Therapeutic Goods Administration

As per the TGAct, the TGR, and the G-CTHandbook, the Therapeutic Goods Administration (TGA) is the regulatory authority responsible for clinical trial approvals, oversight, and inspections in Australia at the national level. The TGA allows for the supply of unapproved therapeutic goods to be used in clinical trials for experimental purposes in humans in accordance with the provisions in the TGAct and the TGR. There are two (2) regulatory schemes for supplying unapproved therapeutic goods in clinical investigations, which are more fully examined in the Scope of Assessment section.

As per AUS-28, the TGA is part of the Health Products Regulation Group (HPRG) within the Australian Department of Health and Aged Care. The TGA’s Pharmacovigilance Branch is responsible for evaluating and authorizing certain clinical trials for all types of therapeutic products. According to the G-TrialsSOP and AUS-32, the TGA also regulates the supply, import, export, manufacturing, and advertising of therapeutic goods. Per AUS-31, therapeutic goods include prescription medicines, vaccines, sunscreens, vitamins and minerals, medical devices, blood, and blood products.

The TGA manages the Australian Register of Therapeutic Goods (ARTG) (AUS-22), a public database of therapeutic goods that can be legally supplied in Australia. According to the TGAct, the TGA grants exemptions from inclusion in the ARTG for unapproved therapeutic goods to be supplied in clinical trials.

Other Considerations

According to AUS-74, the TGA closely aligns its regulatory approaches to therapeutic products with those of comparable international regulatory counterparts, including the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Medicines Agency (EMA), and the United States Food & Drug Administration (FDA), wherever possible. For more information on the international scientific guidelines adopted in Australia, see AUS-74.

Contact Information

Per AUS-23 and AUS-47, the contact information for the TGA is as follows:

Postal Address:
P.O. Box 100
Woden ACT 2606
Australia

For general questions:

Phone: 1 800 020 653 (free call within Australia) or +61 2 6289 4124 (international calls)
Fax: 02 6203 1605
E-mail: use online form (see AUS-11)

For clinical trial questions:

Phone: Same as the general questions numbers
E-mail: clinical.trials@health.gov.au

National Health Surveillance Agency (ANVISA)

As delineated in ResNo945 and ResNo705 (amending ResNo585), the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is the regulatory authority responsible for clinical trial oversight, approval, and inspection of drugs to be registered in Brazil. ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of ResNo945 and ResNo705 (amending ResNo585).

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

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

Additionally, as delineated in ResNo705 and ResNo800 (amending ResNo585), with respect to active pharmaceutical ingredients and medicines, the General Management of Medicines (Gerência-Geral de Medicamentos (GGMED)), which operates within ANVISA’s Collegiate Board, coordinates and supervises the organizational units responsible for regulation; manages the implementation of international cooperation activities; improves regulations; assesses quality, safety, and effectiveness; supervises registration/post-registration; and cooperates with inspection activities.

Per ResNo705 (amending ResNo585), the Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is another administrative unit operating within the Collegiate Board. COPEC is responsible for overseeing clinical research on medicines and biological products conducted for registration and post-marketing surveillance purposes; evaluating petitions; carrying out Good Clinical Practice (GCP) inspections; assisting with international cooperation activities related to the regulation of clinical research on medicines involving human beings; and issuing regulations for granting or denying petitions subject to approval for the clinical research of medicines and biological products and decisions resulting from GCP inspections. See ResNo705 (amending ResNo585) for detailed information on GGMED, COPEC, and ANVISA’s organizational structure and administrative units.

Other Considerations

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

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

Contact Information

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

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

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

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

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

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

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

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

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

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, the Therapeutic Goods Administration (TGA) allows for the supply of unapproved therapeutic goods to be used in clinical trials under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. The G-CTHandbook specifies that the scope of the TGA’s assessment includes all clinical trials (Phases I-IV).

Under either regulatory scheme, per the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve the research protocol. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

For summaries of the clinical trials regulatory environment, legislation, and guidance, see AUS-40.

Clinical Trial Review Process

Per the G-CTHandbook, the sponsor is responsible for the overall decision as to whether the CTN or CTA scheme should be used. Consulting the EC responsible for protocol approval may assist the sponsor in making the decision. The main difference between the CTN and CTA schemes is the TGA’s level of involvement in reviewing data about the therapeutic goods before the clinical trial commences.

See AUS-27 for more information on choosing a clinical trial scheme.

CTN Scheme

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, under the CTN scheme, the sponsor must notify the TGA of its intention to sponsor a clinical trial involving an unapproved therapeutic good. The TGA does not assess any data relating to the proposed trial at the time of submission. As further indicated in AUS-47, sponsors may submit the CTN to the TGA concurrently with the EC’s and institution’s review and approval/authorization. However, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

The G-CTHandbook indicates that a clinical trial is deemed to be notified as soon as the online CTN form (via the TGA Business Services (TBS) webpage (AUS-36)) has been submitted and the relevant fee has been paid. If there are any changes to the trial details notified to the TGA (such as a change in the details of the principal investigator (PI), the address of the site, or the therapeutic good), the sponsor must update the relevant fields on the online CTN form.

The G-CTHandbook further states that the TGA may request additional information if the trial raises any concern, or ask specific questions to address any deficiencies. Specifically, the TGA can request certain information or documents from the sponsor relating to the supply and handling of the goods, as well as the monitoring and results of the supply of the goods. If the TGA directs a trial notified under the CTN scheme not to be conducted or becomes aware that conducting or continuing the trial would be contrary to the public interest, then the goods used in the trial would no longer be exempt from inclusion in the Australian Register of Therapeutic Goods (ARTG) (AUS-22) and cannot be lawfully supplied. This may occur if the TGA becomes aware that allowing the trial to proceed or continue carries an unacceptable risk of death, serious illness, or serious injury.

CTA Scheme

According to AUS-47, parties that are considering submitting a CTA application are strongly encouraged to contact the TGA at clinical.trials@health.gov.au for advice regarding the application process (some class IV biologicals must be submitted under the CTA scheme). Pre-submission meetings with the TGA may be requested through the forms found on AUS-17.

AUS-47 indicates that the CTA scheme consists of a two (2)-part process. Part 1 constitutes the formal CTA application, which the sponsor completes and submits directly to the TGA. Part 2 requires the sponsor to notify the TGA when a trial commences and alert the TGA to new sites in ongoing CTA trials.

As per the G-CTHandbook, the TGA reviews relevant, but limited, scientific data, and its primary responsibility is to review the safety of the product. In addition, the TGA can request certain information or documents from the sponsor about therapeutic goods approved under the CTA scheme relating to the supply and handling of the goods, as well as the monitoring and results of the supply of the goods.

AUS-47 further specifies that the evaluation of a CTA application includes consideration of the manufacturing and quality and safety data in conjunction with the trial's usage guidelines, to inform a risk-benefit decision by the TGA on whether or not to approve the clinical trial. Any significant changes to the information provided in support of the trial are considered a variation and need to be approved, since they have the potential to affect the initial decision to approve a trial. The TGA advises clinical trial sponsors to contact them via clinical.trials@health.gov.au if they intend to change a previously approved CTA application.

The G-CTHandbook further states that the TGA can revoke an approval of a clinical trial under the CTA scheme where the conditions of approval are not met.

Inspection

According to the G-GCP-Inspect, clinical trials of medicines and biologicals regulated under the CTN or CTA schemes are subject to the TGA’s Good Clinical Practice (GCP) inspection program. The TGA can conduct a GCP inspection at any stage of the clinical trial lifecycle from the early phase of participant recruitment to completed trials. Additionally, the TGA can request certain information or documents about therapeutic goods exempt under the CTN scheme or approved under the CTA scheme. This can include the investigator’s brochure and protocol, further information about safety reports, clarification about the safety profile of a specific therapeutic good, and/or details of problems or complaints. The TGA will normally give advance notice of its intention to conduct a GCP inspection but has the right to perform an inspection at any time. In exceptional circumstances, the TGA can perform an inspection without notice.

See the G-GCP-Inspect for more details on how the TGA prioritizes and schedules GCP inspections, the kinds of inspections the TGA might conduct, the inspection process, and how the TGA reports and follows up on inspections.

Overview

As set forth in ResNo945 and ResNo705 (amending ResNo585), the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento Clínico de Medicamento (DDCMs))) for drugs to be registered in Brazil. (Note: Applications are also known as petitions in Brazil). Per ResNo945 and the G-DDCMManual, clinical trials with drugs must have all or part of their clinical development in Brazil. ResNo945 also notes that the DDCM may be submitted at any stage of clinical drug development for one (1) or more phases of clinical trials. However, Phase IV post-marketing trials and non-interventional clinical research are not covered by this regulation, and should be initiated after obtaining the relevant ethical approvals in accordance with the specific standards of the National Research Ethics Authority.

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

Clinical Trial Review Process

As described in ResNo705 (amending ResNo585), ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is responsible for conducting the review and approval of clinical trial applications (DDCMs). Per ResNo945 and the G-DDCMManual, ANVISA’s technical analysis of a primary DDCM petition will only occur after the filing of at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)). A DEEC is defined as a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) in the DDCM. ResNo945 explains that the absence of the DEEC will result in the rejection of the DDCM without technical analysis, except in cases of clinical trials involving more than one (1) experimental drug, with a primary DEEC petition that has already been linked to one (1) of the DDCMs of these drugs. See the Timeline of Review section for ANVISA’s petition review timelines. See also BRA-40 for information on ANVISA drug registration requirements.

Pursuant to ResNo945, substantial modifications to the investigational product (IP) refer to changes that potentially have an impact on the quality or safety of the experimental drug, active comparator, or placebo. Per ResNo945 and the G-DDCMManual, substantial IP modifications and substantial protocol amendments must be linked as secondary petitions to the corresponding DDCM. Non-substantial IP modifications must always be submitted to ANVISA in the next petition for substantial IP modification, or as part of the drug development safety update (DSUR), whichever occurs first. ANVISA will issue a supplementary normative act regarding IP modifications considered to be substantial and non-substantial. See also the G-DDCMAmdmts for clarifying information on substantial and non-substantial protocol modifications. Refer to the Submission Process and Submission Content sections for IP modification submission process and documentation requirements.

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

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

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

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

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

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

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

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

Inspection

In accordance with LawNo14.874, ANVISA is authorized to carry out good clinical practice (GCP) inspections of clinical research centers, sponsors, and contract research organizations (CROs) (clinical research representative organization (CRPO) in Brazil). ResNo945 further specifies that ANVISA may carry out GCP inspections of clinical trial centers, sponsors, CROs, laboratories, and other institutions involved in the development of the IP to verify the degree of adherence to current Brazilian legislation and compliance with GCP, in addition to ensuring the rights and duties that concern the scientific community and Brazil. In addition to specific GCP inspection standards issued by ANVISA, GCP inspections will follow the harmonized guidelines of the ICH’s Guideline for Good Clinical Practice E6(R2) (BRA-28) and its updates which Brazil has formally adopted. (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025). Refer to ResNo945 for more information on ANVISA’s GCP inspection requirements.

