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

Health Canada

As per the CanadaFDA, the CanadaFDR, and the G-CanadaCTApps, Health Canada (HC) is the competent authority responsible for clinical trial approvals, oversight, and inspections in Canada. The G-CanadaCTApps states that the HC grants permission for clinical trials to be conducted in the country, and regulates the sale and importation of drugs for use in clinical trials in accordance with the CanadaFDR provisions.

As per CAN-29, HC is one (1) of five (5) federal agencies within Canada’s “Health Portfolio” overseen by the Minister of Health. Per CAN-31, HC assesses clinical trial protocols to evaluate participant protection and safety; reviews drug quality; assures institutional ethics committee review; verifies principal investigator qualifications; and monitors and reviews adverse drug reactions. As delineated in CAN-23, HC’s Health Products and Food Branch (HPFB) is the national authority that regulates, evaluates, and monitors therapeutic and diagnostic product safety, efficacy, and quality, and reviews the information submitted in the clinical trial application. Per CanadaFDA, if the Minister believes on reasonable grounds that the use of a therapeutic product, other than the intended use, may present a risk of injury to health, the Minister may, by order, establish rules in respect of the importation, sale, conditions of sale, advertising, manufacture, preparation, preservation, packaging, labelling, storage, or testing of the therapeutic product for the purpose of preventing, managing, or controlling the risk of injury to health.

Per CAN-16, HPFB’s activities are carried out by nine (9) Directorates and one (1) office, including the Pharmaceutical Drugs Directorate (PDD) and the Biologic and Radiopharmaceutical Drugs Directorate (BRDD). Per CAN-18 and CAN-17, the PDD and the BRDD, respectively, regulate pharmaceutical drugs, and biological drugs and radiopharmaceuticals for human use. In addition, the G-CanadaCTApps indicates that the PDD’s Office of Clinical Trials (OCT) and the BRDD’s Office of Regulatory Affairs (ORA), among others, are directly involved with the clinical trial review and approval process for pharmaceutical, biological, and radiopharmaceutical drugs. Per the G-MDSA, the Therapeutic Products Classification Committee (TPCC) may be consulted when it is not clear whether a product should be classified as a drug or device. The committee makes recommendations on the classification of a product as either a drug, medical device, or combination product. If a product does not readily meet one (1) of the statutory definitions, other regulatory areas of HC are asked to participate in the committee's discussion.

As per CAN-41, Health Canada has established a regulatory innovation agenda, which aims to provide more regulatory flexibility to support innovative research and health product development. For more details, see CAN-41.

Per CAN-10, Canada is an official member of the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH). Per CAN-50, HC-implemented ICH guidelines take precedence over other HC guidance when they are not consistent. Per CAN-50, Canada has implemented the ICH’s Guideline for Good Clinical Practice E6(R2) (CAN-52). Also see CAN-50 for details on all the ICH guidelines implemented by HC. For any questions or comments, contact HC’s ICH Coordinator via email at ich@hc-sc.gc.ca.

Contact Information

According to the G-DrugApp and CAN-18, Health Canada PDD contact information is as follows:

Office of Clinical Trials
Pharmaceutical Drugs Directorate
Health Products and Food Branch
Address Locator: 3105A
Health Canada
Ottawa, Ontario, Canada
K1A 0K9

Phone (General Enquiries): 613-957-0368
Fax (General Enquiries): 613-952-7756
Office of Clinical Trials Inquiries: oct.enquiries-requetes.bec@hc-sc.gc.ca

Per CAN-17, the following is the contact information for biologic clinical trials:

Biologic and Radiopharmaceutical Drugs Directorate
Health Products and Food Branch
Health Canada
Building 6, Address Locator: 0601B
100 Eglantine Driveway
Tunney’s Pasture
Ottawa, Ontario, Canada
K1A 0K9

Phone: 613-863-8405
General Enquiries E-mail: brdd.dgo.enquiries@hc-sc.gc.ca

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 CanadaFDA, Health Canada (HC) reviews, evaluates, and approves applications for clinical trials using authorized therapeutic products. HC also approves the sale or importation of drugs for use in clinical trials. (See the Manufacturing & Import section for additional information on importation.) As delineated in the CanadaFDR and the G-CanadaCTApps, institutional ethics committee (EC) review is required for each clinical trial site and may occur in parallel with HC’s clinical trial application (CTA) review and approval. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. See CAN-23 and CAN-19 for background information on HC’s scope of assessment.

Per the CanadaFDA, a “therapeutic product” is defined as a drug or device, or any combination of drugs and devices, but does not include natural health products; and “therapeutic product authorization” refers to a license that is approved for the import, sale, advertisement, manufacture, preparation, preservation, packaging, labeling, storage, or testing of a therapeutic product. As per the G-CanadaCTApps, a drug is defined as a pharmaceutical, biologic, gene therapy, blood product, vaccine, and radiopharmaceutical for human use that is to be tested in a clinical trial. HC’s scope of assessment includes clinical trials (Phases I - III) using:

• Drugs not authorized for sale in Canada in development and in comparative bioavailability studies
• Marketed drugs where the proposed use of the drug for one (1) of the following is different: indication(s) and clinical use; target patient populations(s); route(s) of administration; or dosage regimen(s)

Clinical Trial Review Process

As set forth in the G-CanadaCTApps and CAN-23, HC’s Health Products and Food Branch (HPFB) coordinates the CTA approval process. The G-CanadaCTApps and CAN-23 state that prior to initiating the trial, the sponsor must file a CTA to the appropriate HPFB Directorate. CTAs involving pharmaceutical drugs should be sent to the Pharmaceutical Drugs Directorate (PDD), and CTAs involving biologics and/or radiopharmaceuticals should be sent to the Biologic and Radiopharmaceutical Drugs Directorate (BRDD).

The G-CanadaCTApps and CAN-23 indicate that upon receipt of a CTA, the HPFB Directorate (PDD/BRDD) screens the application package for completeness. If deficiencies are found, the Directorate sends the sponsor a Request for Clarification or a Screening Rejection Letter. If the Directorate finds the application complete, an acknowledgement letter is issued to indicate the 30-day default review period commenced on the date of receipt.

Per the G-CanadaCTApps, once a clinical trial is authorized, the sponsor is allowed to sell or import a drug for use in a trial, if a CTA has been filed with HC and has not received an objection within 30 days. As delineated in the G-CanadaCTApps and CAN-23, if the clinical trial is authorized, a No Objection Letter (NOL) is issued. If the CTA is rejected, a Not Satisfactory Notice (NSN) is issued. As specified in the G-CanadaCTApps and CAN-23, during the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. Please see the G-CanadaCTApps for special requirements regarding reviews of comparative bioavailability studies and joint reviews of clinical trials covering a combination of devices, biologics, and pharmaceuticals. See the Submission Process section for detailed application submission requirements.

Per the G-CanadaCTApps, soon after HC issues an NOL, it will publish the following information about the clinical trial in HC’s publicly accessible database:

• Protocol number
• Protocol title
• Drug name
• Medical condition
• Study population
• Authorization date
• Sponsor name
• HC control number
• Trial start and end dates, if known

The CanadaFDR and the G-CanadaCTApps also delineate that a clinical trial application-amendment (CTA-A) is required for proposed changes to a previously authorized study when the changes to clinical trial drug supplies affect the quality or safety of the drug, or when the changes to an authorized protocol alter the risk to clinical trial participants, or both. CTA-As must be authorized by HC prior to implementation of the changes. However, if the sponsor is required to immediately implement changes because the clinical trial or the use of the clinical trial drug endangers the health of participants or other persons, the sponsor may immediately make the amendment without prior review by HC. Sponsors must notify HC of this change, provide the relevant rationale in support of the immediate implementation, and file a CTA-A that clearly identifies the change and rationale for immediate implementation of the change within 15 days after the amendment implementation date. In addition, sponsors may make the following changes immediately if it notifies HC in writing within 15 days after the date of the change: a change to the chemistry and manufacturing information that does not affect the quality or safety of the drug; or a change to the protocol that does not alter the risk to the health of a participant.

Per the CanadaFDR, HC will suspend the authorization to sell or import a drug for clinical trial purposes if it has reasonable grounds to believe that:

• The sponsor has contravened any relevant laws or regulations
• Any information submitted in respect of the drug or clinical trial is false or misleading
• The sponsor has failed to comply with good clinical practices
• The sponsor has failed to provide information or samples as required by the regulation

See the CanadaFDR for additional details on HC’s suspension and cancellation responsibilities.

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).

According to CAN-33, there are no fees to submit a clinical trial application in Canada.

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

As indicated in the CanadaFDR and the G-CanadaCTApps, Canada has a decentralized process for the ethical review of clinical trial applications, and requires the sponsor to obtain institutional ethics committee (EC) approval for each participating trial site. (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information.

Per CAN-35 and CAN-13, all proposed or ongoing research involving human participants carried out by, funded by, or otherwise under the auspices of Health Canada (HC) or the Public Health Agency of Canada (PHAC) must obtain approval from a joint EC representing those two (2) agencies—as well as complying with the CanadaFDR and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50. This joint EC is known as the HC-PHAC REB. Further, if an institution is conducting an HC- or PHAC-funded project, the HC-PHAC REB must review and approve the research even if it has been previously reviewed and approved by another EC. See CAN-35 for details on the HC-PHAC REB’s development, responsibilities, and composition. HC’s operational policy (CAN-13) outlines policies and procedures that the joint HC-PHAC REB must follow when reviewing clinical trials.

Institutional ECs are required to comply with the provisions delineated in the CanadaFDR, the G-CanadaCTApps, and CAN-52. Note that per CAN-50, HC-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. In addition, institutional ECs are guided by the G-TCPS2. Jointly developed by Canada’s three (3) federal research agencies: the Canadian Institutes of Health Research (CIHR), the Natural Sciences and Engineering Research Council of Canada (NSERC), and the Social Sciences and Humanities Research Council (SSHRC), the G-TCPS2 is a policy that sets the ethical benchmark for all Canadian institutional ECs. However, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guideline as a condition of funding. According to CAN-14, the CIHR, the NSERC, and the SSHRC created the Panel on Research Ethics (PRE) to promote the ethical conduct of research involving human participants. The PRE develops, interprets, and implements the G-TCPS2.

