsibilities of 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 to agree to comply with BRA-20; justification for inclusion of healthy participants; forms of recruitment)

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

Clinical Protocol

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

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

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

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

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

Regulatory Authority Approval

As specified in ResNo9, upon receipt of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), ANVISA has 90 calendar days to evaluate the application. If the agency fails to issue a response within 90 days of receipt, clinical development can begin as long as all of the ethical approvals have been obtained. ResNo9 further notes that ANVISA will conduct a technical review within 180 days following receipt of DDCMs that fall into at least one (1) of the following categories: national development, biological product clinical development including vaccines, and Phase I or II clinical development studies. For DDCMs in one (1) of these categories, ANVISA’s technical area only evaluates the clinical study technical reports.

Timeline information for ANVISA’s simplified analysis of DDCMs that meet the criteria for ServBltnNo104 is not available. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.) 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 Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (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, with an issuance of a notification of requirement or a manifestation 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), BRA-8, and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.

Ethics Committee Approval

As set forth in LawNo14.874, which comes into force on August 27, 2024, a research ethics review carried out by the EC (CEP), with the issuance of the opinion, may not exceed 30 business days from the date of acceptance of all research documents, and 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 researcher or research sponsor or make adjustments to the research documentation, for up to 20 business days. See the Scope of Review section for details on the EC (CEP) review processes.

The ClinRegs team will provide additional information on the implementation of LawNo14.874 as it becomes available. See also BRA-117 for additional information.

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.

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

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.

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

In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, a clinical trial can only commence after the sponsor, the designated contract research organization (CRO), or the sponsor-investigator receives clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside Brazil require an additional review and approval by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. Please refer to Scope of Review and Oversight of Ethics Committees sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. No waiting period is required following the sponsor’s receipt of these approvals.

In addition, per ResNo9, 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). The trials should be conducted in compliance with the PANDRH-GCPs, ResNo466, and ResNo9. Clinical trials must also be conducted in a laboratory complying with the Organisation for Economic Co-operation and Development (OECD)’s Principles on Good Laboratory Practice (GLP) (BRA-15) as mandated by Brazil’s National Institute of Metrology, Quality and Technology (INMETRO). Refer to BRA-15 and BRA-48 for additional information on GLP requirements.

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

Clinical Trial Agreement

As delineated in the PANDRH-GCPs, the sponsor or the CRO must sign an agreement or contract with the participating institution(s) and the investigator. In addition, if a sponsor decides to engage a CRO to conduct the trial, a letter of agreement should also be submitted to ANVISA as specified in the PANDRH-GCPs and ResNo9.

Clinical Trial Registration

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

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). BRA-44 provides public information about the status of each clinical trial, the trial location, and the researchers responsible for conducting the trial. See BRA-32 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 the PANDRH-GCPs, ResNo9, the AESafetyManual, and CLNo13, the following definitions provide a basis for a common understanding of Brazil’s safety reporting requirements (Note: 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) – All harmful unintended responses to a medicinal product related to any dose
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any unfavorable occurrence that at any dose results in death, is life-threatening, requires or extends patient hospitalization, results in persistent or significant disability or permanent damage, or is a birth defect or congenital anomaly; significant medical occurrence, which based on appropriate medical judgment, may harm the participant and/or require medical or surgical intervention to prevent any of the other occurrences mentioned
• Unexpected Adverse Drug Reaction – One whose nature or severity is inconsistent with the applicable product information (i.e., the investigator’s brochure for an unapproved investigational product (IP), or package insert/summary of the characteristics of an approved product)

Safety Reporting Requirements

Investigator Responsibilities

As specified in ResNo9 and the AESafetyManual, the investigator must inform the sponsor within 24 hours of all SAEs/SADRs occurring during the study. The PANDRH-GCPs also states that the immediate reports should be followed promptly by detailed, written reports in which the participants are identified by unique code numbers. AEs/ADRs identified in the protocol as critical to safety evaluations should also be reported to the sponsor. Per the AESafetyManual, the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the research ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)) with any additional requested information (e.g., autopsy reports and terminal medical reports).