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

Priority Submissions

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

New Drugs for Rare Diseases Submissions

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

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

Optimized Analysis Procedure Reviews

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

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

Drug & Biological Product Registration/Post-Registration

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

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

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

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

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

As per ResNo945, RegNo338, and BRA-122, the optimized analysis procedure based on Reliance is also applicable to primary DDCM and DEEC petitions, and secondary petitions for substantial modifications to the IP and substantial amendments to the clinical trial protocol. Pursuant to ResNo945, ANVISA will review the AREE documentation for compliance. Per ResNo945 and RegNo338, for the purposes of admissibility for analyzing primary and secondary petitions, the related documents must have been approved by at least one (1) of the AREEs recognized by ANVISA.

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

• EMA and its member countries
• Health Canada
• Swissmedic
• MHRA
• FDA
• Pharmaceuticals and Medical Devices Agency (PMDA), Japan

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

According to RegNo338 and RegNo345 (amending RegNo338) following its evaluation, ANVISA will issue one (1) of the responses listed below:

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

ResNo945 and BRA-122 further state that the admissibility of the optimized analysis procedure by Reliance does not presuppose prioritization of petition analysis, however, per ResNo945, ANVISA may create specific queues for the allocation and analysis of these petitions. BRA-122 also indicates that petitions will be analyzed in accordance with the chronological order of submission (issue date of the file), regardless of whether they fit into the optimized procedure. However, petitions prioritized under the terms of ResNo204 and ResNo205 may also be included in the criteria for applying the optimized analysis procedure when requested by the applicant.

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

See the Submission Process and Submission Content sections for details.

DDCM & IP Substantial Modifications by Risk Assessment

As delineated in ResNo945, the optimized analysis procedure may also be applied based on the risk or complexity criteria of the clinical trial or IP. When requested by the sponsor, this type of technical analysis applies to DDCMs and substantial IP modifications. The required documents for each type of petition or process may be partially or fully exempted from technical analysis, through the optimized analysis procedure, according to the risk and complexity of the clinical trial. ANVISA categorizes clinical trial risk as low, moderate, or high. Refer to RegNo338 for more information on risk assessment criteria. ResNo945 further notes that in cases where the placebo, when used, is identical to the registered IP, differing from it only by the absence of the active pharmaceutical ingredient, and/or the active comparator is identical to the registered drug, ANVISA’s evaluation of the documents present in the IMPD or DPI may also be analyzed by the optimized procedure by risk assessment. Per RegNo338, ANVISA will provide a specific petition characterization form for the sponsor to complete for the proper identification of situations in which the optimized analysis procedure is supported by experience using the IP.

Therapeutic Goods Administration

As per the TGR, the sponsor is responsible for paying a fee to the Therapeutic Goods Administration (TGA) to submit an application under the Clinical Trial Notification (CTN) or Clinical Trial Approval (CTA) scheme for evaluation. Per the G-FeesCharges, the fees are as follows:

• $429 Australian dollars for unapproved medicines CTN, and for each notification of one (1) or more additional trial sites
• $2,046 Australia dollars for unapproved medicines CTA (30-day evaluation)
• $562 Australian dollars for unapproved medicines CTA – variation (30-day evaluation)
• $25,426 Australian dollars for unapproved medicines CTA (50-day evaluation)
• $6,940 Australian dollars for unapproved medicines CTA – variation (50-day evaluation)
• $429 Australian dollars for unapproved biologicals CTN, and for each notification of one (1) or more additional trial sites
• $30,964 Australian dollars for unapproved biologicals CTA
• $8,448 Australian dollars for unapproved biologicals CTA – variation

According to AUS-47, a higher fee is applicable to clinical trial applications under the CTA scheme due to the more complex nature of the evaluation process. Certain variations to an existing CTN may incur a fee, such as the addition of a new site, change to a previously notified therapeutic good that creates separate and distinct goods, or the addition of a new therapeutic good to a previously notified trial. For additional fee information, refer to Schedules 9 and 9A of the TGR and the G-FeesCharges.

Payment Instructions

AUS-66 indicates that regulatory fees and charges may be paid online or by bank transfer (electronic funds transfer (EFT)). Online payment by credit card is the preferred payment option, and all payments must be in Australian dollars.

As stated in AUS-25, online payment is made via the TGA Online Payment Portal (AUS-16). Once the payment has been finalized, the Portal will confirm that the payment has been successful. The user may request an email confirmation. Certain payments, including a CTN fee and a variation to a medicine (e.g., a therapeutic good), may be made online without an invoice. See AUS-25 for more information on TGA fees and payments. Also see AUS-49 for additional guidance and system screenshots related to paying CTN fees.

AUS-66 further indicates that to ensure all payments made by EFT are correctly allocated, the organization’s Identification Number (e.g., TGA00xxxxx) should be included in the payment ‘Reference’ field. Bank transfer fees are the payer’s responsibility. Additionally, bank transfers must be accompanied by a remittance advice, which must be issued within 24 hours for all bank transfers. Remittance advices must be emailed to TGARemittanceAdvices@health.gov.au and contain the organization’s Identification Number in the subject field. The TGA’s bank account details are as follows:

Bank: Commonwealth Bank of Australia
BSB: 062-909
Account Number: 10215498

Per AUS-66, payments from overseas can only be accepted in Australian denominations. Payers must ensure that their payment covers any international banking fees. The TGA’s international banking details are as follows:

IBAN: 06290910215498
Swift Code: CTBAAU2S

National Health Surveillance Agency (ANVISA)

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

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

Payment Instructions

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

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

Overview

As indicated in the TGAct, the TGR, the G-CTHandbook, the G-NatlStmt, and AUS-47, Australia has a decentralized process for the ethics review and approval of clinical trial research. According to the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, Australia requires human research protocols to be reviewed by an institutional-level ethics committee (EC). The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. (Note: Institutional ECs are referred to as Human Research Ethics Committees (HRECs) in Australia.)

The G-NatlStmt indicates that one (1) or more institutions can individually or jointly establish an EC or any other ethics review body. Institutions that establish an EC are responsible for adequately resourcing and maintaining it, including providing sufficient administrative support. Per the TGAct and AUS-20, ECs are required to be constituted and operate in accordance with the guidelines issued by the National Health and Medical Research Council (NHMRC), and to have notified the NHMRC of their existence. According to the TGR, the G-NatlStmt, the G-TrialsSOP, and AUS-20, institutional ECs ensure that clinical trial research complies with the NHMRC’s ethical standards published in the G-NatlStmt. See the Oversight of Ethics Committees section for more information on notification.

For summaries of the clinical trials regulatory environment, legislation, and guidance, see AUS-40.

Ethics Committee Composition

As stated in the G-NatlStmt, an EC must be composed of at least eight (8) members in the following categories:

• A chairperson with suitable experience
• Two (2) people who bring a broader community or consumer perspective and have no paid affiliation with the institution
• One (1) person with knowledge of and current experience in the professional care, counseling, and/or treatment of people
• One (1) person who performs a pastoral care role in the community
• One (1) qualified lawyer, who may or may not be currently practicing and, where possible, is not engaged to advise the institution on research-related or any other matters
• Two (2) people with current research experience relevant to the research proposals to be considered at the meetings they attend

The G-NatlStmt further states that wherever possible, one (1) or more of the members listed above should be experienced in reflecting on and analyzing ethical decision-making. As far as is practicable, institutions should ensure that their EC’s membership at each meeting has diversity, including gender diversity, and at least one third of those participating in each meeting are from outside of the institution. ECs that review research about Aboriginal and Torres Strait Islander people or communities should appoint one (1) or more members who have knowledge of research with Aboriginal and Torres Strait Islander peoples or are familiar with relevant cultural knowledge, if such a person has not already been appointed.

Per the G-NatlStmt, ECs may also include other members with the above areas of expertise or with additional areas of expertise. Institutions are encouraged to establish a pool of appointed EC members to draw on as needed to help meet minimum membership requirements and/or provide additional experience or expertise. The institution should ensure that its EC has access to the expertise necessary to properly review research, which may necessitate going outside of the EC’s membership.

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in the G-NatlStmt, institutional ECs must ensure that it documents, implements, and publicizes standard operating procedures (SOPs) that promote good ethics review, including:

• Meeting frequency, attendance, and conduct
• Minutes and agenda preparation
• Timely distribution of materials to members before meetings
• Timely consideration of applications
• Methods of deliberation and decision-making
• Processes, if any, for reviewing applications from unaffiliated or international researchers
• Disclosure of interests and management of conflicts of interest
• Appropriate confidentiality of the content of applications and the deliberations of review bodies
• Prompt notification of decisions to researchers
• Communicating with researchers, including face to face, by telephone and in writing, (including available forms of electronic communication)
• Record keeping
• Monitoring of approved research
• Reporting and handling of adverse events
• Receiving and handling of complaints
• Advising the institution(s) of decisions to suspend or withdraw ethics approval of research projects
• Attendance of people other than members at meetings

Pursuant to the G-NatlStmt, EC members should be familiar with the G-NatlStmt and other relevant guidelines; prepare for and attend EC meetings or, if unavailable, provide opinions before the meetings; and attend research ethics training programs or continuing education at least every three (3) years. Members should be appointed to an EC using open and transparent processes, and institutions should consider reviewing appointments to the EC at least every three (3) years.

The G-NatlStmt states that as far as possible, each EC meeting should be arranged to enable attendance of all members of the minimum membership categories listed above and other relevant appointed members, either in person or via available technology. Meeting papers should be provided enough in advance to enable members to be fully informed. An EC’s decision about whether a research proposal meets the requirements of the G-NatlStmt must be informed by an exchange of opinions from all members of the EC participating in the meeting. The exchange should, ideally, take place at a meeting with all those members present. Where there is less than full attendance of the minimum membership categories at a meeting, the chairperson must be satisfied, before a decision is reached, that the views of those absent who belong to the minimum membership have been received and considered. The EC should attempt to reach decisions by general agreement or consensus. Voting is neither required nor prohibited. Some decisions may not be unanimous, and a dissent should be recorded in the minutes of the meeting. Where requested by a dissenting member, the reasons for the dissent should also be recorded in the minutes of the meeting.

According to the G-NatlStmt, ECs may invite researchers, and researchers may request, to be present for discussion of their proposed research. In addition, ECs may seek advice from external experts to help in considering a research proposal. Communication between the sponsor and the EC is not prohibited but should be restricted so that it does not inappropriately influence the review of any relevant research proposals.

As delineated in the G-NatlStmt, ECs must maintain a complete record of all research proposals received and reviewed. Approved project documentation and any relevant correspondence must also be retained. Records must be maintained in accordance with the requirements of relevant Commonwealth and state or territory legislation and guidelines. See G-NatlStmt for detailed records requirements.

For more details on the governance and responsibilities of Australian institutional ECs, see the G-NatlStmt.