Ethics Committee Composition

As delineated in the CanadaFDR, the G-CanadaCTApps, and CAN-52, institutional ECs must have at least five (5) members representing a mixed gender composition, the majority of which are Canadian citizens or permanent residents, and must include:

• Two (2) members from a scientific discipline, with broad experience in the relevant research methods and areas, one (1) of whom is from a medical or dental discipline
• One (1) member knowledgeable in ethics
• One (1) member knowledgeable in relevant Canadian biomedical research laws
• One (1) member from a nonscientific discipline
• One (1) community representative

The G-TCPS2 mirrors these EC composition requirements. As mentioned earlier, only CIHR-, NSERC-, and SSHRC-funded institutions are required to comply with this guidance as a condition of funding.

Terms of Reference, Review Procedures, and Meeting Schedule

According to CAN-52, institutional ECs must establish written standard operating procedures (SOPs) to cover the entire review process. The SOPs should include EC composition, meeting schedules, notifications, frequency of reviews, protocol deviations, reporting to the EC, and recordkeeping. Further, ECs should make decisions at announced meetings where a quorum is present. Only those members who participate in the EC review and discussion should vote, provide their opinion, or advise. For detailed EC procedures and information on other administrative processes, see CAN-52. For examples of EC SOPs, see CAN-13 for the HC-PHAC REB operational policy.

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 CanadaFDR, the G-CanadaCTApps, the G-TCPS2, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), the primary scope of information assessed by institutional ethics committees (ECs) (called Research Ethics Boards (REBs) in Canada) relates to maintaining and protecting the dignity and rights of human research participants and ensuring their safety throughout their participation in a clinical trial. ECs must also pay special attention to reviewing informed consent and protecting the welfare of certain classes of participants deemed vulnerable. (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations.) Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

CAN-52, which Canada has implemented per CAN-50, also states that ECs must ensure an independent, timely, and competent review of all ethical aspects of the clinical trial protocol. They must 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. See CAN-52 for detailed ethical review guidelines.

Role in Clinical Trial Approval Process

As per the CanadaFDR and CAN-52, HC must approve a clinical trial application (CTA) and an institutional EC(s) must give ethical clearance prior to a sponsor initiating a clinical trial. In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, institutional EC review for each clinical trial site may occur in parallel with HC’s CTA review and approval. Once HC completes its review, the department issues a No Objection Letter (NOL) if the CTA is approved. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until an institutional EC approval for each participating trial site is submitted. The sponsor should use the Clinical Trial Site Information Form (CAN-6) to submit the required information. The CanadaFDR also states that the EC must review and approve any protocol amendments prior to those changes being implemented. For HC’s interpretation of the relevant provisions of CanadaFDR, see the G-FDR-0100.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires EC review and approval of research involving living human participants and human biological materials. Further, ECs must have procedures in place to receive and respond to reports of new information, including, but not limited to, safety data, unanticipated issues, and newly discovered risks.

See TCPS2-InterpReview for the Panel on Research Ethics (PRE)’s interpretations of the G-TCPS2, including on the EC’s review of secondary use of non-identifiable information, delegated review of minimal risk studies, and ongoing review.

The G-TCPS2 lays out options, procedures, and considerations for the ethics review of multi-jurisdictional research either entirely within Canada, or in Canada and other countries. An institutional EC may approve alternative review models for research with multiple ECs and/or institutions but remains responsible for the ethics and conduct of research in its jurisdiction or under its auspices regardless of where the research is conducted. The SingleECRev provides guidance on the G-TCPS2’s single EC review model for multi-jurisdictional minimal risk, which seeks to streamline the research ethics review process where additional ethics reviews are not expected to add greater participant protections. In line with a proportionate approach to research ethics review, if research is of minimal risk and spans multiple jurisdictions, institutions that have approved the use of the single EC review model authorize the review of the research by one (1) EC. See the G-TCPS2 for more information about the various review models for multi-jurisdictional research.

Per CAN-8, an attestation must be completed by the EC that reviewed and approved the clinical trial. The completed attestation must be retained by the clinical trial sponsor for a period of 15 years. The attestation should not be submitted to HC unless requested. (See the Submission Process section for detailed submission requirements.)

The G-TCPS2 directs the researcher to submit an annual report to enable the EC to evaluate the continued ethical acceptability of the research. Per the G-CanadaCTApps, in the event that an EC terminates or suspends any prior approval or favorable opinion, it must document its views in writing, clearly identifying the trial, the documents reviewed, and the date for the termination or suspension.

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.

Institutional ethics committees (ECs) may independently decide whether to charge fees to conduct protocol reviews. For example, an institutional EC may require industry sponsors or other for-profit organizations to pay a fee. See specific examples of institutional fee requirements in CAN-3 and CAN-1.

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.

There are no applicable regulations or guidance regarding the registration, auditing, and accreditation of institutional ethics committees (ECs).

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 CanadaFDR and the G-CanadaCTApps, Canada requires the sponsor to obtain clinical trial authorization from Health Canada (HC) prior to initiating the trial. The sponsor must file a clinical trial application (CTA) to the appropriate Directorate within HC’s Health Products and Food Branch (HPFB). In addition, as delineated in the CanadaFDR and the G-CanadaCTApps, the sponsor may submit a CTA for clinical trial authorization to the HC in parallel with its submission to an institutional ethics committee (EC) (known as a Research Ethics Board (REB) in Canada) for a favorable ethical opinion. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form (CAN-6)) for each participating trial site is submitted. The HCNotice-CTSIForm indicates that the CTSI form improves efficiencies and supports the submission of CTAs using the electronic Common Technical Document (eCTD) format. See CAN-30 for instructions on filling out and submitting CAN-6.

CAN-19 provides a full list of HC’s forms for drug-related applications and submissions. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100. 

Regulatory Submission

Per the G-CanadaCTApps, CTAs (CAN-4) should be sent directly to the appropriate HPFB Directorate for review—the Pharmaceutical Drugs Directorate (PDD) for pharmaceutical drugs or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) for biological drugs and radiopharmaceuticals. The outer label should be clearly identified with "Clinical Trial Application." Per CAN-44, applicants must submit CTAs electronically in either eCTD format or non-eCTD format. According to the G-MDSA, HC does not accept paper copies of CTAs, CTA amendments, and CTA notifications.

The G-MDSA and the G-CanadaCTApps indicate that sponsors may request a pre-submission/application meeting with the appropriate Directorate within the HPFB if they have any questions or concerns prior to filing a CTA. Additional details on requesting a meeting and meeting procedures are available in the aforementioned guidance documents. According to CAN-4, the submission can be in French or English. For CTAs that use pharmacometric approaches, sponsors should consider the policy statements in G-Pharmacometrics. Pharmacometrics is the science of using quantitative analysis and modelling and simulation approaches to inform and enhance drug development and regulatory review. In addition, see the G-CTACell for guidance on preparing CTAs for use of cell therapy products in humans.

Per the CanadaFDR, an application by a sponsor for authorization to sell or import a drug for the purposes of a clinical trial must be submitted to HC, signed and dated by the sponsor’s senior medical or scientific officer in Canada and senior executive officer. The sponsor’s clinical trial attestation must be submitted with the application (CAN-4). For guidance on completing CAN-4, see the G-DrugApp.

eCTD Electronic Submission

As indicated in the G-eCTD, clinical trial applications in eCTD format are recommended, not mandatory. However, once a sponsor files a regulatory activity in eCTD format, all additional information and subsequent regulatory activities for the same dossier must be filed in eCTD format. CAN-36 explains that prior to filing the first regulatory transaction for a dossier in eCTD format, the sponsor must request a dossier ID using the online dossier ID request. Per the ElecSubms, CAN-20 is the request form for biological clinical trial dossiers and CAN-21 is for pharmaceutical clinical trial dossiers. A request for a dossier ID should be sent a maximum of eight (8) weeks prior to submitting the CTA. In addition, applicants should review the Rules-eCTD for validation rules before submission. (Note: As per ElecSubms, G-eCTD and CAN-36 are only available upon request at no-reply.ereview.non-reponse@hc-sc.gc.ca. Please ensure the text 'Request for eCTD Guidance Document' is in the subject line of the email.)

Per the G-eCTD and CAN-28, all regulatory transactions in eCTD format must be sent via the Common Electronic Submissions Gateway (CESG) (CAN-25), except for those exceeding 10 gigabytes (GB) in size. The CESG allows users to submit secure regulatory transactions electronically to HC, including CTAs. The G-eCTD and CAN-36 describe how to file CTAs and other clinical trial regulatory transactions (e.g., CTA amendments, responses to requests for information, and other in-scope activities) in eCTD format to CESG. The G-eCTD clarifies that prior to using the CESG for sending transactions, sponsors must register as a trading partner. To access and use CESG, CAN-34 instructs sponsors to follow these steps:

• Register as a trading partner with the US Food & Drug Administration (FDA) by completing the FDA Electronic Submissions Gateway (ESG) (CAN-51) registration for an account (CAN-47).
• Send regulatory transactions to HC by selecting “HC” as the center on the FDA ESG system; CTAs intended for HC will be automatically redirected.

For detailed information on how to become a trading partner and send regulatory transactions, refer to CAN-25 and the FDA User Guide (CAN-47).

As indicated in the G-eCTD, the following media formats are acceptable for eCTD transactions greater than 10 GB: Universal Serial Bus (USB) 2.0 or 3.0 drive; or portable external hard drive with USB 2.0 or 3.0 interfaces. (Contact HC at hc.ereview.sc@canada.ca for other media formats that may be acceptable at the time of filing.) A paper copy of the cover letter must accompany the media (unless otherwise indicated), and a pre-paid envelope must be provided if the media is to be returned. The complete regulatory transaction must be provided on a single drive, and the label on the drive should contain the following information:

• Stakeholder Name
• Brand Name
• Dossier ID, which is based on the protocol number
• Sequence (regulatory transaction) number

Media must be mailed to HC at the address below:

Health Canada
Finance Building
101 Tunney’s Pasture Driveway
Address Locator: 0201A1
Ottawa, Ontario
K1A 0K9

See the G-CESG, the G-eCTD, CAN-47, CAN-34, CAN-36, CAN-25, and CAN-28 for details on registering as a trading partner for CESG transactions, how to use CESG, and submitting CTAs in eCTD format. (Note: As per ElecSubms, G-CESG is only available upon request at no-reply.ereview.non-reponse@hc-sc.gc.ca. Please ensure the text 'Request for eCTD Guidance Document' is in the subject line of the email.)