Sponsor Responsibilities

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

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

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

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

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

Per BRA-73, Brazil has implemented the ICH Harmonised Tripartite Guideline: Clinical Safety Data Management: Definitions and Standards for Expedited Reporting (E2A) (BRA-66) and the ICH Harmonised Tripartite Guideline: Development Safety Update Report (E2F) (BRA-72).

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

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

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

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

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

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

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

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

Final Report

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

• Trial title
• Protocol code
• Breakdown of the number of participants recruited or removed from the trial
• Description of participants included in each statistical analysis and those who were excluded from the efficacy analysis
• Participant demographics and statistics
• Number/description of protocol deviations and violations
• All adverse events/laboratory abnormalities with causality assessment occurring in participants
• Results obtained in the measurement of outcomes for each participant
• Rationale for early termination in Brazil or elsewhere in the world, where applicable

Per G-CTReptsManual, the annual and final reports for each clinical protocol shall contain the minimum requirements set forth in Articles 68 and 69 of ResNo9, or they may be submitted using the ICH E3 format (BRA-27). See BRA-23 for the annual/final report form.

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

Other Reporting Requirements

As stated in ResNo9 and the G-CTReptsManual, in addition to submitting a final report, the sponsor is also responsible for submitting clinical trial start and end date forms for trials conducted in Brazil. The forms with the trial start and end dates must be filed as a secondary petition to the corresponding trial dossier within 30 calendar days after each start and end date. The secondary petition should be submitted to ANVISA using the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) Petition Request Form (BRA-21). See BRA-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 ResNo466, ResNo9, and the PANDRH-GCPs, a sponsor is defined as an individual, company, institution, or organization that supports research through the initiation, management, or financing of a clinical trial.

ResNo9 states that a sponsor can authorize a contract research organization (CRO) to carry out certain work and obligations regarding the trial. As delineated in ResNo9, any trial-related responsibilities to be transferred and assumed by a CRO should be specified in a written agreement or contract.

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

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 in the PANDRH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial while taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by education, training, and experience to assume responsibility for the proper conduct of the trial. Investigator(s) should also 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 regulatory authority(ies).

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 PANDRH-GCPs and ResNo9, the sponsor may transfer any or all of the sponsor’s study related duties and functions to a contract research organization (CRO). 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. Other duties, functions, or responsibilities not specifically transferred shall be deemed as retained by the sponsor. However, as per ResNo9, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.

Data Safety and Monitoring Board

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

Multicenter Studies

Per the PANDRH-GCPs, in the event of a multicenter clinical trial, the sponsor or the CRO should ensure that all investigators conduct the trial in strict compliance with the protocol as well as with the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s and the EC (CEP)’s requirements. 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 PANDRH-GCPs, the sponsor is responsible for providing insurance coverage for any unforeseen injury to research participants. Before the clinical trial begins, the sponsor should also provide insurance or indemnify the investigator and the institution against claims arising from malpractice or negligence.

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

Compensation

Injury or Death

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

Trial Participation

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

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

Post-Trial Access

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

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

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 stated in ResNo9, the sponsor or the contract research organization (CRO) must ensure that quality assurance and quality control be implemented in all areas of the institution’s development of the investigational drug in accordance with the PANDRH-GCPs and the International Conference on Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28). The PANDRH-GCPs and BRA-28 specify that the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol, good clinical practices (GCP), and other applicable requirements.

Per the PANDRH-GCPs and BRA-28, the sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.

Additionally, the PANDRH-GCPs and BRA-28 state that the sponsor must also obtain the investigator(s) and the institution(s) agreement to:

• Conduct the trial in compliance with GCP, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP))
• Comply with data recording and reporting procedures
• Permit monitoring, auditing, and inspection
• Retain essential documents until the sponsor indicates they are no longer needed

Monitoring Requirements

As part of its QA system, the PANDRH-GCPs, and BRA-28, note that the sponsor or the CRO should ensure the trial is adequately monitored. The PANDRH-GCPs and BRA-28, also explain 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. The sponsor must also verify that the audit is conducted in accordance with their own SOPs, the auditor observations are documented, and data is available as needed for the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s review.