Overview

New National System of Ethics in Research with Human Beings

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

CEP/CONEP System

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

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

Ethics Committee Composition

National Research Ethics Commission (CONEP)

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

Research Ethics Committees (CEPs)

National Research Ethics Authority

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

National Research Ethics Commission (CONEP)

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

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

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

Terms of Reference, Review Procedures, and Meeting Schedule

National Research Ethics Authority

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

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

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

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

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

Also, per LawNo14.874, in the case of research involving a special group, to be established by regulation, the EC (CEP) must ensure, whenever possible, during the protocol discussion, the participation of one (1) representative of the special group as an ad-hoc member; and one (1) consultant familiar with the language, customs, and traditions of the specific community, when the research involves that community. EC (CEP) members may also invite external experts and representatives of vulnerable groups to issue an opinion on specific issues related to the research projects, but these individuals should not have the right to vote. Once duly accredited or certified, ECs (CEPs) have complete autonomy to issue their opinions, in compliance with GCP. The EC (CEP) will also keep all project related documents on file for a period of five (5) years after the end of the research, with digital archiving permitted. As stated in LawNo14.874, the institution hosting the EC (CEP) will promote and support the training of its committee members, with an emphasis on ethical and methodological aspects related to the rights of research participants. The EC’s (CEP)’s activities are subject to inspection and monitoring by the National Research Ethics Authority. Failure by the EC (CEP) to comply with the provisions of LawNo14.874 will result in its de-accreditation by the National Research Ethics Authority, in accordance with regulations.

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

National Research Ethics Commission (CONEP)

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

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

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

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

Overview

According to the G-NatlStmt, the institutional ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) is responsible for protecting the interests of research participants and for promoting good research by ensuring adherence to the values of research merit and integrity, beneficence, justice, and respect for persons throughout the conduct of the research project. The EC must review the recruitment and consent processes, weigh the benefits and risks of the research, and consider the impact of the research on certain groups of participants deemed to merit special consideration. Additionally, ECs may conduct both scientific and ethics review or may delegate scientific review to a sub-committee.

Pursuant to the G-NatlStmt, the establishment and maintenance of ethics review processes and processes for assessing the risk level of the research are part of an institution’s overall governance responsibility. In addition to ethics approval, research must also be authorized by each institution with responsibility for oversight of the research before it can proceed. See the Oversight of Ethics Committees, Submission Process, Submission Content, Timeline of Review, and Initiation, Agreements & Registration sections for more information on research governance requirements.

Role in Clinical Trial Approval Process

According to the G-CTHandbook, the G-TrialsSOP, and AUS-47, ECs are responsible for reviewing and approving protocols involving unapproved therapeutic goods under one (1) of two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme—prior to the sponsor initiating a trial. According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

The G-CTHandbook states that a CTN scheme is a notification scheme under which the Therapeutic Goods Administration (TGA) does not review or evaluate any data relating to the clinical trial. The EC is responsible for assessing the scientific validity of the trial design, the balance of risk versus harm of the therapeutic good(s), and the overall ethical acceptability of the trial. Per AUS-47, EC and institutional review and approval/authorization may be conducted in parallel to the CTN form submission to the TGA; however, it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

Under the CTA scheme, as delineated in the G-CTHandbook, the TGA reviews relevant, but limited, scientific data, while the EC is responsible for considering the scientific and ethical issues of the proposed trial protocol.

Per the G-CTHandbook, the sponsor determines whether to conduct a clinical trial under the CTN or CTA scheme. Consulting the EC responsible for protocol approval may assist the sponsor in making the decision. One of the determining factors for an EC is whether the committee has access to appropriate scientific and technical expertise in order to assess the safety of the product. If an EC feels that it requires additional expertise to review a CTN, it may seek advice from external authorities or it may seek to collaborate with another EC that has the required expertise. An EC may also determine that it does not have access to the appropriate scientific and technical expertise to review the proposed trial under the CTN scheme and recommend review under the CTA scheme.

AUS-14 states that prior to approving a clinical trial, the EC must be satisfied that the trial protocol complies with the following requirements:

• G-NatlStmt
• Declaration of Helsinki (AUS-52)
• AU-ICH-GCPs
• TGA requirements, including the G-CTHandbook and the G-SafetyDataMgt
• Any relevant Australian Government and/or state/territory laws

The G-CTHandbook and the TGR state that during its review, the EC also needs to be aware of relevant state and territory laws pertaining to the supply of therapeutic goods or other clinical trial-related matters. The G-CTHandbook further indicates that ECs have a high level of independence and are responsible for establishing their own processes for reviewing research proposals. According to the G-CTHandbook and the AU-ICH-GCPs, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCPs, the TGA recommends compliance with the G-NatlStmt.

As stated in AUS-20, ECs also consider the protection of privacy for humans participating in research and their data. ECs do this by considering whether the research proposal conforms to relevant legislation, principles, and guidelines, including federal and/or state/territory legislation as well as the G-PrivacyAct95 and G-PrivacyAct95A guidelines. See the Personal Data Protection section for more information.

Per the G-NatlStmt, an EC may approve, request modification of, reject, or withdraw approval of a research proposal. The EC must clearly communicate its decision to the researcher(s):

• Where a proposal is approved or rejected, or where approval is withdrawn, communication must be in writing (which may include electronic formats) and should include an explicit statement that the proposal meets or did not meet the requirements of the G-NatlStmt. If rejecting or withdrawing approval of a research proposal, the EC should provide the rationale for its decision, including citing the provisions of the G-NatlStmt or relevant institutional policy that underpins its decision, if relevant.
• Where modifications are requested, communication may be written or, where appropriate, informal; however, a record should be kept of any informal communication, and guidance should be clearly communicated regarding to whom the researcher’s response should be directed .

According to the G-NatlStmt, varying processes may be used for the review and approval of project extensions, amendments to an approved project, progress reports, and renewal of project approval. Appropriate processes depend on the nature of the original project and any proposed changes, but any process authorized by an institution for these purposes must prioritize the safety and well-being of participants, researchers, and/or the community.

Pursuant to the G-CTHandbook and the TGR, when the EC approves a trial protocol, it takes responsibility for monitoring the progress and conduct of the trial. However, the G-NatlStmt indicates that each institution has ultimate responsibility for ensuring, via its research governance arrangements, that all its authorized research is monitored. Monitoring arrangements should be commensurate with the risk, size, and complexity of the research. Monitoring responsibilities that are performed by the institution’s EC should be based on the EC’s review of the project. However, where research that will take place at multiple sites has been reviewed by only one (1) EC, the ECs of the other institutions participating in the project do not have knowledge of the project. In such cases, only the reviewing EC can take on those elements of monitoring a research project that are commonly performed by ECs.

Per the G-NatlStmt, if the EC or institution has reason to believe that continuance of a research project would compromise participants' welfare, or if the conditions of ethics approval for the project are not being adhered to, it should immediately seek to establish whether ethical approval for the project should be suspended or withdrawn. If an institution or EC considers that suspension of research is necessary, the instruction to stop should come from the management of the institution. If ethics approval for a research project is suspended, the researcher, the institution(s), and, where possible, the participants should be informed of the suspension.

As indicated in the G-NatlStmt, ECs may require researchers to amend research procedures to protect participants. If an EC determines that such changes cannot achieve that end, the EC may decline to grant an extension to project approval or decide to withdraw approval for the research. Where ethics approval for a research project is withdrawn:

• The researcher, the institution(s), and, where possible, the participants should be informed of the withdrawal
• Continuation of the research project is subject to re-application and re-approval by the EC

See the G-NatlStmt for more details on institutional and EC responsibilities regarding research monitoring.

External Ethics Approval and the National Mutual Acceptance Scheme

The G-NatlStmt encourages the minimization of unnecessary duplication of ethics review, including for research conducted in multiple Australian jurisdictions or across international boundaries. Institutions may accept an ethics review conducted by an entity external to the institution (including overseas review bodies) and should determine their criteria for this acceptance.

Per the G-NatlStmt, researchers who wish to submit evidence of ethics approval by an external EC in support of single ethics review should be aware of existing national or international programs, protocols, policies, standards, and guidance that may be relevant to the institutional decision to accept the review. To facilitate the efficient ethics review of research, researchers must inform any EC of:

• All sites at which the research will be conducted
• Any information on local site circumstances that is relevant to the ethics review
• Any other body that will be considering ethical issues related to the research
• Any previous decisions to approve, re-consider, or deny approval of the research by another review body in Australia or elsewhere

See the G-NatlStmt for more information on external ethics approval.

As described in AUS-21 and AUS-41, the National Mutual Acceptance (NMA) scheme further supports the acceptance of a single scientific and ethical review of multicenter research conducted in publicly funded health services. All state and territory-certified public health organizations in Australia are part of the NMA scheme.

Per AUS-68, in order for ethics reviews of human research to be accepted under NMA, the EC conducting the review must be certified under the National Health and Medical Research Council (NHMRC) National Certification Scheme of Institutional Processes Related to the Ethical Review of Multi-centre Research (National Certification Scheme), and also be a “Certified Reviewing HREC” under the NMA scheme.

For more information on submissions to ECs under the NMA scheme and the National Certification Scheme, see the Submission Process and Oversight of Ethics Committees sections.

Exemption from Ethics Review

As stated in the G-NatlStmt, some research may be eligible for exemption from ethics review. Where appropriate, exemption is granted, or not, by the institution responsible for the research. Where there is no institution providing oversight of the research, researchers should request a grant of exemption from an EC. Research that may be eligible for exemption from ethics review includes research that carries a lower risk to participants or the community, and satisfies one (1) or more of the following conditions:

• The research involves the use of collections of information or data from which all personal identifiers have been removed prior to being received by the researchers, and where researchers explicitly agree: (i) not to attempt to re-identify those with whom the information or data is associated; (ii) to take all reasonable steps to prevent re-identification of the information or data for unauthorized purposes or access to the information or data by those who are not authorized; and (iii) that any sharing of any research data during or after the project will not create any additional risks of re-identification of the information or data
• The research is restricted to surveys and observation of public behavior using information that was or will be collected and recorded without personal identifiers and is highly unlikely to cause distress to anyone associated with the information or the outcomes of the research
• Is conducted as part of an educational training program in which the research activity is for training purposes only and where any outcomes or documentation are for program use only
• The research uses only information that is publicly available through a mechanism set out by legislation or regulation and that is protected by law, such as mandatory reporting information, information obtained from registries of births and deaths, coroner’s investigations, or reports of the Australian Bureau of Statistics

The G-NatlStmt indicates that institutions or other granting bodies must keep a record of any decision to grant exemption from ethics review. See the G-NatlStmt for more information on ethics review exemption.

Overview

New National System of Ethics in Research with Human Beings

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

National Research Ethics Authority

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

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

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

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

National Research Ethics Commission (CONEP)

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

Per ResNo466, ResNo251, and OSNo001, the CEP/CONEP System members must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). ResNo304 further establishes specific ethical requirements for research studies involving indigenous populations. Detailed information on documentation and consent requirements for studies involving indigenous populations is available in the Documentation Requirements, Vulnerable Populations, and Consent for Specimen sections.

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

CONEP-Designated Protocol Reviews

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

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

CONEP Review Pathways

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

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

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

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

Role in Clinical Trial Approval Process

National Research Ethics Authority

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

In addition, as indicated in ResNo945, the EC (CEP) must review and approve any protocol amendments prior to those changes being implemented. There is no stated expiration date for an EC (CEP) approval in ResNo945.