Non-eCTD Electronic Submission

For non-eCTD electronic submissions, G-Non-eCTD indicates that HC requires both PDF and MS-Word formats for the CTA (CAN-4). The PDF documents must be generated from electronic sources (not scanned material), except when access to an electronic source document is unavailable or where a signature is required. It is important that PDF files be properly bookmarked and hyperlinked. Documents that legally require signatures may be signed with an electronic signature, or the signature page can be printed, signed, scanned, and saved as a PDF file. The cover letter does not require a signature, but should include a printed name, phone number, and email address. All regulatory submissions should be validated prior to transmitting to HC. For validation rules, see the Rules-Non-eCTD. The ElecSubms contains a zip file of the folder structure for clinical trial non-eCTD submissions. (Note: As per ElecSubms, G-Non-eCTD is only available upon request at no-reply.ereview.non-reponse@hc-sc.gc.ca. Please ensure the text 'non eCTD Guidance Document' is in the subject line of the email.)

Per the G-Non-eCTD, CTA submissions to the appropriate Directorate within HC’s HPFB must be in one (1) of these accepted media formats:

• Compact Disc-Recordable (CD-R) conforming to the Joliet specification
• USB 2.0 or 3.0 drive
• Digital Versatile Disc (DVD-RAM and DVD+R/-R) in Universal Disk Format (UDF) standard

All media should be labelled and contain the following information:

• Stakeholder Name
• Brand Name
• Dossier ID (if known)

Subsequent to burning the CD/DVD or transferring data to a drive, applicants should ensure that all files can be opened, files are not corrupted, and that "Thumb.db" files are removed.

As per the G-Non-eCTD, CAN-18, and CAN-17, non-eCTD CTAs involving pharmaceutical drugs should be sent to PDD, and CTAs involving biologics and/or radiopharmaceuticals should be sent to BRDD at the addresses listed below.

Office of Clinical Trials
Pharmaceutical Drugs Directorate
Health Canada
5th Floor, Holland Cross, Tower B
1600 Scott Street
Address Locator: 3105A
Ottawa, Ontario, Canada
K1A 0K9
General Inquiries E-mail: oct.enquiries-requetes.bec@hc-sc.gc.ca

Office of Regulatory Affairs
Biologic and Radiopharmaceutical Drugs Directorate
Ground Floor, Health Canada Building 6
100 Eglantine Driveway
Address Locator: 0601C
Ottawa, Ontario, Canada
K1A 0K9
General Enquiries E-mail: brdd.ora@hc-sc.gc.ca

Per the HCNotice-CTSIForm, questions related to pharmaceutical CTSI forms should be sent to: oct.enquiries-requetes.bec@hc-sc.gc.ca and questions related to biologic CTSI forms should be sent to brdd.ora@hc-sc.gc.ca.

Per the G-Non-eCTD, if an applicant submits a non-eCTD CTA via email, they should meet the following requirements:

• The maximum email size accepted by the corporate mail server is 20 megabytes. If the clinical trial submission is larger than 20 megabytes, the submission may be split and sent as separate emails (e.g., an email for Module 1, and another email for Module 2/3). The subject line of the emails should clearly link to each other (e.g., "Email 1 of 2" in the relevant subject line)
• A duplicate copy must not be provided by mail
• The submission should be organized in folders and the body of the email should only contain the zipped regulatory submission
• Zipped files and documents contained in the email should not be password protected

The G-Non-eCTD provides additional information on emailing other clinical trial submissions, including responses to a clarification request, responses to a no objection letter, notifications, and development safety update reports.

Ethics Review Submission

As indicated in the CanadaFDR and the G-CanadaCTApps, all research involving human participants in Canada must be reviewed by an institutional ethics committee (EC). (Note: institutional ECs are referred to as Research Ethics Boards (REBs) in Canada.) Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements. Further, Canadian provinces may have varying requirements, and, therefore, the sponsor should consult with the applicable province(s) for more information. See CAN-35 for submission requirements to the joint HC-Public Health Agency of Canada (PHAC)’s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

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 CanadaFDR, the G-CanadaCTApps, and CAN-31, Health Canada (HC) requires the sponsor to apply for clinical trial authorization by submitting a clinical trial application (CTA) to HC. As specified in the G-CanadaCTApps and the G-QCM-PharmCTAs, the CTA should be organized into three (3) modules in Common Technical Document (CTD) format:

• Module 1 - Administrative and clinical information about the proposed trial
• Module 2 - Quality (Chemistry and Manufacturing) summaries about the drug product(s) to be used in the proposed trial
• Module 3 - Additional supporting quality information

Per the CanadaFDR, the clinical trial application form (CAN-4) and the following information and documents must be submitted:

• Protocol
• Summary of potential risks/benefits
• Clinical trial attestation that includes drug information (chemistry, names, classifications, dosage, therapeutic purpose, human-sourced excipient, drug identification number or notice of compliance, manufacturing information); sponsor’s contact information; if the drug is to be imported, contact information for the sponsor’s representative in Canada who is responsible for the sale of the drug; and contact information for the qualified investigator at each site, if known at the time of submittal
• Contact information for each institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) that approved the protocol, if known at the time of submitting the application
• Contact information of any institutional EC that previously refused to approve the protocol, its reasons, and refusal date
• Investigator’s Brochure (IB)
• Informed consent form (ICF)
• Information about use of a human-sourced excipient
• Chemistry and manufacturing information
• Proposed date for trial commencement at each site, if known

Refer to the CanadaFDR, the G-CanadaCTApps, the G-DrugApp, the G-QltyBioCTs, and the G-QCM-PharmCTAs for detailed submission information.

Ethics Committee Requirements

Each institutional EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies to be supplied and application format requirements. However, the following requirements comply with the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, and are basically consistent across all Canadian ECs:

• Clinical protocol
• ICFs and participant information
• Participant recruitment procedures
• IB
• Safety information
• Participant payments and compensation
• Investigator(s) current curriculum vitaes (CVs)
• Additional required institutional EC documentation

See section 3.1.2 of CAN-52 for additional submission content requirements.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, requires clinical trial researchers to include a plan for monitoring safety, efficacy/effectiveness (where feasible), and validity in their proposal for EC review. See the G-TCPS2 for additional details on the plan’s required contents.

See CAN-35 for submission requirements to the joint HC-Public Health Agency of Canada (PHAC)'s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

Clinical Protocol

As delineated in CAN-52, the clinical protocol should include the following elements:

• General information
• Background information
• Trial objectives and purpose
• Trial design
• Participation selection/withdrawal
• Participant treatment
• Efficacy assessment
• Safety assessment
• Statistics
• Direct access to source data/documents
• Quality control/quality assurance procedures
• Ethical considerations
• Data handling and record keeping
• Financing and insurance
• Publication policy
• Supplements

For complete protocol requirements, see section 6 of CAN-52.

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

As delineated in the CanadaFDR and the G-CanadaCTApps, the review and approval of a clinical trial application (CTA) by Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada) may be conducted in parallel. However, per the CanadaFDR, the G-CanadaCTApps, CAN-6, and CAN-30, HC will not authorize the sponsor to begin the clinical trial until an institutional EC approval (provided in the required Clinical Trial Site Information (CTSI) form) for each participating trial site is submitted. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Regulatory Authority Approval

According to the CanadaFDR and the G-CanadaCTApps, an authorized clinical trial is one that has been filed with HC and has not received an objection within 30 days. All CTAs are subject to the 30-day default period from the date of receipt of the completed application at the appropriate Directorate within HC’s Health Products and Food Branch (HPFB). While the Directorates can establish shorter administrative targets of seven (7) days for the review of bioequivalence trials, the 30-day default system remains the regulatory requirement. Applications to conduct Phase I clinical trials using somatic cell therapies, xenografts, gene therapies, prophylactic vaccines, or reproductive and genetic technologies are not included in the seven-day target system. Please see the G-CanadaCTApps for special requirements regarding reviews of comparative bioavailability studies and joint reviews of clinical trials covering a combination of devices, biologics, and pharmaceuticals.

As specified in the G-CanadaCTApps and the G-MDSA, during the review period, the Directorate may request additional information from the sponsor, who has two (2) calendar days to provide such information. The G-MDSA clarifies that, where warranted, HC can adjust the timelines to be longer or shorter based on the complexity of the request, dialogue with the sponsor, and/or circumstances of the review, including pausing the clock during the scientific review. According to the G-CanadaCTApps and the G-MDSA, if HC authorizes the CTA, then it issues a No Objection Letter (NOL). If HC rejects the CTA, it sends a Not Satisfactory Notice (NSN). HC will issue an NSN if it identifies significant deficiencies, or, if a timely response to requested information has not been provided. The sponsor may resubmit the information and material at a future time, and it will be processed as a new CTA.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. However, according to the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, the institutional EC should review a proposed clinical trial within a reasonable time. The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, recommends a proportionate approach to ethics review—the lower the level of risk, the lower the level of scrutiny (delegated review); the higher the level of risk, the higher the level of scrutiny (full board review). In either case, pursuant to the G-TCPS2, the institutional EC should make its decisions in an efficient and timely manner. See CAN-35 for ethics review timelines with the joint HC-Public Health Agency of Canada (PHAC)'s REB. This joint EC reviews all research involving human subjects that is carried out by HC or PHAC researchers, on the premises, or in collaboration with external researchers.

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 CanadaFDR and the G-CanadaCTApps, a clinical trial can only commence after the sponsor receives authorization from both Health Canada (HC) and an institutional ethics committee (EC) (known as Research Ethics Board (REB) in Canada). No waiting period is required following the applicant’s receipt of these approvals. CAN-30 specifies that for purposes of the Clinical Trial Site Information (CTSI) Form (CAN-6), the trial commencement date is the date when the clinical trial site is ready to enroll participants. The commencement date is a date after which the sponsor has both the HC authorization from the appropriate Directorate (date on the No Objection Letter (NOL)) and approval from the relevant EC. Further, the commencement date would be the date when the sponsor implements the protocol, which includes the screening period that occurs prior to the check-in date. See the Scope of Review section for detailed institutional EC requirements, and the Submission Content section for additional HC approval information. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

In addition, per the G-CanadaCTApps, if a sponsor (Canadian or foreign) wants to import a drug into Canada to conduct a clinical trial, a copy of HC’s clinical trial authorization (i.e., the NOL) must be included with the drug shipment. According to the G-CanadaCTApps and CAN-32, if a sponsor plans to import investigational drugs directly to each trial site, then the sponsor must also authorize the importer (i.e., the clinical trial site) when submitting the clinical trial application using Appendix I of HC’s Drug Submission Application Form (CAN-4). See the Manufacturing & Import section for detailed import requirements.