No specific timeframe is provided for the audit process. Refer to the PANDRH-GCPs and BRA-28 for detailed audit requirements.

In addition, per ResNo449, which amends ResNo9, ANVISA is allowed to use remote GCP inspection mechanisms for temporary and emergency use in lieu of in-person inspections. Remote inspections are carried out by means of videoconferencing and data transmission technologies for GCP verification. Remote inspections replace the need for in-person inspectors in the establishment. Establishments under inspection may be inspected remotely at any time by ANVISA.

RegNo122 provides further guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with the GCPs delineated in ResNo9, the PANDRH-GCPs, and the BRA-28. Per BRA-30, ANVISA’s administrative unit, the Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)), requires all clinical trial inspections to be conducted in accordance with BRA-28.

In the event of a routine inspection, RegNo122 states that ANVISA 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 shall also notify the principal investigator (PI) of the scheduled visit to the center to be inspected, when applicable, by means of a GCP Inspection Notification Letter. For more detailed information on ANVISA’s inspection process, refer to RegNo122.

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.

GuideNo35-2020 and GuideNo36-2020 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.

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

Premature Study Termination/Suspension

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

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

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

In addition, ResNo9 states that ANVISA may, at any time, cancel or suspend a DDCM or any related clinical trial if it believes that the approval conditions have not been met or if there are safety or efficacy reports that significantly affect either the trial participants or scientific validity. In this case, ANVISA will inform the sponsor of the reasons for this cancellation or suspension. Per ResNo9, the sponsor must immediately inform those involved in a clinical trial when it is prematurely cancelled or suspended for any reason. The PANDRH-GCPs and BRA-28 also explain 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 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, per the PANDRH-GCPs and BRA-28, 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

Per the PANDRH-GCPs, when using electronic trial data processing systems, the sponsor or the contract research organization (CRO) must ensure that the system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance, and that standard operating procedures (SOPs) are maintained when using these systems. Refer to the PANDRH-GCPs for detailed information on electronic trial data systems.

Records Management

As set forth in ResNo9, the sponsor or the CRO should maintain the clinical trial data on file in physical or digital format for a period of five (5) years after the last approval of a request for registration in Brazil. ResNo9 and the PANDRH-GCPs also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, a marketing application receives the last approval, or there are no pending or contemplated marketing applications. Per the PANDRH-GCPs, the sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

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 and 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. See also BRA-116 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.

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, 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.

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 the PANDRH-GCPs, ResNo466, and the G-ClinResSubjectRts. Per OMREC and G-ClinResSubjectRts, the informed consent form (ICF) is also known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.

As per the PANDRH-GCPs, ResNo466, the G-ClinResSubjectRts, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by an research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and provided to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) with the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). CLNo51 further clarifies that the ICF should be written as an invitation rather than as a statement as this may reduce the participant’s autonomy. Refer to CLNo51 for detailed information. See the Required Elements section for details on contents to be included in the form.

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the investigator, or their designated representative, must provide detailed research study information to the participant or legal representative/guardian. As delineated in ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, OMREC, and the G-ClinProtocols-FAQs, the ICF content should be presented in a clearly organized format using practical and non-technical language commensurate with the participant’s level of understanding. Per the PANDRH-GCPs and the G-ClinResSubjectRts, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. The PANDRH-GCPs further explains that none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or legal representative/guardian to waive or to appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. ResNo466 and the G-ClinResSubjectRts further note that the investigator must bear in mind that the prospective participant’s ability to understand the information required to give consent depends on their maturity, ethics, intelligence, education, and cultural beliefs. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and the G-ClinProtocols-FAQs, the information should be in both written and oral form, and the participant and the legal representative/guardian should also be given adequate time to consider whether to participate. See also BRA-29 for additional information on informed consent.