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

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

After the start of the research, per LawNo14.874, if there is a need for a change that interferes with the risk-benefit relationship or the approved documentation, the coordinating investigator will submit, in writing, an amendment to the research project, duly justified, for analysis and opinion by the EC (CEP) that analyzed the research. The amendment may only be implemented after approval by the EC (CEP), in accordance with this law, except when the safety of the research participant depends on its immediate implementation. The provisions for the initial research project review are also applicable to amendments to the research project.

LawNo14.874 also notes that the ethical analysis of research involving more than one (1) research center in the country will be carried out by a single EC (CEP), preferably the one linked to the research coordinating center, which will issue the opinion and notify the ECs (CEPs) of the other participating centers of its decision. Additionally, research of strategic interest to the MOH’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53) and relevant to responding to public health emergencies will be given priority in ethical analysis and will be subject to special analysis procedures, including deadlines. See the Timeline of Review section for detailed timeline information.

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

National Research Ethics Commission (CONEP)

As per ResNo466 and OSNo001, ANVISA and the EC (CEP) (and CONEP, if applicable) must approve a clinical trial application before a trial is permitted to commence. Per OSNo001, the EC (CEP) must also review and approve any protocol amendments prior to those changes being implemented. If applicable, CONEP may also review protocol amendments. (See CLNo038 for the criteria CONEP uses to process protocol amendments.) ResNo466 and OSNo001 specify that the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via BRA-34. CLNo24 and CLNo24-Note for CONEP’s general guidelines for investigators and ECs (CEPs) on conducting clinical trials.

Additionally, CLNo040 specifies that if investigational brochure (IB) updates result in modifications to the detailed protocol and/or the informed consent form (ICF), then a protocol amendment must be submitted. In this case, the EC (CEP) will analyze the IB together with the other documents pertaining to the amendment, and, if necessary, the required amendments and/or clarifications will be requested.

Per CLNo29, in the case of an appeal, only the investigator responsible for the protocol, which had a substantiated opinion of non-approval, may submit a request to the CEP/CONEP System via Platforma Brasil (BRA-34). The appeal must be filed within 30 calendar days, counting from the first day following the issuance of the substantiated opinion of non-approval. Appeals submitted to the EC (CEP) will be reviewed and a substantiated opinion analyzing the appeal will be issued within 30 calendar days following receipt. If the EC (CEP) considers the requirements and justifications presented in the appeal to be appropriate in order to continue the ethical analysis, the appeal will be approved, or pending approval, if the protocol requires adjustments prior to approval. However, if the appeal is not approved by the EC (CEP), the investigator may appeal to CONEP. CONEP, in turn, has a deadline of up to 45 days after receiving the appeal to issue a substantiated opinion of approved, pending, or not approved, when evaluating the appeal in relation to the substantiated opinion issued by the EC (CEP). If CONEP does not approve the appeal, the investigator, upon receiving the non-approval opinion from CONEP, may file an appeal directly to CONEP itself. From an analysis of the resources submitted to the EC (CEP) and/or CONEP, CONEP may issue an “Approve with Recommendation” opinion to the EC (CEP), when applicable. If CONEP does not approve the appeal, the processing of the appeal is terminated, the research protocol is archived, and no other appeal requests will be permitted. There is no stated expiration date for an EC (CEP) approval in ResNo466 or OSNo001. See the Timeline of Review section for detailed timeline information.

Foreign Research

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

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

Multicenter Research

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

See ResNo346 for additional multicenter protocol processing information.

Exemption from Review

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

The G-NatlStmt indicates that when establishing an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia), an institution must set out and publicize its terms of reference, including its schedule of fees charged, if any, for ethics review. The institution is responsible for ensuring that its EC operates in accordance with the G-NatlStmt, which includes being satisfied that any fees charged for EC review do not discourage research that the institution has an obligation to support.

National Research Ethics Authority

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

National Research Ethics Commission (CONEP)

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

Overview

As per the TGAct, the G-TrialsSOP, and the G-CTHandbook, the National Health and Medical Research Council (NHMRC) is responsible for receiving applications from ethics committees (ECs) (Human Research Ethics Committees (HRECs) in Australia) to be registered. The NHMRC was established by the NHMRCAct. Per the NHMRCAct, the NHMRC’s activities are designed to raise the standard of individual and public health throughout Australia; to foster the development of consistent health standards between the various states and territories; to foster medical and public health research and training throughout Australia; and to foster consideration of ethical issues relating to health.

Research Governance

Pursuant to the G-NatlStmt, institutions may fulfill their research governance responsibilities by establishing and overseeing different levels of ethics review. One (1) or more institutions can individually or jointly establish an EC or any other ethics review body. Institutions that establish an EC are responsible for adequately resourcing and maintaining it, including providing sufficient administrative support.

According to the G-NatlStmt, institutions should ensure that all ethics review processes and the criteria that are used for determining the appropriate process are clear, transparent, and published to enable researchers to submit their research proposals efficiently.

The G-NatlStmt further states that institutions should clearly publicize their policy for access to their EC or other ethics review processes by researchers who are not affiliated with the institution. Additionally, institutions should regularly assess all their ethics review processes, including the criteria for allocating research to different levels of review, to ensure that those processes continue to enable the institution to meet its responsibilities under the G-NatlStmt. Where possible this assessment should be informed by the documented experience of research participants and/or by involving participants or the wider community in the assessment.

Furthermore, as delineated in the G-NatlStmt, institutions should have in place an auditing process to confirm that research is being reviewed at the levels of review that their criteria require and research is being exempted from review only in accordance with the criteria set out in the G-NatlStmt. See the Scope of Review section for more information on exemption criteria.

Registration, Auditing, and Accreditation

According to the G-NatlStmt, institutions that have responsibility for oversight of research and maintain ECs must register their ECs with the NHMRC. ECs that are not associated with institutions must register themselves with the NHMRC.

Per AUS-20, registration means that the EC has notified the NHMRC of its existence and declared that it meets the requirements of the G-NatlStmt. In order to review and monitor clinical trials of unregistered therapeutic goods, an EC must be notified to the NHMRC, and constituted and operating in accordance with the G-NatlStmt. Forms for registering an EC, notifying the NHMRC of changes to the EC, or terminating an EC’s registration are available at AUS-20.

As per the G-NatlStmt, an institution and its EC must report annually, or upon request, to the NHMRC. The NHMRC, through the Australian Health Ethics Committee (AHEC), will review the activities of ECs to ensure conformance with the G-NatlStmt. Reportable information may include:

• Membership/membership changes
• Number of meetings
• Confirmation of participation in meetings by members in minimum membership categories
• The number of research proposals presented, the number approved, the number requiring modification prior to approval, and the number rejected
• Monitoring procedures that are in place and any problems encountered with monitoring of projects
• Complaints procedures and number of complaints handled
• Any other relevant policies, procedures, or processes as determined by the NHMRC

The G-NatlStmt further indicates that failure to comply with the requirements of the G-NatlStmt may result in the EC being removed from the list of ECs registered with NHMRC. See AUS-20 for more information and the list of registered ECs.

National Certification Scheme

According to AUS-21, the NHMRC developed the National Certification Scheme of Institutional Processes Related to the Ethical Review of Multi-centre Research (National Certification Scheme) to enable the single ethics and scientific review of human research occurring at multiple institutions in Australia. Under this scheme, certified institutions can have their ethics review accepted by other institutions participating in the research project. As part of the National Certification Scheme, certified institutions and their ECs are required to report to the NHMRC on their multicenter research activities.

As per AUS-21, the NHMRC assesses each institution’s interest in certification on a case-by-case basis. Certification respects institutional decisions about research governance matters, including whether research should be conducted at a given site. Before commencing steps to apply for certification, institutions should contact HREC.admin@nhmrc.gov.au.

For more information on the National Certification Scheme and the NHMRC’s continuous certification process, see AUS-21.

As stated in AUS-68, EC certification under the National Certification Scheme is required in order for ethics reviews of human research to be accepted under the National Mutual Acceptance (NMA) scheme. The NMA scheme facilitates single scientific and ethical review of clinical trials conducted in participating jurisdiction’s public health organizations. See the Scope of Review section for more information on NMA.

Overview

New National System of Ethics in Research with Human Beings

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

National Research Ethics Authority

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

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

National Research Ethics Commission (CONEP)

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

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

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

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

Registration, Auditing, and Accreditation

National Research Ethics Authority

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

National Research Ethics Commission (CONEP)

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

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

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

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

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

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

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

See CNSResNo506 for additional documentation requirements.

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

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

High-Risk Research Protocols

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

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

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

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

Suspension and Cancellation of Accreditation

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

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

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

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, Australia requires the sponsor to obtain clinical trial authorization from the Therapeutic Goods Administration (TGA) for the supply of unapproved therapeutic goods for clinical trials for experimental purposes in humans. The sponsor can apply under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme.

Under either regulatory scheme, per the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve the research protocol. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. AUS-47 indicates that the review and approval/authorization by an EC and institution may be conducted in parallel to the CTN form submission to the TGA, but it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel. However, EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted. While there is no submission language requirement stated in the requirements, the official language of Australia is English.

Regulatory Submission

Per AUS-17, sponsors may request pre-submission meetings with the TGA. See AUS-17 for the applicable forms.

CTN Scheme

According to AUS-47 and AUS-30, CTN forms are submitted online through the TGA Business Services (TBS) webpage (AUS-36). The sponsor must have or obtain a TGA Client Identification Number.

As per AUS-49, to submit the online CTN form successfully through AUS-36, the sponsor must accept a declaration to assume responsibility for the trial. After accepting the declaration, a webpage will advise the sponsor that the CTN submission has been successful. According to AUS-47, the TGA does not send an acknowledgement letter by email since this information is available for viewing and printing via the online portal. The TGA advises clinical trial sponsors to obtain and save a printout of notification at each stage of the submission process.

AUS-49 indicates that the sponsor may delegate duties and correspondence with the TGA to an authorized agent, which is able to create and submit a CTN on behalf of a sponsor. If an agent has submitted a CTN on the sponsor’s behalf, the sponsor will not have access to view or vary the CTN. Access is only granted to the agent.

See AUS-30 and AUS-49 for additional information on using and submitting the online form.

CTA Scheme

According to AUS-47, the sponsor must complete and submit two (2) forms (AUS-56 and AUS-57) to the TGA via email at clinical.trials@health.gov.au. Supporting data for the CTA application should be provided in electronic format, preferably on USB or CD-ROM via post. The trial commencement notification form (AUS-57) must be sent to the TGA within 28 days of commencing supply of the unapproved therapeutic goods.

Per AUS-47, those with queries regarding the CTA scheme are encouraged to contact the TGA directly at clinical.trials@health.gov.au.

Ethics Review Submission

AUS-46 indicates that the National Health and Medical Research Council (NHMRC) developed the Human Research Ethics Application (HREA) form (AUS-9) as a concise application to facilitate timely and efficient ethics review for research involving humans. The HREA assists researchers in considering the ethical principles of the G-NatlStmt in relation to their research and is accepted by institutions that participate in the National Mutual Acceptance (NMA) scheme, which facilitates single ethics review by multiple public health organizations for most human research.

According to the G-CTHandbook, trial sponsors and researchers should use the HREA unless advised otherwise. AUS-19 contains resources for using the HREA.