Clinical Trial Agreement

Prior to initiating the trial, as delineated in the G-FDR-0100 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, the sponsor must sign an agreement between all involved parties, including ECs, Qualified Investigators (QIs), contract research organizations, and others, to ensure full compliance with the regulatory requirements. Further, the sponsor should obtain the investigator’s/institution's agreement:

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

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

In accordance with the G-CanadaCTApps, prior to initiating a clinical trial, the sponsor must ensure that a Qualified Investigator Undertaking (QIU) form (CAN-37 or similar documentation that meets the CanadaFDR requirements) has been completed and is kept on file by the sponsor. Per the CanadaFDR, the form certifies that the QI will conduct the clinical trial in accordance with good clinical practice and will immediately inform trial participants and the institutional EC of trial discontinuance and the reason for this discontinuance. If there is a change in the QI at a site, a new CTSI Form must be submitted to HC, and a new QIU form must be maintained by the sponsor.

See CAN-6, CAN-8, and CAN-19 for additional clinical trial forms.

Clinical Trial Registration

As per the G-CanadaCTApps, sponsors should register their clinical trials on one (1) of two (2) publicly accessible registries accepting international clinical trial information and recognized by the World Health Organization (WHO), ClinicalTrials.gov (CAN-45), and the International Standardized Randomized Controlled Trial Number (ISRCTN) Registry (CAN-46). According to HCNotice-CTRegDisc, clinical trial registration is not a mandatory requirement at this time. However, per the G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, clinical trials must be registered before recruitment of the first trial participant in a publicly accessible registry that is acceptable to the WHO or the International Committee of Medical Journal Editors (ICMJE). In addition, following registration, researchers are responsible for ensuring that the registry is updated in a timely manner with: new information; safety and, where feasible, efficacy reports; reasons for stopping a trial early; and the location of findings.

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 CanadaFDR and G-CanadaCTApps, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), the following definitions provide a basis for a common understanding of Canada’s safety reporting requirements:

• Adverse Event (AE) – Any adverse occurrence in the health of a clinical trial subject who is administered a drug that may or may not be caused by the administration of the drug, and includes an adverse drug reaction.
• Adverse Drug Reaction (ADR) – Any noxious and unintended response to a drug that is caused by the administration of any dose of the drug.
• Serious Adverse Drug Reaction (SADR) or Serious Adverse Event (SAE) – 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 or incapacity, or causes a congenital anomaly/birth defect.
• Serious, Unexpected ADR – A serious ADR that is not identified in nature, severity, or frequency in the risk information set out in the investigator’s brochure or on the label of the drug.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs), requires researchers to promptly report new information revealed during the conduct of the trial that might affect the welfare or consent of participants to the EC, to a publicly accessible registry, and to other appropriate regulatory or advisory bodies. In addition, when new information is relevant to participants’ welfare, researchers must promptly inform all participants to whom the information applies (including former participants). Researchers must work with their ECs to determine which participants must be informed, and how the information should be conveyed.

For Health Canada (HC)’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Safety Reporting Requirements

Investigator Responsibilities

Per CAN-52, which Canada has implemented per CAN-50, all SAEs should be reported immediately to the sponsor except for those SAEs that the protocol or other document (e.g., Investigator's Brochure) identifies as not needing immediate reporting. The immediate reports should be followed promptly by detailed, written reports. The immediate and follow-up reports should identify participants by unique code numbers assigned to the trial subjects rather than by their names, personal identification numbers, and/or addresses. The investigator should also comply with the applicable regulatory requirement(s) related to the reporting of unexpected serious ADRs to the regulatory authority(ies) and the EC. AEs and/or laboratory abnormalities identified in the protocol as critical to safety evaluations should be reported to the sponsor according to the reporting requirements and within the time periods specified by the sponsor in the protocol. For reported deaths, the investigator should supply the sponsor and the EC with any additional requested information (e.g., autopsy reports and terminal medical reports).

Sponsor Responsibilities

As delineated in the CanadaFDR, the G-CanadaCTApps, and CAN-22, the sponsor is required to expedite reports of ADRs to HC that meet these three (3) criteria: serious, unexpected, and having a suspected causal relationship. ADR reports that are expected or unexpected, but not serious, should not be reported to HC, but rather monitored and tracked by the sponsor. Further detail and clarifications on AE/ADR reporting criteria can be found in CAN-22. As specified in the G-CanadaCTApps, when evaluating whether an AE is serious and unexpected, the Qualified Investigator’s (QI) and sponsor’s determination of causality is important. Only serious and unexpected ADRs found to have a reasonable suspected causal relationship to the drug should be reported by the sponsor to HC.

Per the CanadaFDR and the G-CanadaCTApps, during a clinical trial, the sponsor is required to inform HC of any serious, unexpected ADR that has occurred inside or outside Canada. An ADR report must be filed in the following specified timelines:

• When the ADR is neither fatal nor life-threatening, within 15 days after becoming aware of the information
• When it is fatal or life-threatening, immediately when possible and, in any event, within seven (7) days after becoming aware of the information
• Within eight (8) days after having informed HC of the ADR, submit a report that includes an assessment of the importance and implication of any findings

Other Safety Reports

The G-DSUR delineates that the development safety update report (DSUR) and the DSUR Checklist (CAN-38) should be provided when requested by HC. A DSUR may be submitted voluntarily to HC when important new safety information on a drug needs to be conveyed by a clinical trial sponsor. In these cases, a rationale/justification for the filing of the DSUR should be included in the cover letter. For additional details, see the G-DSUR.

The G-DSUR-CanUK describes the region-specific requirements for DSURs submitted to the regulatory authorities of Canada and the United Kingdom. This guidance applies to both marketed and non-marketed drugs that are used in clinical trials and applies to DSURs prepared by the manufacturer and/or marketing authorization holder of the investigational drug.

Form Completion & Delivery Requirements

As per the G-CanadaCTApps and CAN-22, all serious and unexpected ADRs should be reported individually to HC. According to CAN-48 (which Canada adopted pursuant to CAN-50), at a minimum, the report should include an identifiable patient, the name of a suspect medicinal product, an identifiable reporting source, and an event or outcome that can be identified as serious and unexpected and for which, in clinical investigation cases, there is a reasonable suspected causal relationship. The G-CanadaCTApps requires the sponsor to complete the expedited reporting form (CAN-5) and the CIOMS Form I (CAN-7) and fax them to the appropriate HC Directorate: BRDD Fax: 613-957-0364; PDD Fax: 613-941-2121.

Additionally, the G-DSUR indicates that HC recommends that DSURs in electronic Common Technical Document (eCTD) format be submitted via the Common Electronic Submission Gateway (CESG). For information on eCTD format, refer to the ElecSubms. For technical questions on eCTD filings, contact ereview@hc-sc.gc.ca as instructed in the G-DSUR.

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

Pursuant to the CanadaFDR, the G-CanadaCTApps, CAN-22, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), investigators and sponsors share responsibility for submitting interim and annual reports on the status of a clinical trial. The investigator is required to provide annual progress reports to the institutional ethics committee (EC) and submit interim progress reports to the EC and Health Canada (HC) if there are any significant changes affecting the trial or risk to participants. The sponsor is required to submit annual reports (in the form of an updated Investigator’s Brochure (IB)) to HC. Note that per CAN-50, HC-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

As per CAN-52, which Canada has implemented per CAN-50, the investigator should promptly provide written reports to the sponsor and the institutional EC on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.

According to the G-TCPS2, investigators must report new information that may affect the welfare or consent of participants to the institutional EC, HC, and other appropriate regulatory or advisory entities. When new information is relevant to participants’ welfare, researchers must promptly inform all participants to whom the information applies (including former participants). Researchers should work with their ECs to determine which participants must be informed, and how the information should be conveyed. New information may comprise a range of issues, including, but not limited to:

• Changes to the research design
• Evidence of any new risks
• Unanticipated issues that have possible health or safety consequences for participants
• New information that decisively proves the benefits of one (1) intervention over another
• New research findings, including relevant non-trial findings
• Unanticipated problems
• Closure of trials at other sites for reasons that may be relevant to the welfare or consent of participants in the ongoing trial

Pursuant to CAN-52, the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested.

Final Report

Upon completion of the trial, as delineated in CAN-52, the investigator is required to submit a final report to the institutional EC summarizing the trial’s outcome. The CanadaFDR does not require submission of a final study report to HC.

Per the G-CanadaCTApps, the sponsor should notify the HC Directorate when a clinical trial is completed or a clinical trial site is closed. A study is considered to be completed after the last participant globally completes the "end of study" visit as defined in the protocol. The "end of study visit" is the final visit for study-related tests and procedures, including the capture of any final potential study-related adverse events, and usually occurs after the participant has completed/discontinued study drug administration. The "end of study visit" is normally an in-person visit, but for some studies it can also be carried out over the telephone. There may be certain scenarios (e.g., gene therapies, drugs with very long half-lives) where a study may be considered to be ongoing well beyond the period of study treatment, i.e., where long-term safety monitoring and reporting would be required. The reporting requirements with regards to such long-term follow-up of safety are normally specified in the study protocol and agreed to between the sponsor and HC prior to the authorization of the clinical trial in Canada.

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 per the CanadaFDR and the G-CanadaCTApps, a sponsor is defined as an individual, corporate body, institution, or organization that conducts a clinical trial. The International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, expands on this definition to include individuals, companies, institutions, or organizations that take responsibility for the initiation, management, and/or financing of a clinical trial.

In accordance with CAN-52, Canada also permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO) and/or institutional site(s). However, the ultimate responsibility for the trial data’s quality and integrity always resides with the sponsor. Any trial-related responsibilities transferred to a CRO should be specified in a written agreement. The CRO should implement quality assurance and quality control. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

According to the CanadaFDR and G-CanadaCTApps, a sponsor may be domestic or foreign. A foreign sponsor is required to have a senior medical or scientific officer who is residing in Canada who will represent the sponsor, and sign and date the application and the clinical trial attestation form.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

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

As set forth in the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, the sponsor should select the investigator(s) and the institution(s) for the clinical trial, taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by training and experience. Furthermore, the sponsor must sign an agreement or contract with the participating institution(s). Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

In accordance with the G-CanadaCTApps, prior to initiating a clinical trial, the sponsor must ensure that a Qualified Investigator Undertaking (QIU) form (CAN-37) (or similar documentation that meets the CanadaFDR requirements) has been completed and kept on file by the sponsor; it should be retained by the sponsor for 15 years. Per the CanadaFDR, the form certifies that the qualified investigator will conduct the clinical trial in accordance with good clinical practice, and will immediately inform trial participants and the institutional ethics committee (EC) (known as Research Ethics Boards in Canada) of trial discontinuance, and the reason for this discontinuance. (See the Submission Content section for additional information on clinical trial application requirements). For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Per CAN-11, the Canadian Clinical Trials Asset Map (CCTAM) (CAN-26) is a pan-Canadian research inventory of investigators, clinical research sites, and other resources across the country. Sponsors can use CCTAM to identify potential sites and investigators, which may expedite study feasibility and start-up timelines. To view the CCTAM, the user must register and create an account.