Re-Consent

According to the PANDRH-GCPs and CLNo17, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by the EC (CEP) and submitted to ANVISA before such changes are implemented. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and CLNo51, the 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, the PANDRH-GCPs and the G-ClinResSubjectRts require the ICF to be presented orally and in writing at a level that the participant is able to understand. Per the PANDRH-GCPs, the investigator should provide the ICF in the participant’s own language when they do not speak the language currently spoken in the country. The G-ClinProtocols-FAQs further notes that the ICF must be adequately adapted and be fully revised in Portuguese to ensure that the document is properly translated.

Documenting Consent

The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the participant or legal representative/guardian, and the investigator(s) must sign and date the ICF. In addition, the PANDRH-GCPs explains that if the participant or legal representative/guardian is illiterate, an impartial witness should be present throughout the 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 the PANDRH-GCPs, OMREC, and the G-ClinResSubjectRts, the participant should receive a copy of the signed and dated ICF, and any other written information provided during the informed consent process. ResNo466 and the G-ClinProtocols-FAQs specify that two (2) original copies of the ICF should be prepared with all pages initialed and signed by the participant 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 information on waivers pertaining 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 the PANDRH-GCPs, ResNo466, and OMREC, 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, the procedures, and duration of the trial
• The participant’s responsibilities
• Experimental aspects of the study
• The approximate number of participants in the study
• Any expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
• Any expected benefits to the participant; if no benefit is expected, the participant should be informed of this point
• Treatments available to participants, how they are administered, and the probability of receiving every treatment
• Compensation and/or treatment available for the participant in the case of trial-related injury
• The disclosure of specific appropriate alternative procedures or therapies available to the participant
• The probability for random assignment to each treatment
• Any expenses the participant needs to pay to participate in the trial
• Confidentiality of records identifying the participant will be maintained, and permission given to monitors, auditors, the ethics committee(s), and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to access the participant’s medical records to verify the procedures or trial data without violating the participant’s confidentiality, insofar as the applicable laws and regulations permit
• That participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
• Contact information for the sponsor and investigator in the event of participant problems or trial-related injuries
• Foreseeable circumstances under which the investigator(s) may remove the participant without 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 ResNo466, the PANDRH-GCPs, and OMREC, Brazil’s ethical standards promote respect for all human beings and safeguard the rights of research participants, including rights to their autonomy, culture, beliefs, and values. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.)

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. 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 ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, 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, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, 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, the PANDRH-GCPs, and OMREC, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The PANDRH-GCPs also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identities and records of research participants.

The Right of Inquiry/Appeal

The PANDRH-GCPs, OMREC, and the G-ClinResSubjectRts explain that the research participant 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

ResNo466 and PANDRH-GCPs 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 per the PANDRH-GCPs, 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 research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must provide documented approval in order to protect the participant’s rights, safety, and well-being, pursuant to the applicable regulations. The participant or legal representative/guardian should provide consent as soon as possible. OMREC and ResNo251 similarly state that the EC (CEP) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner 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 per the PANDRH-GCPs and the G-ClinResSubjectRts, in all Brazilian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The PANDRH-GCPs, ResNo466, and the G-ClinResSubjectRts characterize vulnerable populations as those who are relatively (or absolutely) incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes. These participants may include those with incurable diseases, people in convalescent homes, the unemployed or indigent, patients in emergency situations, ethnic minorities, homeless people, seasonal workers, refugees, minors, and those who cannot give their consent.

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

The ResNo466 and PANDRH-GCPs specify that research ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) must pay special attention to protecting participants who are from vulnerable populations. If the EC (CEP) regularly evaluates studies involving vulnerable populations, it should consider including members or consultants who know or have had experience working with the group in question. ResNo466 and the G-ClinResSubjectRts also state that vulnerable groups should not be included unless the research is necessary to promote the health of the population represented, and this research cannot instead be performed on legally competent participants.

See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (CEPs) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. 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 PANDRH-GCPs, ResNo466, and OMREC, when the research participant is a child, the child’s parent/legal guardian must sign the informed consent form. However, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand.

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

In addition, per CLNo11, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (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.

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 states that researchers 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.