Per AUS-46, research proposals should be submitted to ECs associated with public health institutions in New South Wales, Queensland, South Australia, Australian Capital Territory, and Victoria, as well as Mater Research, via the Research GEMS system (AUS-55), the Ethical Review Manager (ERM) website (AUS-8), and/or the Research Ethics and Governance Information System (REGIS) (AUS-10), depending on which jurisdictions are involved. For research in the Northern Territory, Tasmania, or Western Australia, the EC should be contacted for their local submission requirements.

The G-CTHandbook further states that ECs have a high level of independence and are responsible for establishing their own processes for receiving research proposals.

Research Governance

According to the G-NatlStmt, institutions should publish (such as on their website) clear policies and procedures for institutional authorization of research. As noted in the G-CTHandbook, individual jurisdictions have specific requirements as a part of their SSA and authorization processes. South Australia sites use the online SSA form found in the Research GEMS system (AUS-55), while the ERM website (AUS-8) is used for SSA form submission for Mater Research, Queensland, and Victoria. New South Wales and the Australian Capital Territory use REGIS (AUS-10) for site governance applications.

Overview

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

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

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

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

Regulatory Submission

Primary Petitions

As per ResNo945, the primary DDCM petition may be submitted to ANVISA at any stage of clinical drug development for one (1) or more clinical trial phases. ResNo945 and the G-DDCMManual further note that the DDCM must also be filed with at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) for analysis. A DEEC is defined as a collection of documents submitted as part of the Investigational Drug Development Plan (PDME) in the DDCM. DEECs must be filed in the form of individual processes for each clinical trial and linked to the respective DDCM. Per the G-DDCMManual, DEECs must be submitted as primary petitions and, therefore, will have a case number, with specific subjects for each clinical trial that is to be carried out in Brazil and that have not yet been submitted to ANVISA. Also, only DEECs from clinical trials to be carried out in Brazil should be submitted. ResNo945 further indicates that the sponsor, CRO, or sponsor-investigator may link new DEECs to the submitted DDCM at any time following the initial submission.

ResNo945 provides the following additional DDCM submission requirements:

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

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

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

Secondary Petitions

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

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

A stated in ResNo945 and the G-DDCMManual, for substantial protocol modifications of the investigational product (IP), the sponsor must submit to ANVISA a secondary petition linked to the corresponding DDCM. ResNo945 also indicates that non-substantial IP modifications must always be submitted to ANVISA in the next petition for substantial IP modification, or as part of the drug development safety update report (DSUR), whichever occurs first. The G-DDCMAmdmts further notes that these modifications may be made at any time after initial DDCM submission, including before ANVISA issues its final decision. See the G-DDCMAmdmts for detailed submission instructions for DDCM modifications. See also BRA-127 for the Substantial Modification of the Investigational Product form. Refer to the Submission Content section for substantial IP modification documentation requirements.

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

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

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

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

As delineated in ResNo945, RegNo338, the G-DDCMManual, and BRA-122, the sponsor may also submit a request for technical analysis by the optimized procedure based on regulatory trust practices (Reliance) or by risk or complexity criteria of the clinical trial or the IP at any time, by means of a secondary petition, before ANVISA begins its technical evaluation of the corresponding DDCM petition. Per ResNo945 and RegNo338, for the purposes of admissibility for analyzing primary and secondary petitions, the related documents must have been approved by at least one (1) of the Equivalent Foreign Regulatory Authorities (Autoridades Reguladoras Estrangeiras Equivalentes (AREEs)) recognized by ANVISA. The AREE approved documents must also be the same versions as those presented to ANVISA.

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

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

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

BRA-122 also explains that only a single subject code (12102) is used to submit a request to ANVISA to apply the optimized analysis procedure by Reliance for the DEEC. Additionally, per the G-DDCMManual and BRA-122, the petitioning system does not allow a secondary petition to be linked to another secondary petition. Since requests for the application of the optimized analysis procedure must be made through secondary petitions, and petitions for substantial IP modifications and clinical protocol amendments are also secondary petitions, requests referring to these petitions must be linked to the DDCM and DEEC by subject codes 11634 and 12103, respectively. Therefore, in the case of a DDCM petition and linked DEECs, for both petitions to be analyzed according to the optimized procedure, a company must make the request in parallel and individually for each of the petitions (codes 12102 and 12104), including for each related secondary petition, if applicable. Refer to the G-DDCMManual and BRA-122 for additional information. See also the Scope of Assessment section for detailed optimized analysis procedure requirements by Reliance or based on risk assessment of the clinical trial or IP.

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

• In the Clinical Trial Submission Form (FAEC) (BRA-22), marking the option "(X) to the question, “We request the application of the optimized analysis procedure, pursuant to Article 8 of IN No. 338/2024", or answering "yes" to the question "Request for the application of the optimized analysis procedure (based on the risk assessment supported by the experience of using the investigational product).”
• In the Petition Form for Substantial Modification of the Investigational Product (BRA-127), answering "yes" to the question "Request for the application of the optimized analysis procedure (based on the risk assessment supported by the experience of using the IP), pursuant to Article 8 of IN No. 338/2024".

Electronic Filing

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

The G-DDCMManual, and BRA-58 explain that when the DDCM has been submitted, the sponsor is then required to electronically file all the documents corresponding to the initial DDCM petition’s subject code checklist. As described in BRA-75, the sponsor must electronically attach all the documents required in the related DDCM checklist (accessed online via BRA-56) that corresponds to one (1) of the following related subject codes: 10748, 10749, 10750, 10751, 10752, 10753, 10754, and 10755. ResNo945 also specifies that the documentation presented must allow for textual searches, copying, and contain bookmarks and hyperlinks that facilitate navigation. Refer to BRA-47 and BRA-59 for instructions for submitting the DDCM checklist documents via BRA-56. Additionally, per the G-DDCMManual, for DEEC petition electronic submissions, one (1) file needs to be attached for each item contained on the corresponding checklist. DEECs can be submitted to ANVISA using one (1) of the following subject codes: 10482, 10479, 10476, 10773, 10483, 10478, 10477, 10774. See the G-DDCMManual and BRA-47 for additional DEEC petition submission instructions. See also ResNo947 for details on ANVISA’S electronic filing requirements.

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

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

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

BRA-59 explains that once the fee is paid, a reference (transaction) number is generated that will be required for the subsequent submission of the associated checklist documents. The processing of this request can take up to two (2) days, which is the time given to the banking network to clear the payment. Refer to BRA-59 for additional instructions. See also BRA-47 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition Consent Form. See BRA-38 for additional information on accessing ANVISA’s electronic petitioning request systems.

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

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

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

Ethics Review Submission

National Research Ethics Authority

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

National Research Ethics Commission (CONEP)

Per ResNo466 and OSNo001, the PI must obtain approval from the EC (CEP). The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional EC (CEP) review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil EC (CEP) and investigator manuals. Please refer to Scope of Review and Oversight of Ethics Committee sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. See also CLNo183 for instructions on linking investigator/institutions to the responsible EC (CEP) in submissions; CLNo062 for guidance on submitting documentation required for CONEP analysis; and CLNo046 for instructions on submitting requests for inclusion/exclusion of research center(s).

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

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

Regulatory Authority Requirements

Clinical Trial Notification (CTN) Scheme

As delineated in AUS-49, the following information must be submitted to the Therapeutic Goods Administration (TGA) through the online form on the TGA Business Services (TBS) webpage (AUS-36):

• Sponsor name and address
• Sponsor declaration
• Notification fee (See Regulatory Fees section)
• Organization-nominated contact’s name, phone number, and email
• An optional alternative contact, which may be chosen from the contacts for the agent or sponsor organization submitting the CTN. An Australian contact number is required to be listed with either the primary sponsor contact or the alternate sponsor contact
• Protocol number
• Expected trial start and completion dates
• Potential use of restricted goods
• Study title and description, which must be a minimum of 250 characters (spaces included) and up to a maximum of 2,500 characters
• “This Trial” check boxes indicating whether the trial involves the use of a medicine, a medical device, and/or a biological. For a medicine or biological, additional information must be provided, such as dosage form, route of administration, indication, and the good manufacturing practice (GMP) license/clearance number of a relevant exemption
• Trial type
• Whether the trial is a first in human trial
• Whether the trial, in part or as a whole, has been halted/stopped/withdrawn or rejected in another country due to safety concerns
• Total number of trial participants
• Therapeutic area
• Investigational product (IP) details
• Whether it is a multi-center trial
• Whether the trial is being conducted in other countries
• Preceding trial details
• Trial site details

See AUS-49 for detailed descriptions of each required item.

Clinical Trial Approval (CTA) Scheme

AUS-47 states that the CTA scheme application consists of two (2) forms – Part 1: the application (AUS-56), and Part 2: Notification of the conduct of a trial under the CTA scheme (AUS-57).

The Part 1 CTA application form (AUS-56) requires general information (sponsor name, data details, and sponsor declaration) and details on the medicine (active ingredient)/biological be submitted to the TGA.

The Part 2 CTA application form (AUS-57) requires trial sponsor information (name and client ID code), the IP or biological, and the notification type, as well as trial and trial site details (title of study and trial type). The form also requires signed certifications from the sponsor, the principal investigator (PI), the ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia), and the authority approving the conduct of the trial.

Ethics Committee Requirements

Per the G-CTHandbook, the EC and the institution are responsible for establishing what information should be provided in support of an application. The EC should request any additional information that it believes is necessary to undertake review of the proposed research. Unless advised otherwise, trial sponsors and researchers should use the Human Research Ethics Application (HREA) for submitting proposals for research involving humans to ECs.

AUS-46 indicates that the HREA assists researchers in considering the ethical principles of the G-NatlStmt in relation to their research. The G-NatlStmt requires that those who conduct and approve human research to consider:

• How the research question/theme is identified or developed
• The alignment between the research aims and methods
• How the researchers and the participants will engage with one another
• How the research data or information are to be collected, stored, and used
• How the results or outcomes will be communicated
• What will happen to the data and information after the project is completed

For more information on the HREA, see the Submission Process section.

The G-NatlStmt further specifies that in an application for review of their research, researchers should determine and state in plain language:

• The research question or questions that the project is intended to explore
• The potential benefit of exploring the question or questions including to whom that potential benefit is likely to flow, and whether that benefit is a contribution to knowledge or understanding, improved social or individual wellbeing, or the skill and expertise of researchers
• The basis for that potential benefit as described in either relevant literature or a review of prior research unless, due to the novelty of the question, there is scarce literature or prior research
• How the design and methods of the project will enable adequate exploration of the research questions and achieve the aims of the research
• How the design of the project will maintain respect for the participants
• Where relevant, that the research meets the requirements of any relevant regulations or guidelines authorized by law (such as those related to privacy and reporting requirements for disclosure of child abuse)
• Whether or not the project has been reviewed by a formally constituted academic, scientific, or professional review process, and, if so, the outcome of that review

Research Governance

According to the G-NatlStmt, institutions should publish (such as on their website) clear policies and procedures for institutional authorization of research. See the Research GEMS system (AUS-55), the Ethical Review Manager (ERM) (AUS-8), and the Research Ethics and Governance Information System (REGIS) (AUS-10) websites for public health organization site-specific assessment (SSA) forms, which may differ between institutions and states or territories.