Foreign Sponsor Responsibilities

According to the CanadaFDR and the G-CanadaCTApps, a sponsor may be domestic or foreign. A foreign sponsor is required to have a senior medical or scientific officer residing in Canada to represent the sponsor, and sign and date the application and the clinical trial attestation form.

Data and Safety Monitoring Board

Although not specified as a sponsor requirement, CAN-52 states that a Data and Safety Monitoring Board (DSMB) (known as an Independent Data-Monitoring Committee in Canada) may be established 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 G-TCPS2 provides the following considerations to help researchers and ECs determine whether a DSMB is needed:

• The magnitude of foreseeable research-attributable harms to participants
• Whether the circumstances of the participants make them vulnerable in the context of research
• The feasibility of interim data analysis
• The complexity of the study
• Conflicts of interest

Multicenter Studies

Per CAN-52, if a multicenter trial will be conducted, the sponsor must organize a coordinating committee or select coordinating investigators. In addition, the sponsor must ensure that:

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

The CanadaFDR and the G-CanadaCTApps, require the sponsor to complete and retain the Research Ethics Board (REB) Attestation (CAN-8) and Qualified Investigator Undertaking (QIU) (CAN-37) forms at each trial site, while submitting in electronic format the Clinical Trial Site Information Form (CAN-6) to the appropriate HC Directorate for each trial site.

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ECs, provides that in multi-site clinical trials, a lead principal investigator (PI) is a designated PI who is responsible for the ethical conduct of the study for all sites. The lead PI is responsible for communicating any changes to the study, new information, and/or unanticipated events to the EC, to the sponsor, and to local site PIs.

Per CAN-50, Canada has implemented the ICH Guidance E17: Multi-Regional Clinical Trials (CAN-40), which describes general principles for the planning and design of multi-regional clinical trials with the aim of increasing the acceptability of these trials in global regulatory submissions. HC recognizes that the scope and subject matter of current HC guidance may not be entirely consistent with ICH guidance. In such circumstances, HC-implemented ICH guidance takes precedence.

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

The CanadaFDR does not require the sponsor to provide insurance coverage to investigators, institutions, or trial participants. However, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, guides sponsors on providing insurance. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

Compensation

Injury or Death

The Canadian regulations do not require compensation for trial participants in the event of trial-related injuries or death. However, CAN-52 indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries.

Trial Participation

The Canadian regulations do not require compensation for trial participation. However, as per the G-TCPS2 and CAN-52, the informed consent form (ICF) should contain a statement with a description of the anticipated prorated payment to the participant(s) that is reasonably expected for participation in the trial. Any compensation or incentive to participants must not be so excessive that it may unfairly influence participants or cause them to overlook important facts and risks. CAN-35 further states that the ICF should describe any compensation, incentives, or reimbursements to be paid or given to participants and how participant withdrawal will affect the offered compensation (e.g., prorated remuneration). If no compensation will be provided, this should be stated.

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

Per the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, 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. Per CAN-50, Canada implements the ICH Guidance E8(R1): General Considerations for Clinical Studies (CAN-49), which provides guidance on conduct during the clinical trial. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

As indicated in CAN-52, 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

As stated in the CanadaFDR and CAN-52, 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 generated, recorded, and reported in compliance with the protocol, CAN-52, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that both parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.

Per CAN-50, HC adopted and implements the ICH guidance on statistical principles for clinical trials (CAN-53), as well as the ICH addendum on estimands and sensitivity analysis (CAN-39), which presents a framework for defining an appropriate estimand for a clinical trial and conducting sensitivity analyses.

Monitoring Requirements

As part of its QA system, CAN-52 notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, CAN-52, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditors’ qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with their own SOPs and the auditor observations are documented. 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).

Per the HCNotice-ICH-E19, HC adopted and implements ICH guidance on selective safety data collection in specific late stage pre-approval or post-approval clinical trials (CAN-15). Selective safety data collection refers to the recording of certain data by investigators in case report forms. It does not affect the monitoring and clinical care of individual trial participants or documentation of their adverse events in medical records. See the HCNotice-ICH-E19 and the CAN-15 for more information.

Premature Study Termination/Suspension

The CanadaFDR and the G-CanadaCTApps state that if a trial is prematurely terminated or suspended, the sponsor should inform HC no later than 15 days after the termination or suspension. In addition, the sponsor should provide HC with the reason(s) for the termination or suspension and its impact on the proposed or ongoing clinical trials related to the drug in Canada by the sponsor. The sponsor should also promptly notify the qualified investigators of the termination or suspension and advise them in writing of any potential risks to the participants’ health. Further, the G-CanadaCTApps states that the sponsor’s notification to HC should include confirmation that the sale or importation of the drug to the discontinued sites has been stopped and that reasonable measures to ensure the return of all unused quantities of the drug will be taken. This notification must also be submitted for premature discontinuation of a clinical trial or clinical trial site outside Canada where there are ongoing trials with the drug in Canada.

According to CAN-52, 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 ethics committee (EC) should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.

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

Per the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain standard operation procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Note per CAN-50, HC-implemented ICH guidelines take precedence over other HC guidance when they are not consistent. Refer to CAN-52 for additional information.

The G-FDR-0100 provides that if electronic records are generated during a clinical trial, then the electronic system must be validated to confirm that the system’s specifications meet the goals and requirements for the clinical trial. This evidence of validation should be kept for the required record retention period and available for inspection by Health Canada (HC) inspectors. See the G-FDR-0100 for additional details.

Records Management

As set forth in the CanadaFDR and the CanadaFDR1024, the sponsor must record, handle, and store all trial-related information to allow complete and accurate reporting, interpretation, and verification. The CanadaFDR requires the sponsor to maintain all trial-related records for a period of 15 years. Per the G-FDR-0100, sponsors may also be required to maintain records under provincial law, institutional policies, and contractual agreements with investigators, ethics committees (ECs), or others. Where it is not possible to comply with both sets of requirements, the CanadaFDR would govern and the records must be maintained for 15 years.

Pursuant to CanadaFDR1024, the sponsor must submit requested records to HC within 48 hours if safety concerns arise. Additionally, to facilitate inspection of a site, the sponsor must submit information to HC within seven (7) days of a request. Per CAN-8, an attestation must be completed by the EC that reviewed and approved the clinical trial. The completed attestation must be retained by the clinical trial sponsor for a period of 15 years. The attestation should not be submitted to HC unless requested.

In addition, CAN-52 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.

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

The G-TCPS2, which sets the ethical benchmark for all Canadian institutional ethics committees (ECs), states that where researchers seek to collect, use, share, and access different types of information or data about participants, they should determine whether the information or data proposed in research may reasonably be expected to identify an individual. Researchers and ECs must consider whether information is identifiable or non-identifiable.

Data Protection

Per CAN-42, the Office of the Privacy Commissioner of Canada provides advice and information for individuals about protecting personal information, and enforces the two (2) federal privacy laws that set out the rules for how federal government institutions and certain businesses must handle personal information, including health data. The PrivAct covers the personal information-handling practices of federal government departments and agencies in Canada, and the PIPEDA regulates private businesses’ data protection practices. In addition, some provinces and territories have laws that deal specifically with protection of personal health information. See CAN-43 for a list of provincial and territorial privacy laws and webpages.

Per the G-TCPS2, in the research context, the most simplified method to protect participants is through the collection and use of anonymous or anonymized data. When anonymized data is not possible or desirable, a next best alternative is to use de-identified data, which is provided to the researcher in de-identified form and the existing key code is accessible only to a custodian or trusted third party who is independent of the researcher. Where it is not feasible to use anonymous or anonymized data for research, the ethical duty of confidentiality and the use of appropriate measures to safeguard information become paramount. Researchers should consult their ECs if they are uncertain about whether information proposed for use in research is identifiable (e.g., when proposing to link anonymized or coded data sets).

Consent for Processing Personal Data

Both PIPEDA and the PrivAct require consent for the use of personal data, including health data, except under prescribed conditions, such as for research or during emergencies. Also see CAN-43 for provincial and territorial privacy laws.

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 all Canadian clinical trials, a freely given informed consent is required from each participant in accordance with the requirements set forth in the CanadaFDR, the G-TCPS2, CAN-35, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

As per the CanadaFDR, the G-TCPS2, and CAN-52, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a Research Ethics Board (REB) in Canada) and provided to HC with the clinical trial application (CTA). (See the Required Elements section for details on what should be included in the form.)

The G-TCPS2 and CAN-52 state that the qualified investigator (QI) must provide detailed research study information to the participant or legal representative/guardian. As delineated in the G-TCPS2, CAN-35, and CAN-52, the ICF content should be in plain language (i.e., non-technical and easy to understand) and provided in a format that facilitates understanding. For example, written documentation may be supplemented with audio and/or visual aids. The participant and legal representative/guardian should also be given adequate time to consider whether to participate. CAN-35 notes that the person obtaining consent may also need to explain the consent form verbally to ensure that the participant fully understands the information. See CAN-35 for informed consent and assent templates and sample forms.

Re-Consent

According to CAN-52, any change in the ICF that is relevant to the participant’s consent should be approved by the institutional EC prior to implementing any changes. The participant or legal representative/guardian should also be informed in a timely manner if new information becomes available that may be relevant to the participant’s willingness to continue participation in the trial. The communication of this information should be documented.

Per the G-TCPS2, consent must be maintained throughout the research project. Researchers have a continuous duty to provide participants with all information relevant to their ongoing consent to participate in the research. Consent begins with the initial contact (e.g., recruitment) and carries through to the end of participation in the study. Throughout the clinical trial, researchers have a continuous responsibility to provide participants and ECs with all information relevant to participants’ ongoing consent to participate in the research. The researcher also must notify participants of any changes to the research project that may affect them. These changes may have ethical implications, may be relevant to their decision to continue in the study, or may be unique to the particular circumstances of individual participants. Specifically, researchers must disclose changes to the risks or potential benefits of the research. Change in participant capacity is an important element of ongoing consent. Rather than an age-based approach to consent, researchers should use an approach based on decision-making capacity in compliance with any laws governing research participation. This includes those whose decision-making capacity is in the process of development, those whose decision-making capacity is diminishing or fluctuating, and those whose decision-making capacity remains only partially developed. Mechanisms should be in place from the outset to identify and address any changes that could affect consent. Further, within the limits of consent provided by the participant, researchers should disclose to the participant any material incidental findings discovered in the course of research. Incidental findings are considered to be material incidental findings if they are reasonably determined to have significant welfare implications for the participant or prospective participant. Where material incidental findings are foreseeable, researchers should inform participants during the initial consent process. In addition, researchers should develop a management plan for review by the EC. For more information on how to address material incidental findings, see G-ConsentMatIncFindings.

Language Requirements

CAN-35 further specifies that consent forms should be provided in the language that participants are most comfortable with. The G-TCPS2 and CAN-52 require the ICF to be presented in plain language that the participant is able to understand. Per CAN-35, ICFs should be translated where it is relevant to particular communities. If there is a language barrier, the G-TCPS2 indicates that the qualified investigator should select an intermediary who has the necessary language skills to ensure effective communication. Further, per CAN-35, the level of language used should be appropriate to the age and comprehension/reading level of the participant population, generally at approximately a grade 6-8 reading level.

Documenting Consent

As per the G-TCPS2, CAN-52, and CAN-35, the participant or legal representative/guardian, as well as the qualified investigator, must sign and date the ICF. CAN-52 and the G-FDR-0100 state that the QI should retain the signed ICF. CAN-35 indicates that information letters and ICFs must be presented on institutional/department letterhead.

According to CAN-52, where the participant is illiterate and/or the legal representative/guardian is illiterate, 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 to be 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 have signed and dated the ICF, if capable of doing so

Before participating in the study, the participant or legal representative/guardian should receive a copy of the signed and dated ICF.

As per the G-TCPS2 and CAN-52, 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 appear to waive the participant’s legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representative(s) from their liabilities for any negligence.

Per CAN-35, in some situations, written consent is not be feasible or desirable, for example due to logistical issues or because of the preferences of the participants. In addition, some individuals may perceive written consent as an attempt to legalize the consent process, thereby creating mistrust. It is also important to recognize that in some cultures written consent is not consistent with community traditions. In these cases, it may be more appropriate to use a handshake, a verbal agreement, or oral consent. Article 10.2 of the G-TCPS2 further indicates that researchers can use a range of procedures to seek and document consent, including oral consent documented in field notes, and other forms of recording (e.g., a consent log, audio or video recordings, or other electronic means). Evidence of consent may also be documented via completed questionnaires (in person, by mail, or by email or other electronic means). ECs should consider the power relationship that might exist between researchers and participants, and whether a waiver of the requirement for signed written consent may affect the welfare of the participants. If researchers plan to obtain non-written consent, they must explain their strategy to the EC.

Waiver of Consent

As explained in the G-TCPS2, there are research situations that call for alterations of consent. The EC may approve research that involves an alteration to the consent requirements if the EC is satisfied, and documents, that all of the following apply:

• The research involves no more than minimal risk to the participants
• The change to consent requirements is unlikely to adversely affect the welfare of participants
• It is impossible or impracticable to carry out the research and to address the research question properly, given the research design, if the prior consent of participants is required
• In the case of a proposed alteration, the exact nature and extent of any proposed alteration is defined
• There is a plan to brief participants and offer the option of refusing consent and/or withdrawing data and/or human biological materials

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.

Based on the G-TCPS2, the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), and CAN-35, the informed consent form (ICF) should include the following statements or descriptions in plain language, 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 involves research and an explanation of its purpose and duration
• The trial treatment(s) and the probability for random assignment to each treatment
• The procedures to be followed, including all invasive procedures
• The participant’s responsibilities
• Those aspects of the trial that are experimental
• Any reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
• Any reasonably expected benefits; if no benefit is expected, the participant should be made aware of this
• The disclosure of specific alternative procedure(s) or therapies available to the participant, and their important potential benefits and risks
• Compensation and/or treatment available to the participant in the event of a trial-related injury
• The anticipated prorated payment, if any, to the participant for participating in the trial
• Any expenses the participant needs to pay to participate in the trial
• That participation is voluntary, and that the participant can refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the participant is otherwise entitled
• Information concerning the possibility of commercialization of research findings, and the presence of any real, potential, or perceived conflicts of interest on the part of the researchers, their institutions, or the research sponsors
• Confidentiality of records identifying the participant will be maintained, and permission given to monitors, the auditors, the ethics committee (EC), and Health Canada (HC) to access the participant’s medical records to verify the procedures and/or data, without violating the confidentiality of the participant, insofar as the applicable laws and regulations permit, and that, by signing a written ICF, the participant or legal representative/guardian is authorizing such access
• That records identifying the participant will not be made publicly available, insofar as the applicable laws and/or regulations permit; 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 information becomes available that may affect the participant’s willingness to continue
• The qualified investigator’s contact information for further information regarding the trial and the rights of participants, and whom to contact in the event of a trial-related injury
• The identity and contact information of a qualified designated representative who can explain scientific or scholarly aspects of the research to participants
• Information on stopping rules, foreseeable circumstances, and/or reasons under which the participant’s involvement in the trial may be terminated
• The approximate number of participants in the trial

Per CAN-50, Canada has implemented CAN-52.

Per CAN-35, if blood is taken, indicate total volume (e.g., teaspoons and milliliter equivalent) and note the possibility of bruising or swelling while giving blood, or other possible discomforts at the site where blood is drawn. Further, state that there may be minimal chance of infection and that discomforts experienced will be brief and transient.

CAN-35 also indicates that participants should not be told if an EC has approved the study, since this may appear to offer a guarantee of safety. Further, no clause or language should be used to excuse or appear to excuse investigators or other persons or institutions involved from liability for their negligence or other faults. Sample consent forms can be found in CAN-35.

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

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

In accordance with the CanadaFDR, the G-TCPS2, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), Canada’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-TCPS2 and CAN-52, which Canada has implemented per CAN-50, state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

The informed consent template in CAN-35 provides that if a participant has any questions about their rights, they should contact:

Health Canada-PHAC Research Ethics Board Secretariat
70 Colombine Driveway, Room 941C, PL: 0909C
Brooke Claxton Building, Tunney's Pasture
Ottawa, ON K1A 0K9
Telephone: 613-941-5199
Fax: 613-941-9093
reb-cer@hc-sc.gc.ca

The Right to Participate, Abstain, or Withdraw

As stated in the G-TCPS2 and CAN-52, 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.

Per CAN-35, participants should be assured that their participation is completely voluntary, they are under no obligation to participate, and they are free to withdraw at any time without consequence. It should be made clear that their decision to withdraw will not influence their relationship with the researcher in any way. The researcher should explain what will happen to participant samples or data if they choose to withdraw. If applicable, clearly state the point in the study at which removal of samples or data becomes difficult or impossible.

The Right to Information

As per the G-TCPS2 and CAN-52, 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 or treatment in the case of injury, and any significant new information regarding the research study.

The Right to Privacy and Confidentiality

According to the G-TCPS2 and CAN-52, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right.

Per CAN-35, the ICF should explain what information will be collected about participants and for what purpose, including the type of information that will be collected (e.g., will it be coded or de-identified?) and how it will be stored. Further, the ICF should state who will have access to the collected information and describe the efforts that will be made to prevent the risk of participant re-identification. Limits to confidentiality and additional requirements for projects led by HC or the Public Health Agency of Canada (PHAC) are provided in CAN-35.

The Right of Inquiry/Appeal

The G-TCPS2 and CAN-52 state that the research participant or legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or the participant’s rights.

The Right to Safety and Welfare

CAN-52, which upholds the Declaration of Helsinki, clearly state that a research participant’s right to safety and the protection of their health and welfare 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.

The G-TCPS2 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by medical emergencies. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. As per CAN-52, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant or legal representative/guardian, or, if an effective treatment is lacking but the investigational product could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the ethics committee (EC) (known as Research Ethics Board (REB) in Canada) must approve the protocol in advance. The participant or legal representative/guardian should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.

Per G-TCPS2, research involving medical emergencies must be conducted only if it addresses the emergency needs of the individuals involved, and then only in accordance with criteria established in advance of such research by the EC. The EC may allow research that involves medical emergencies to be carried out without the consent of participants, or legal representatives/guardians, if all of the following apply:

• A serious threat to the prospective participant requires immediate intervention
• Either no standard efficacious care exists, or the research offers a realistic possibility of direct benefit to the participant in comparison with standard care
• Either the risk is not greater than that involved in standard efficacious care, or it is clearly justified by the prospect for direct benefits to the participant
• The prospective participant is unconscious or lacks capacity to understand the risks, methods, and purposes of the research project
• Authorization from the legal representative/guardian cannot be secured in sufficient time, despite diligent and documented efforts to do so
• No relevant prior directive by the participant is known to exist

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

As per the G-TCPS2, in all Canadian 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 International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52) characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response from not participating. Examples are 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 subjects 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.

CAN-52, which Canada has implemented per CAN-50, specifies that ethics committees (ECs) (known as Research Ethics Boards in Canada) must pay special attention to protecting participants who are from vulnerable populations. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; 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.

Per CAN-35, because the G-TCPS2 does not specify an age of consent for children, the decision on whether to seek consent from children is based on whether they have the capacity to understand the research and the risks and benefits of their participation. Youth who have not reached the age of majority (either 18 or 19 depending on the province or territory) may still be old enough to provide their own consent. For children who are not sufficiently mature to provide consent but are able to understand the nature of study participation, researchers must obtain the child’s assent in addition to the consent of an authorized third party. The decision of a child not to assent must be respected regardless of whether third-party consent was obtained.