Clinical Protocol

The G-TrialsSOP indicates that where the investigator is responsible for the protocol development, the investigator must ensure the protocol follows the outline in the AU-ICH-GCPs. Specific content of a protocol will vary depending on the research area, the level of risk to participants, the phase of the research and study design, and whether a medicinal product or a device or a therapeutic intervention is being researched. If satellite sites for a teletrial are involved in the study, no specific additional wording is required in the protocol, as relevant considerations will be addressed in other study-specific documents which may be annexed to the protocol.

The AU-ICH-GCPs provides the following outline of the protocol:

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

Regulatory Authority Requirements

Clinical Drug Development Dossier (DDCM)

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

• DDCM Petition Consent Form (BRA-21)
• Declaration of commitment to distribute to clinical trial centers and use investigational products (IPs) only after authorization from the corresponding DDCM and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)), when import is authorized prior to publication of the approval/rejection in the Official Gazette of the Union (Diário Oficial da União (DOU))
• Investigational Drug Development Plan (PDME)
• Investigator’s Brochure (IB)
• Investigational Medicinal Product Dossier (IMPD) (including information on active pharmaceutical ingredient (API), investigational drug, and placebo and modified comparator drug)
• DEEC (see detailed requirements listed below)
• Declarations on compliance with Good Clinical Practice (GCP), Good Laboratory Practice (GLP), and Good Manufacturing Practice (GMP)
• GCP Certificate or equivalent document for the completed or ongoing clinical trials must be attached to the DDCM, if applicable
• Declaration of commitment to distribute and use IPs only after authorization from DDCM and corresponding initial and subsequent DEEC(s). This document should only be attached to the DDCM if the sponsor is interested in receiving the Import Document (DI) prior to the DDCM's analysis and approval. If the company has attached this to the DDCM, the DI will be issued for early importation both for the initial DEECs submitted together with the DDCM, and for the clinical trials submitted after the approval of the DDCM.

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

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

Specific Clinical Trial Dossier (DEEC)

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

• Clinical Trial Submission Form (FAEC) (BRA-22)
• Clinical trial protocol containing the minimum information described in the International Council for Harmonisation’s Guideline E6(R2) (BRA-28) and its updates (Please note that the ICH Guidelines for Good Clinical Practice E6(R3) (BRA-121) was finalized on January 6, 2025)
• Statistical analysis plan (PAE), at least in draft version, in the case of phase 3 clinical trials and adaptive clinical trials
• Opinion of any country/region's scientific advisory board, if any, on the clinical trial
• Pediatric investigation plan of any country/region, if any
• Sample investigational drug label
• Proof of registration of the clinical trial, in the same version of the clinical protocol submitted to ANVISA, in the registration database of the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE) (Note: The Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.); and, if proof of registration is not available at the time of DEEC submission, it must be submitted together with the notification of commencement of the clinical trial.)

Substantial IP Modifications

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

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

Substantial Protocol Amendments

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

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

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

Optimized Analysis Procedure (Reliance) Submissions

Pursuant to ResNo945, to comply with the documentation requirements for the optimized analysis procedure by Reliance, the sponsor must present official proof issued by an Equivalent Foreign Regulatory Authority (Autoridade Regulatória Estrangeira Equivalente (AREE)) regarding the clinical protocol approval or clinical protocol amendment, or, official proof of the DDCM or substantial IP modification of the IMPD or Investigational Product Dossier (DPI). In the absence of this official document, a declaration signed by the sponsor's legal and technical representatives must be presented with due justification and additional information, if applicable.

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

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

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

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

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

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

Ethics Committee Requirements

National Research Ethics Authority

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

No other information is currently available regarding EC (CEP)/National Research Ethics Authority submission documentation requirements.

National Research Ethics Commission (CONEP)

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

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

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

Clinical Protocol

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

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

For complete protocol requirements, refer to OMREC and OSNo001.

Overview

In accordance with the G-CTHandbook, the G-TrialsSOP, and AUS-47, the Therapeutic Goods Administration (TGA) is responsible for authorizing the supply of unapproved therapeutic goods for clinical trials under two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme and the Clinical Trial Approval (CTA) scheme. According to the TGR, the G-CTHandbook, the G-TrialsSOP, and AUS-47, under either regulatory scheme, an ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) must approve research protocols. The G-NatlStmt further specifies that any research that involves greater than low risk must be reviewed by an EC. AUS-47 indicates that the review and approval/authorization by an EC and institution may be conducted in parallel to the CTN form submission to the TGA, but it is the sponsor’s responsibility to ensure that all relevant approvals and authorizations are in place before commencement of the trial.

According to AUS-40, all public and private health organizations must also undertake a site-specific assessment (SSA) of each research project. Per the G-TrialsSOP, the SSA and ethics review may occur in parallel.

Regulatory Authority Approval

AUS-47 states that the TGA’s target time to process online CTNs is five (5) to seven (7) working days, but the agency tries to process the notification as soon as possible. This timeframe does not include the time taken for TGA finance to match the payment (if required) to a submission. For information on how to check the status of a CTN, see AUS-49.

No timeline information is available for applications under the CTA scheme. Per AUS-47, parties that are considering submitting a CTA application are strongly encouraged to contact the TGA at clinical.trials@health.gov.au for advice regarding the application process.

Ethics Committee Approval

The EC review and approval process timeline varies by institution. However, according to the G-NatlStmt, the institutional EC must implement standard operating procedures that promote good ethics review, including timely consideration of applications.

Research Governance

The G-GovHndbk indicates that ethical review and site assessment, both components of research governance, are two (2) distinct processes relating to the ethical approval and institutional authorization of research involving humans. However, because evidence of EC approval is a component of the site assessment process, institutional authorization of a research project cannot be given until EC approval has been provided. The G-TrialsSOP further specifies that EC approval must be obtained and submitted to the research governance officer (RGO) of each participating institution before institutional authorization is granted.

While some parts of the research governance review must occur after the EC review, the G-GovHndbk recommends that as part of the national approach to single ethical review, institutions establish processes to facilitate parallel review. Project documentation processes related to site assessment may be considered as falling into these categories:

• That which can be assessed independent of ethical review, such as evidence of research qualifications, supporting department approval forms, contracts, budgets, and insurance and indemnity documents
• That which is subject to ethical review, but can be submitted prior to or in parallel with ethical review to enable independent assessment of other documentation, such as initial project application documents
• That which can only be assessed subsequent to ethical approval, such as approved project application documents, fully signed regulatory documents, and a certificate of ethical approval

See the G-GovHndbk for additional National Health and Medical Research Council (NHMRC) guidance on best practices in the governance of multicenter human research as part of the national approach to single ethical review.

The NHMRC also developed the GPP-SiteAssess to help institutions streamline the research governance process and shorten clinical trial start-up times. See the GPP-SiteAssess for more information.

Overview

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

Regulatory Authority Approval

As set forth in LawNo14.874, ANVISA’s analysis of the primary petitions for clinical trials with human beings (Clinical Drug Development Dossiers (Dossiês de Desenvolvimento de Medicamentos Clínicos (DDCMs))) must be completed within 90 business days. If no response is provided after regular receipt of the primary DDCM petition, clinical development may be initiated, provided that it contains the relevant ethical approvals. ResNo945 further specifies that upon receipt of the primary DDCM and the Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions, ANVISA has 90 business days, counting from the date of issuance of the DEEC document, to evaluate the application. If the agency fails to issue a response within 90 days of receipt, the DDCM and respective DEEC will be released after the deadline, and clinical development can begin after the relevant ethical approvals have been obtained. The 90-day deadline also applies to primary petitions for new DEECs subsequently linked to the DDCM, and to secondary petitions for substantial modifications to the investigational product (IP) and substantial amendments to the clinical protocol. See Scope of Assessment section for detailed DDCM and DEEC submission requirements.

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

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

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

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

Priority Submissions

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

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

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

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

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

See also ResNo811 (which partially amends ResNo205) and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.

Ethics Committee Approval

New National System of Ethics in Research with Human Beings

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

National Research Ethics Authority

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

LawNo14.874 further explains that the decision contained in the EC (CEP)’s opinion may be appealed, in the first instance, within 30 business days, to the EC (CEP) itself that issued the opinion, and in the second and final instance, within 30 business days, to the National Research Ethics Authority. The appeals provided will be decided by the National Research Ethics Authority within 30 business days. See the Scope of Review section for details on the EC (CEP) review processes. See also BRA-117 for additional information.

Additionally, per LawNo14.874, the EC (CEP) opinion regarding research of strategic interest to the Ministry of Health (MOH)’s Unified Health System (Sistema Único de Saúde (SUS)) (BRA-53) and relevant to responding to public health emergencies will be issued within a period of 15 business days from the date of receipt of the research documents.

National Research Ethics Commission (CONEP)

As delineated in OSNo001 and BRA-91, the institutional EC (CEP) is required to issue an initial report in 30 days from the date the principal investigator (PI) submits an application for review. The CEP’s review of the protocol documentation for completeness should be accomplished within 10 days following submission. Per BRA-91, the review period must be counted from the date the project entered “Ethical Assessment” (i.e., after going through the validation of documents which takes around 10 days and when the Certificate of Presentation for Ethical Assessment (Certificado de Apresentação de Apreciação Ética) (CAAE)) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment. If these deadlines have expired, BRA-91 further suggests that the investigator responsible for the research project, contact the CEP to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation. Additionally, per CLNo040, if an amended project needs to go through CONEP’s appraisal, the deadline for document validation is 15 days and for ethical review, 45 days.

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

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

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

Overview

In accordance with the G-TrialsSOP, the G-CTHandbook, and AUS-47, clinical trials involving unapproved therapeutic goods can only commence under the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme. According to the G-GovHndbk and the G-TrialsSOP, under either scheme, both institutional ethics committee (EC) (Human Research Ethics Committees (HRECs) in Australia) approval and research governance authorization are required before a research project can commence at a site.

Research Governance

Per the G-GovHndbk, research must be governed by the institution at all stages of a project. Ethical review and site assessment, both components of research governance, are two (2) distinct processes relating to the ethical approval and institutional authorization of research involving humans. According to AUS-40, all public and private health organizations must undertake a site-specific assessment (SSA) of each research project. This allows the institution to consider whether the project is suitable for the site, and whether it has the capacity to conduct the research at that site. Pursuant to the G-NatlStmt, authorization of research by the institution should consider, but not re-review, any issues raised during the ethics review of the research proposal, and each institution should have a process or processes for assessing the risk level of the research. These processes may involve seeking advice from relevant clinical or administrative staff, members of an EC, or a full meeting of the EC. All research should be developed, reviewed, authorized, conducted, and monitored in accordance with a research governance framework as described in an institution’s policy. For more information on institutional responsibilities, see the Site/Investigator Selection section.

The G-TrialsSOP states that in the case of a teletrial, the principal investigator (PI) must ensure that a robust site assessment is undertaken that fully quantifies the capabilities of each satellite site to inform the extent to which trial related activities can be delegated to the site. This may include a pre-commencement assessment before a specific trial is proposed so that the process of trial start up is expedited when a suitable trial is identified.

Per the G-TrialsSOP, prior to a study’s commencement, the PI must:

• Submit the primary site's Clinical Trial Research Agreement (CTRA), EC approval, the SSA form, evidence of any relevant good clinical practice (GCP) training, and any other required documentation to the institution’s research governance officer (RGO)
• Ensure all documentation and correspondence pertaining to the submission and approval processes is filed in the study master file (SMF) (see Appendix 8 of the G-TrialsSOP)
• Ensure each satellite site completes and submits to their RGO a clinical trial sub-contract and a SSA form
• Await site specific RGO authorization before any study related activity can occur at that site
• Ensure the satellite site files all documentation in the satellite site study file (SSSF)

The G-TrialsSOP further states that prior to the initiation of a study, the investigator must also mutually agree with the sponsor on a scheduled date, time, and location for a study initiation visit at the participating site to ensure the site is prepared to commence the study. In the case of a teletrial, this may be at the primary site only, or could include (remotely) the satellite site(s) as determined by the study complexity by the sponsor/PI.

See the G-TrialsSOP for more information on site initiation requirements for primary and satellite sites.

The G-GovHndbk further indicates that in the national approach to single ethical review, site assessment and project authorization are the responsibility of each institution participating in a multicenter human research project while ethical review is provided by a single EC using certified ethical review processes. Each institution collaborating in a multicenter project utilizing the outcome of a single ethical review must individually authorize the commencement of research at their institution. To avoid unnecessary delays in research commencing at all collaborating centers and sites, each institution should consider relevant local matters prior to or in parallel with ethical review.

Clinical Trial Agreement

As delineated in the AU-ICH-GCPs, the sponsor must sign an agreement between all involved parties, including investigators, institutions, contract research organizations, and others for documentation purposes. 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.

For the purposes of the G-TrialsSOP, the CTRA for the primary site and the sub-contract for each satellite site constitute part of a research governance application, which is submitted to the RGO. The CTRA covers matters such as confidentiality, intellectual property, ownership of data, insurance, and indemnity. The Medicines Australia CTRA (see AUS-38) is the recommended standard form.

Clinical Trial Registration

The G-NatlStmt requires that clinical trials be registered on a publicly accessible register complying with international standards before recruitment of the first participant. For information on these standards, see the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (AUS-67). Per AUS-15, the Australian and New Zealand Clinical Trials Registry (ANZCTR) (AUS-12) recommends applying for registration at the same time as ethics submission.

Overview

New National Ethics System of Ethics in Research with Human Beings

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

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

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

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

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

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

ResNo945 further states that the forms indicating the start and end date of the clinical trial in Brazil must be filed as a secondary petition to the corresponding Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) process, within 30 business days after each start and end date. (See Clinical Trial Start Date Form in Brazil (BRA-25)).

Clinical Trial Agreement

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

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

The sponsor and the investigator/institution should sign the protocol, or an alternative document, to confirm this agreement. In addition, per ResNo945, any trial-related functions that are transferred to a CRO must also be specified in writing in a document signed by the sponsor and CRO. In the case of delegating responsibilities and activities, a written document must also be signed between the parties.

Clinical Trial Registration

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

In addition, per BRA-32, ANVISA has developed a clinical trials search tool to obtain detailed information about scientific/academic research or clinical trials authorized by the agency to support the registration of medicines since 2015. The Clinical Trials (Ensaios Clínicos) tool may be accessed via ANVISA’s Consultation System webpage (BRA-44), which provides public information about the status of each clinical trial, the trial location, and the investigators responsible for conducting the trial. See BRA-32 and BRA-129 for additional instructions on searching BRA-44.

Safety Reporting Definitions

According to the G-SftyRpt, the following definitions provide a basis for a common understanding of Australia’s safety reporting requirements:

• Adverse Event (AE) – Any untoward medical occurrence in a patient or clinical trial participant administered a medicinal product and that does not necessarily have to have a causal relationship with this treatment
• Adverse Reaction (AR) – Any untoward and unintended response to an investigational medicinal product related to any dose administered
• Unexpected Adverse Reaction (UAR) – An adverse reaction, the nature or severity of which is not consistent with the applicable product information (e.g., investigator's brochure (IB) for an unapproved investigational medicinal product)
• Serious Adverse Event (SAE) or Serious Adverse Reaction (SAR) – Any adverse event/adverse reaction that results in death, is life-threatening, requires hospitalization or prolongation of existing hospitalization, results in persistent or significant disability or incapacity, or is a congenital anomaly or birth defect
• Suspected Unexpected Serious Adverse Reaction (SUSAR) – An adverse reaction that is both serious and unexpected
• Significant Safety Issue (SSI) – A safety issue that could adversely affect the safety of participants or materially impact the continued ethical acceptability or conduct of the trial
• Urgent Safety Measure (USM) – A measure required to be taken in order to eliminate an immediate hazard to a participant’s health or safety (Note: This type of SSI can be instigated by either the investigator or sponsor and can be implemented before seeking approval from ethics committees (ECs) or institutions)

Safety Reporting Requirements

Investigator Responsibilities

As specified in the G-SftyRpt, the investigator is responsible for recording and assessing all AEs that occur at the site. The investigator is also required to inform the sponsor of all SAEs, and all USMs instigated by the site, within 24 hours of becoming aware of the event. All safety critical events must be reported to the sponsor, and for reported deaths, the investigator should supply the sponsor with any additional requested information. Further, the investigator must report to the institution all SSIs and SUSARs arising from the local site within 72 hours of becoming aware of the event.

However, the G-TrialsSOP states that the investigator must also report any SUSARs to the sponsor within 24 hours of becoming aware of the event, and USMs instigated by the investigator or site must be reported to the sponsor within 72 hours. Furthermore, the investigator must report all other significant issues to the sponsor within 15 days of instigating or becoming aware of the event. The investigator must notify the sponsor promptly regarding any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants. The investigator must also be available to meet with the sponsor to discuss study progress, issues, and safety.

The G-TrialsSOP requires that within 72 hours of instigating or becoming aware of the event, the investigator must notify the institution of:

• USMs
• SUSARs arising from the local site
• Any information received from the sponsor that may be new and have an impact on the continued ethical acceptability of the trial or may indicate the need for amendments to the trial protocol, including monitoring of safety

The G-TrialsSOP indicates that for satellite site(s) in teletrials, staff must report safety issues directly to the sponsor as per the timelines specified in the clinical trial protocol and the safety monitoring plan or similar document, in the same way as the primary site. Certified copies of the relevant safety reports/documentation generated at the satellite site must be sent to the primary site for filing in a study master file.

According to the G-TrialsSOP, the principal investigator (PI) must ensure that study staff, including those at teletrial satellite sites, are trained in the protocol, investigator’s brochure (IB), study procedures, and AE/SAE reporting. The PI must also ensure that a system for safety reporting duties is in place for all study staff. For more information on investigator responsibilities related to standard operating procedures (SOPs), see the G-TrialsSOP.

Sponsor Responsibilities

As delineated in the G-SafetyDataMgt, the G-SftyRpt, and the G-CTHandbook, the sponsor is required to expedite reporting of SUSARs to the Therapeutic Goods Administration (TGA).

The G-SafetyDataMgt indicates that other situations requiring expedited reporting may include information that might materially influence the benefit-risk assessment of an investigational product, or that would be sufficient to consider changes in the administration or conduct of a clinical trial.

According to the G-SftyRpt and the G-TrialsSOP, expedited reporting requires the sponsor to file reports to the TGA in the following specified timelines:

• For an Australian SUSAR that is fatal or life-threatening, immediately, but no later than seven (7) calendar days, with any follow-up information within eight (8) calendar days
• For all other Australian SUSARs, no later than 15 calendar days after becoming aware of the case

The G-SftyRpt and the G-TrialsSOP further indicate that the TGA, the EC, and investigators must also be notified of all SSIs that adversely affect the safety of participants, or materially impact the continued ethical acceptability or conduct of the trial. SSIs that meet the definition of a USM should be reported within 72 hours, and all other SSIs should be reported within 15 calendar days of the sponsor being made aware of the issue. It is strongly recommended that the sponsor contact the TGA within 24 hours of a USM being taken, and if initial contact is by telephone, it should be followed up with a written notification provided by e-mail within 72 hours. See AUS-53 for additional information on SSIs and USMs.

Per the G-SftyRpt, submitting individual reports of AEs, SAEs, and SUSARs to ECs, institutions, and investigators are no longer required. However, according to the G-TrialsSOP, the sponsor must provide the EC with an updated IB at least annually that supports trial oversight, depicts a clear picture of the evolving trial safety profile, and provides evidence that the sponsor is conducting its safety monitoring appropriately.

The G-CTHandbook and the G-SftyRpt further require the sponsor to maintain records of all other single case AEs and submit them to the TGA upon request. The G-CTHandbook indicates that the TGA does not require sponsors to submit individual SUSARs from outside Australia. Sponsors should continually monitor the safety of their clinical program and advise the TGA of any SSIs that arise from their analysis of overseas reports, or of any action that has been taken by another country’s regulatory agency. Investigators and ECs should also be informed of this information, and sponsors must be able to provide the TGA with the clinical details of any individual overseas AE reports if requested.

According to the G-TrialsSOP, the sponsor’s plans for safety data monitoring should be documented in a safety monitoring plan or similar document and be given to the PI prior to commencement of the clinical trial. The plan must be continually reviewed and updated during the trial, as real-time assessments of safety data are performed, and outcomes are made available.

Other Safety Reports

The G-SftyRpt delineates that the sponsor must provide the EC with an annual safety report including a clear summary of the evolving trial safety profile. The annual safety report should generally include:

• A brief description and analysis of new and relevant findings
• For investigational products (IPs) not on the Australian Register of Therapeutic Goods (ARTG) (AUS-22), a brief analysis of the safety profile of the IP and its implications for participants
• A brief discussion of the implications of the safety data to the trial’s risk-benefit ratio
• A description of any measures taken or proposed to minimize risks

A Development Safety Update Report (DSUR) or other similar document may also serve as the annual safety report. See the G-SftyRpt for more information.

Form Completion & Delivery Requirements

As per the G-CTHandbook, all SUSARs from Australian sites must be reported to the TGA using one (1) of three (3) formats:

• The Electronic Data Interchange (EDI) functionality, which allows sponsors to submit AE reports directly from their system to the TGA (more information can be found at AUS-26)
• The online reporting form, which can be accessed from AUS-51
• The CIOMS Form I (AUS-4) or the TGA’s Blue Card Adverse Reaction Reporting Form (AUS-3)

Per AUS-3, the Blue Card form may be emailed to adr.reports@tga.gov.au or mailed to Pharmacovigilance and Special Access Branch, Reply Paid 100, Woden ACT 2606. More information about reporting to the TGA may be found at AUS-7.

See AUS-37 for the SSI/USM reporting form.