CAN-35 provides the following criteria for determining whether participants can provide their own consent, or whether an authorized third party should be involved:

• The risk level associated with the research project
• The legal requirements for age of consent in that jurisdiction
• The characteristics of the research participant (e.g., maturity level)
• In certain cases, the topic of the research itself

CAN-35 states that it is generally accepted that youth can consent to minimal risk studies at 16 years of age, and that assent should be sought from children beginning at approximately seven (7) years of age. However, it is ultimately up to the researcher to determine whether to obtain assent or consent from children, and to provide the rationale for this decision to the ethics committee (EC) (known as a Research Ethics Board in Canada). Researchers should also consider that within a single research project, some minors may be capable of consenting while others may not. See CAN-35 for additional details regarding obtaining consent from minors.

As per the G-TCPS2 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), when the research participant is a child, the informed consent form (ICF) must be signed by the child’s parent/legal guardian. All pediatric participants, however, should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the ICF. Per CAN-50, Canada has implemented CAN-52. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

As stated in G-TCPS2, children should only participate in clinical studies when the research objective cannot be achieved with adult participants only. When considering the inclusion of children in research, the investigators and ECs must consider a child’s stage of physical, physiological, psychological, and social development to ensure adequate protections for the child’s welfare.

Assent Requirements

Per G-TCPS2 and TCPS2-InterpCnsnt, where a child has some ability to understand the significance of the research, the researcher must ascertain the wishes of that individual with respect to participation. Children—whose decision-making capacity is in the process of development—may be capable of verbally or physically assenting to, or dissenting from, participation in research. While their assent would not be sufficient to permit them to participate in the absence of consent by the child’s parent/legal guardian, their expression of dissent must be respected.

Further, according to CAN-12, which offers best practices and guidance to researchers and ECs in pediatric research and complements the G-TCPS2, provincial laws in Canada vary as to when a child is presumed to be legally competent to provide informed consent. Some provinces use age while others use a competence-based evaluation.

As per CAN-12, if the pediatric participant has the capacity for assent, then affirmative assent is required to participate in a study according to the participant’s level of development and capacities. When the child develops the legal capacity to provide informed consent or attains the legal age of majority (which depends on the province), researchers should obtain an informed consent. Regarding dissent, CAN-12 states that the researchers must respect the dissent of a child who is capable of understanding.

CAN-35 provides sample assent forms and templates. For more detail and guidance about best practices for research involving pediatric participants, see CAN-12.

As per ResNo466, the PANDRH-GCPs, and the G-ClinResSubjectRts, any Brazilian clinical studies involving women of childbearing age or who are pregnant, require additional safeguards to ensure that the participants are fully aware of the risks and that the research assesses the risks and benefits as well as any potential impact on fertility, pregnancy, the embryo or fetus, labor, lactation, and the newborn. ResNo466 further states that research on pregnant women should be preceded by research on women outside the gestational period, except when pregnancy is the fundamental purpose of the study. The investigator(s) should also ensure that female participants have the right to participate in the research without the use of compulsory contraceptives—if they have expressly indicated that they are free from the risk of pregnancy and sexual practices, or they are sexually active in a non-reproductive way.

As per the G-TCPS2, studies involving women of childbearing age, or who are pregnant, require additional safeguards to ensure that the research assesses the risks to the women and the fetuses. The following guidance applies to research involving materials related to human reproduction:

• Research using materials related to human reproduction in the context of an anticipated or ongoing pregnancy must not be undertaken if the information can reasonably be obtained by alternative methods
• Materials related to human reproduction for research use must not be obtained through commercial transaction, including exchange for services

Per the G-TCPS2, research on in vitro embryos already created and intended for implantation to achieve pregnancy is acceptable if:

• The research is intended to benefit the embryo
• Research interventions will not compromise the care of the woman, or the subsequent fetus
• Researchers closely monitor the safety and comfort of the woman and the safety of the embryo
• Consent was provided by the gamete donors

According to the G-TCPS2, research involving embryos that have been created for reproductive or other purposes permitted by law, but are no longer required for these purposes, may be ethically acceptable if:

• The ova and sperm from which they are formed were obtained in accordance with the G-TCPS2
• Consent was provided by the gamete donors
• Embryos exposed to manipulations not directed specifically to their ongoing normal development will not be transferred for continuing pregnancy
• Research involving embryos will take place only during the first 14 days after their formation by combination of the gametes, excluding any time during which embryonic development has been suspended

Per the G-TCPS2, research involving a fetus or fetal tissue:

• Requires the consent of the woman
• Must not compromise the woman’s ability to make decisions regarding continuation of her pregnancy

In accordance with the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, informed consent requirements for conducting clinical trials with pregnant or nursing women or fetuses follow the general requirements listed in the Required Elements section. Specifically, the informed consent form should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

According to the PANDRH-GCPs, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. ResNo466 also states that freedom of consent must be guaranteed to those research participants who are fully competent but are exposed to specific constraints or have restricted autonomy. These participants must have the freedom to decide whether to participate without any fear of reprisal.

According to the G-TCPS2 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. A research study involving prisoners should ensure that these prospective participants are informed and are given the opportunity to make their own decisions without any interference from a higher authority. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

According to ResNo466 and the G-ClinResSubjectRts, the research ethics committee (Comitê de Ética em Pesquisa (CEP)) must approve the participation of research participants who are mentally or physically incapable of giving consent, and sufficient justification must be provided for involving this population in a study. As delineated in the PANDRH-GCPs, consent should only be provided once the participant is informed about the study, to the extent that the participant is able to understand it, and if able, the participant should sign and date the written informed consent in person. The participant’s legal representative/guardian must also be present during the informed consent process and sign and date the informed consent form.

Per CLNo11, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) has also established guidelines related to the process of obtaining consent from research participants people with a "lack of autonomy", permanent or temporary, to consent. The process of consent to participate is essential and should be addressed to those who "lack of autonomy", permanent or temporary, to consent.

CLNo11 further states researchers must ensure the assent is made in the form of an invitation without any pressure or coercion, and written in simple, easy-to-understand language to ensure adequate comprehension of the research. The assent process must consider the discernment of the research participant with a "lack of autonomy", whether permanent or temporary, to consent. See CLNo11 for additional information.

According to the G-TCPS2 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), the ethics committee (EC) (known as Research Ethics Board in Canada) must approve the participation of research participants who are mentally or physically incapable of giving consent. Per CAN-50, Canada has implemented CAN-52.

Per CAN-35, adults with diminished decision-making capacity include:

• Individuals whose decision-making capacity remains only partially developed, such as those living with permanent cognitive impairment, and
• Individuals who once were capable of making an autonomous decision regarding consent but whose decision-making capacity is diminishing or fluctuating (e.g., due to cognitive impairment resulting from an injury or disease).

Per CAN-35, as is the case for any vulnerable population, care must be taken to ensure that adults with diminished decision-making capacity are not inappropriately included in research because of their situation, and neither should they be excluded from participating in research that may benefit them.

The G-TCPS2 indicates that for research involving individuals who lack the capacity, either permanently or temporarily, to decide for themselves whether to participate, the EC must ensure that, at a minimum, the following conditions are met:

• The researcher involves participants who lack the capacity to decide on their own behalf to the greatest extent possible in the decision-making process
• The researcher seeks and maintains consent from the participant’s legal representative/guardian in accordance with the best interests of the persons concerned
• The legal representative/guardian is not the researcher or any other member of the research team
• The researcher demonstrates that the research is being carried out for the participant’s direct benefit, or for the benefit of other persons in the same category; if the research does not have the potential for direct benefit to the participant but only for the benefit of the other persons in the same category, the researcher shall demonstrate that the research will expose the participant to only a minimal risk and minimal burden, and demonstrate how the participant’s welfare will be protected throughout the participation in research
• When authorization for participation was granted by a legal representative/guardian, and a participant acquires or regains decision-making capacity during the course of the research, the researcher must promptly seek the participant’s consent as a condition of continuing participation

Per CAN-35 and the G-TCPS2, the participant’s legal representative/guardian can provide consent for adults who lack the capacity to decide on their own behalf in accordance with the best interests of the persons concerned. In such cases, participants should still be involved to the greatest extent possible in the decision-making process, and their assent to participate must be obtained if they are capable of expressing their wishes in a meaningful way (whether verbally or physically). Importantly, when authorization for participation was granted by the participant’s legal representative/guardian and a participant acquires or regains decision-making capacity during the course of the research, the researcher must promptly seek the participant’s consent as a condition of continuing participation.

Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

As delineated in the PANDRH-GCPs, an investigational product (IP) is defined as a dosage form of an active ingredient or placebo that is being tested or used as a reference in a clinical trial. ResNo9, the G-BioIProdManual, and the G-SynthDrugProdManual add that the IP may also be referred to as an experimental drug, comparator, or any other product to be used in a trial. According to BRA-8, the definition of an IP in ResNo9 differs from that of the PANDRH-GCPs because when ResNo9 was adopted, an IP was mainly thought of in relation to the imports required to carry out each clinical trial. For this reason, the definition of “product under investigation” encompasses all products to be used in a trial, including medicine comparators, equipment, and laboratory kits. In addition, the PANDRH-GCPs definition further states that an IP may include a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form, or when it is used to gain further information about an approved use. Note: The terms experimental drug and IP are used interchangeably throughout the profile.

As delineated in the CanadaFDR, the G-GMP-Annex13, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), an investigational product is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form. Per CAN-50, Canada has implemented CAN-52. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent.

For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

Manufacturing

As stated in ResNo9, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the manufacture of investigational products (IPs) in Brazil. ANVISA approves the manufacture of an IP as part of its review and approval of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))).

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

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

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

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

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

Import

Per ResNo9 and the G-DDCMManual, ANVISA is responsible for authorizing the import of IPs. The sponsor may request approval to import/export IPs for study purposes at the same time that a DDCM is submitted to ANVISA, as indicated in ResNo9. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while their DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation in the case of non-manifestation of the DDCM. The sponsor is required to present one (1) of these ANVISA documents at the location where IPs for import/export are unloaded. (See Submission Process and Submission Content sections for additional application requirements). See also BRA-103 for detailed instructions on obtaining a drug import license authorization. See ANVISA’s Consultation System (BRA-44) to check on the status of a petition submission using the “Document Status” (Situação de Documentos) tool.

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

ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. Pursuant to ResNo74 and BRA-108, the import petition must be submitted electronically. Per the G-LPCOImprtPetition, the first step in initiating ANVISA’s import protocol process is applying for an import license (Licença de Importação (LI)) via the Integrated Foreign Trade System (SISCOMEX)’s Single Foreign Trade Portal (BRA-80). As indicated in BRA-108, the electronic petition must include the documentation specified in ResNo208 (amending ResNo81) and other relevant legislation. ResNo208 (amending ResNo81) explains that the following documentation must be included with the petition:

• Copy of the CE, CEE, and Document for Importation of Product(s) under Investigation from DDCM
• Knowledge of cargo on board
• Commercial invoice
• In cases of imports carried out by others than the DDCM holder, document of delegation of import responsibilities

BRA-108 also indicates that in the case of documents already in electronic form, they should be attached as individual files for each LI request in BRA-80. The documents must be attached, preferably, in the order indicated in the checklist of the procedure specified in ResNo208 (amending ResNo81). Refer to BRA-108 for detailed documentation presentation requirements. See also ResNo208 and ResNo81 for detailed import documentation requirements. See also BRA-8 for frequently asked questions on importation requirements.

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

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

ANVISA has also adopted a new protocol for requests for authorization to import medicines and substances subject to special control in compliance with ResNo81, as indicated in BRA-57. Per ResNo81, the import of goods and products subject to special control are referenced in OrdNo344 (Lists A1, A2, A3, B1, B2, C3, D1, E, and F). OrdNo344 and BRA-110 define the substances included in these lists as follows: "A1" and "A2" (permitted narcotics), "A3”, "B1", and "B2" (permitted psychotropics), "C3" (immunosuppressants), "D1" (permitted precursors), "E" (plants that can originate narcotic and/or psychotropic substances), and "F" (substances for prohibited use in Brazil). See BRA-57 for details. Per ResNo172, investigators accredited by the National Council for Scientific and Technological Development ((Conselho Nacional de Desenvolvimento Científico e Tecnológico) (CNPq)) and whose tax regime is exempt, will be automatically granted an import license via BRA-80.

ResNo172 specifies that imports intended for clinical trials whose objective is registration or alteration of product registration will be analyzed within five (5) days after protocol approval and compliance with legal requirements.

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

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

In addition, per ResNo102, in the case of a company requesting a global transfer of ownership for product registration or the updating of company operation and certification data as a result of corporate transactions or business operations, the CE, CEE, or Document for Importation of Product(s) under Investigation will be issued in the name of the new company. Company registration updates should include any changes to the company operating authorization, Good Manufacturing Practices Certificate (CBPF), or Good Distribution and Storage Practices Certificate (CBPDA). Please refer to ResNo102 for detailed instructions on submitting appropriate documentation for these updates. See also the Submission Process section for detailed information on documentation to be submitted.

Per BRA-96, ANVISA has also modified the global transfer of responsibility request process for a clinical trial or assistance program for medicines and biological products. The requests must be carried out electronically by the company that has requested the transfer via ANVISA’s Solicita Electronic Petition Request System (BRA-56) using the DDCM petition’s subject code 12130 for medicines and 11795 for advanced therapy products. See BRA-96 for additional information.

Advanced Therapy Products

Per BRA-86 and BRA-94, ANVISA has also initiated a project for applicants to request an import license for advanced therapy products to be used for clinical research or commercial/industrial purposes. The process involves obtaining an LI via the steps discussed earlier in this section followed by making a request through the LPCO module of BRA-80, and linking the LI to the LPCO registration. The user will then be able to initiate an import petition via ANVISA’s Solicita Electronic Petition Request System (BRA-56). See G-LPCOImprtPetition for additional information on registering an LI and LPCO for an advanced therapy products via BRA-80, and then initiating an import petition via BRA-56. Per ResNo506, advanced therapy products refer to medicines for human use that are based on genes, tissues, or cells. Refer to ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products.

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

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

Manufacturing

As specified in the CanadaFDR, the G-CanadaCTApps, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), Health Canada (HC) authorizes the manufacture of investigational products (IPs) in Canada. HC approves the manufacture of IPs as part of the clinical trial application (CTA) approval. Per CAN-50, Canada has implemented CAN-52. Note that per CAN-50, HC-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. The G-QCM-PharmCTAs provides guidance and templates to assist sponsors in completing the quality portion of the CTA, which in turn, enables HC to assess IP characteristics adequately. The G-GMP-Annex13 requires the sponsor to ensure that IPs for clinical trials are manufactured and imported in accordance with its provisions and with CanadaFDR requirements. Per the G-CanadaCTApps, sponsors must file amendments or notifications to a previously authorized CTA when manufacturing changes are proposed that may affect the quality or safety of the clinical trial drug or biologic supplies.

Import

Per the CanadaFDR and the G-FDR-0100, HC authorizes the sponsor to import an IP. A sponsor who is not based in Canada must have a Canadian representative who is responsible for the import of the IP and demonstrates compliance with the applicable regulatory requirements. This representative should be the sponsor’s senior medical or scientific officer residing in Canada and is responsible for providing an attestation with respect to the CTA at the time of filing. Per the G-CanadaCTApps, the G-DrugApp, and CAN-4, if clinical trial drugs are to be imported into Canada, the authorization template (Appendix 1) in CAN-4 should be completed and submitted for each importer in Canada. The G-DrugApp states that Canadian importer(s) must be located within Canada. As additional importers are identified, additional copies of the authorization template in CAN-4 should be provided to HC. The G-FDR-0100, provides additional guidance on requirements if a sponsor plans to send the clinical trial IP(s) directly to each trial site:

• Each party, including individual Canadian clinical trial sites, importing drugs directly (i.e., receiving drug shipment directly from outside of Canada) is identified on Appendix 1 of the Drug Submission Application Form (HC/SC 3011 form) (CAN-4) for Phase I-III trials (submitted with the application if known at the time or prior to importation at the site). Appendix 1 may be replicated as many times as necessary to capture all importing parties.
• Clinical Trial Site Information (CTSI) forms (CAN-6) for each Canadian site conducting the clinical trial are submitted to HC for Phase I-III trials, prior to the start of the study.
• Systems are in place, when appropriate, to monitor the transportation and storage conditions from the foreign source to the various clinical trial sites across Canada.
• There is documented accountability of the imported drugs used in clinical trials and distributed to various clinical trial sites located in Canada, including the disposition of drugs returned from the clinical trial sites.
• A written agreement is in place between the sponsor and the qualified investigator describing their specific responsibilities, and this agreement is available at the clinical trial site.
• There is evidence that the drugs used in clinical trials conducted in Canada meet Good Manufacturing Practice (GMP) requirements (e.g., certificates of manufacture, certificates of analysis, and/or evidence of approved lot release by a qualified individual).

The G-CanadaCTApps, the G-HlthProdImprtExptReqs, the G-FDR-0100, and CAN-32 state that if a sponsor wants to import a drug into Canada for a clinical trial, a copy of HC’s authorization (i.e., the No Objection Letter (NOL)) issued by either the Pharmaceutical Drugs Directorate (PDD) or the Biologic and Radiopharmaceutical Drugs Directorate (BRDD) must be included for the applicable trial with the shipment. A copy of this authorization must be provided at the port of entry. The G-HlthProdImprtExptReqs states that drugs without a Drug Identification Number may be imported where authorized for a Canadian clinical trial and a NOL was issued. The G-FDR-0100 further states that if 30 days have passed and the NOL was not issued, specific requests to import IPs should be directed to the Health Product Border Compliance Program at the following email account: hc.hpbcp-pcpsf.sc@canada.ca. Note that a sponsor does not have to submit a CTA for authorization to import an IP used in a Phase IV clinical trial.

Per CanadaFDR, the sponsor can make the following changes to the authorized use or importation of drugs if the sponsor notifies HC in writing within 15 days after the date of the change:

• A change to the chemistry and manufacturing information that does not affect the quality or safety of the drug
• A change to the protocol that does not alter the risk to the health of a clinical trial subject

Other changes must follow the amendment requirements delineated in the CanadaFDR. See the G-FDR-0100 for additional HC interpretations of the relevant provisions of the CanadaFDR.

Investigator's Brochure

In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). ResNo9 and the G-DDCMManual state that the IB must provide coverage for the following areas:

• Experimental drug
• Formulation
• Pharmacological and toxicological effects of the experimental drug in animals and in humans, where applicable
• Information on safety and efficacy in humans obtained from clinical trials that have already been carried out
• Possible risks and adverse events related to experimental medications, based on past experience, as well as precautions or special procedures to be followed during development

The sponsor should also update the IB as significant new information becomes available.

Quality Management

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

As specified in ResNo9 and the PANDRH-GCPs, the sponsor must also ensure that the products are manufactured in accordance with Good Manufacturing Practice (GMP) as laid down in ResNo658. In addition, per ResNo205, the DDCM submitted to National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to conduct a clinical trial using investigational products for rare diseases should also be accompanied by a request for GMP certification. See ResNo205 and ResNo811 (which partially amends ResNo205) for detailed submission information.

International GMP Compliance

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

Additionally, in accordance with ResNo741, RegNo292 establishes specific criteria and procedures for defining Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) for the purposes of the health inspection and Certification of Good Manufacturing Practices (Certificação de Boas Práticas de Fabricação (CBPF)) of active pharmaceutical ingredients (APIs), cannabis products for medicinal purposes, medicines, and biological products. To comply with health inspection and CBPF criteria, AREEs must be regulatory authorities or international entities that are members of the PIC/S and the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) (See Annex in RegNo292 for list of approved AREEs). See RegNo292 for detailed information on AREEs for the purposes of health inspections and GMP certificates. Also, see BRA-64 for additional information. See the Scope of Assessment section for additional information on AREE requirements.

Investigator’s Brochure

In accordance with the CanadaFDR and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (CAN-52), which Canada has implemented per CAN-50, the sponsor is responsible for providing the investigators with an Investigator’s Brochure (IB). The CanadaFDR and CAN-52 specify that the IB must contain all of the relevant information on the investigational product(s) (IPs), including significant physical, chemical, pharmaceutical, pharmacological, toxicological, pharmacokinetic, metabolic, and clinical information. The sponsor must ensure that an up-to-date IB is made available to the investigator(s), and the investigator(s) must provide an up-to-date IB to the ethics committee. Note that per CAN-50, Health Canada (HC)-implemented ICH guidance takes precedence over other HC guidance when they are not consistent. For HC’s interpretation of the relevant provisions of the CanadaFDR, see the G-FDR-0100.

The CanadaFDR and CAN-52 require the IB to provide coverage of the following areas:

• Physical, chemical, and pharmaceutical properties and formulation parameters
• Non-clinical studies (pharmacology, pharmacokinetics, toxicology, and metabolism profiles)
• Effects of IP in humans (pharmacology, pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and post-marketing experiences)
• Summary of data and guidance for the investigator(s)