Safety Reporting Definitions

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

• Adverse Event/Experience (AE) – Any adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
• Adverse Drug Reaction or Adverse Reaction (ADR) – A harmful and unintentional response attributed to a drug and which occurs at doses normally used for the prophylaxis, diagnosis, or therapy of disease, or for the modification of physiological function
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any adverse medical occurrence with an investigational product (IP) that at any dose results in death, risk of death, persistent or significant disability, congenital anomaly/birth defect and situations that require or extend patient hospitalization
• Suspected Serious, Unexpected Adverse Drug Reaction (SUSAR) – An adverse reaction that is simultaneously serious and unexpected, with the reasonable possibility of a causal relationship between the investigational drug and active comparator. One whose nature or severity is inconsistent with the IP (i.e., the investigator’s brochure (IB), Safety Information Summary (SIR) or package insert)

Safety Reporting Requirements

Investigator Responsibilities

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

As explained in the G-SUSARs, the investigator is also responsible for adopting immediate safety measures to protect the clinical trial participant against any imminent risk, and for communicating to the sponsor the occurrence of all AEs. The participant affected by an AE should receive appropriate care and safety measures until resolution or stabilization of their clinical condition, as described in the clinical protocol. The AESafetyManual further states the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the EC (CEP) with any additional requested information (e.g., autopsy reports and terminal medical reports).

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

Sponsor Responsibilities

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

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

ResNo945 and the G-SUSARs also state that the sponsor is required to report SUSARs to ANVISA and is permitted to delegate the reporting responsibility to the contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil). In the case of sponsor-reported SUSARs, where the investigator’s interpretation differs from that of the sponsor, both reports should be submitted with their respective justifications. Per ResNo945, SUSAR notifications to ANVISA must be made independently of the submission of the investigator’s brochure (IB), amendments, reports, or early termination of the clinical trial. The G-SUSARs further notes that, as a joint action to submit SUSAR notifications, the sponsor must also inform the investigators involved in the clinical trial about the SUSARs and adopt the necessary measures to update the safety documents, such as the IB, drug package insert (in the case of a registered drug), and other related documents. While the IB is not updated, it is necessary to notify additional occurrences (follow-ups) of SUSARs to ANVISA. (See Quality Requirements section for detailed IB requirements)

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

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

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

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

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

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

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

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

Ethics Committee Responsibilities

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

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

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

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

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

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

Other Safety Reports

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

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

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

Form Completion & Delivery Requirements

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

Per BRA-37, sponsors of clinical trials that have not yet been registered with VigiMed should complete VigiMed’s Registration/Change of Registration form (BRA-131) and send it to this email address: vigimed.pesquisa@anvisa.gov.br. See also BRA-130 for the VigiMed Company User Manual, and BRA-85 for VigiMed Frequently Asked Questions (FAQs).

Interim and Annual Progress Reports

As per the AU-ICH-GCPs, the G-NatlStmt, and the G-TrialsSOP, the investigator(s) is responsible for submitting progress reports to the ethics committee (EC) (known as Human Research Ethics Committee in Australia) annually, or more frequently if requested. The AU-ICH-GCPs and the G-TrialsSOP state that if there are significant changes in trial conduct or safety, the investigator should submit a written report to the sponsor, the EC, and where applicable, the institution. The G-NatlStmt indicates that at regular periods (reflecting the degree of risk, and at least annually), researchers should provide reports to the relevant EC(s) and institution(s), including information on:

• Progress to date
• The security of project-related data and information
• Compliance with the approved proposal
• Compliance with any conditions of approval

According to the G-NatlStmt, progress report forms should be designed to collect information that can provide meaningful assistance to reviewers in determining whether continuation of ethics approval is warranted. See the G-NatlStmt for more details.

Final Report

AUS-47 indicates that for trials conducted under the Clinical Trial Approval (CTA) scheme, the CTA clinical trial completion advice form (AUS-58) is used to notify the Therapeutic Goods Administration (TGA) of the trial completion. AUS-58 indicates that upon completion, the form may be emailed to the TGA at clinical.trials@tga.gov.au (preferred) or faxed to 02 6232 8112.

Per AUS-49, for trials conducted under the Clinical Trial Notification (CTN) scheme, a completion advice should be submitted through the TGA Business Services (TBS) webpage (AUS-36). The completion advice must include the date the trial was completed at all Australian sites, as well as the completion reason. See AUS-49 for additional information on the completion advice.

The AU-ICH-GCPs and the G-TrialsSOP indicate that the investigator should provide the EC with a final clinical study report. As per the G-TrialsSOP, the investigator must also notify the research governance officer that the trial has been terminated/closed. At the completion of the project, a report with the same information as described above for progress reports (per G-NatlStmt) must also be provided to the relevant EC(s) and institution(s), but it should include information on the outcome of the completed research.

Additionally, the TGA has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s Topic E 3: Structure and Content of Clinical Study Reports (AUS-81). For more information, see AUS-81.

Interim and Annual Progress Reports

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

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

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

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

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

Final Report

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

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

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

Other Reporting Requirements

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

As per the AU-ICH-GCPs and the G-TrialsSOP, a sponsor is defined as an individual, company, institution, or organization that takes responsibility for the initiation, management, and/or financing of a clinical trial.

In accordance with the AU-ICH-GCPs, Australia permits a sponsor to transfer any or all of its trial-related duties and functions to a contract research organization (CRO). Any trial-related duties and functions transferred to a CRO should be specified in a written agreement, and the sponsor should ensure oversight of such transferred responsibilities. Any trial-related duties and functions not specifically transferred to and assumed by a CRO are retained by the sponsor. The sponsor retains overall responsibility for the trial data’s quality and integrity, as well as the conduct of the trial. As stated in the G-TrialsSOP, the sponsor is also responsible for ensuring that appropriate approvals are obtained prior to the commencement of the clinical trial, that conditions of any approvals are adhered to during the course of the clinical trial, and that the ethics principles of research merit and integrity, justice, beneficence, and respect are applied to the conduct of clinical trials.

According to the G-CTHandbook, if the investigator initiates and organizes the trial, the role of trial sponsor is assumed. If another party (such as a pharmaceutical company) provides the IP or other support for an investigator-led trial, that party is not required to assume the sponsor role.

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, a sponsor must be an Australian entity.

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

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

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

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

Overview

As set forth in the AU-ICH-GCPs, 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. 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.

According to the G-TrialsSOP, the principal investigator (PI) must ensure that all required staff who assist with the clinical trial are informed about and trained on the protocol, any investigational product (IP), and their research-related duties and functions. This can be in the form of an initiation meeting held by any communication means, including face-to-face, videoconference, telehealth, etc. The PI must also have sufficient time to properly conduct and complete the research within the specified period, as well as an adequate number of qualified staff and adequate facilities for the foreseen duration of the research. When a teletrial is being conducted, the PI, who is always at the primary site and never at the satellite site, remains responsible for the trial across the cluster. For more information on PI site staff training and qualification requirements, see the G-TrialsSOP.

See AUS-64 for additional clinical trial and researcher resources.

Research Governance

The G-NatlStmt indicates that institutions must ensure that any human research for which they are responsible is designed, reviewed, approved, authorized, conducted, and monitored in accordance with the G-CodeConduct and the G-NatlStmt, along with any policies that they have developed that form part of their research governance framework. Each institution should be satisfied that the human research for which it is responsible meets both relevant ethical standards and scholarly or scientific standards, and ensure that those conducting the research (i) are either adequately experienced and qualified, or supervised; (ii) understand the need to assess risks to their own safety and that of participants; and (iii) are aware they are free to withdraw from research on conscientious grounds. Institutions should publish (such as on their website) clear policies and procedures for ethics review and approval and institutional authorization of research. They may establish their own processes for ethics review of research or use the review processes of another institution or external ethics review body.

Per AUS-63, the Australian Commission on Safety and Quality in Health Care developed the National Clinical Trials Governance Framework (AUS-63), which embeds clinical trials into routine health service provisions and strengthens the clinical and corporate governance arrangements for parties that deliver clinical trials. All jurisdictions have agreed to implement the framework in health service organizations, meaning the organizations will be assessed concurrently for clinical and corporate services and clinical trial service provisions. The framework describes the systems and processes that should be in place to implement an effective governance system considering local needs, values, and the context in which services are provided. For more information about implementation timing and assessments under the National Safety and Quality Health Service (NSQHS) standards, see AUS-63.

Foreign Sponsor Responsibilities

As per the G-CTHandbook, the G-TrialsSOP, and AUS-47, a sponsor must be an Australian entity.

Data Safety Monitoring Boards

G-DSMB indicates that the sponsor may establish a Data Safety Monitoring Board (DSMB) (also referred to as Data Monitoring Committees (DMCs)) to review accumulating trial data in order to monitor the progress of a trial. The role of a DSMB is to provide advice on safety and/or trial conduct issues by making recommendations to the sponsor or trial steering committee on whether to continue, modify, or stop a trial. Per the AU-ICH-GCPs, the DSMB should have written standard operating procedures (SOPs) and maintain written records of all its meetings.

According to the G-TrialsSOP, the sponsor may utilize a DSMB or independent individuals (e.g., a medical monitor) to:

• Review accruing trial safety data in either an unblinded or blinded manner to assess treatment exposure
• Access, assess, and review emerging efficacy data for the trial
• Assess the balance of risks and benefits within the trial
• Document the outcome of these reviews

Additionally, the Therapeutic Goods Administration (TGA) has adopted the European Medicines Agency (EMA)’s Guideline on Data Monitoring Committees (AUS-78), which discusses the key issues involved when sponsors include DSMBs as part of their trial management. For more information, see AUS-78.

Multicenter Studies

As delineated in the AU-ICH-GCPs, in the event of a multicenter trial, the sponsor must ensure that:

• All investigators conduct the trial in strict compliance with the protocol that was agreed to by the sponsor and the TGA (if required), and that was approved by the ethics committee (EC)
• The case report forms (CRFs) 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 among investigators is facilitated

As noted in the G-TeletrialPrncpls, Australian jurisdictions agree that “traditionally” multicenter clinical trials assume one (1) PI per geographic site, differing from teletrials. However, for the purposes of teletrials, multicenter trials may include some sites that have satellite sites supervised under teletrial guidance, including the Clinical Oncology Society of Australia (COSA)’s Australasian Tele-trial Model (AUS-2), the G-TeletrialPrncpls, and the G-TrialsSOP. Sponsor responsibilities in teletrials, as described in the G-TrialsSOP, are discussed throughout the Australia profile alongside other clinical trial regulations and guidance. See each section of the Sponsorship topic for additional applicable information.

Overview

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

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

Foreign Sponsor Responsibilities

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

Data Safety and Monitoring Board

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

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

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

Multicenter Studies

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

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

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

Insurance

The AU-ICH-GCPs and the G-NatlStmt state that the sponsor should provide insurance in accordance with applicable regulatory requirements. In addition, according to the G-NatlStmt, institutions must ensure that sponsors have insurance arrangements in accordance with applicable regulatory requirements. The federal documents cited here do not explicitly require insurance.

Per the G-GovHndbk, the institution and investigator are responsible for managing risks of any proposed research, including providing appropriate insurance coverage.

Compensation

Injury or Death

According to the G-NatlStmt, institutions must ensure that sponsors have indemnity and compensation arrangements in accordance with applicable regulatory requirements, and that arrangements are in place to compensate trial participants for harm resulting from negligence in research. The AU-ICH-GCPs further indicates that the sponsor must explain to participants the compensation and/or treatment available to them in the event of trial-related injuries. The federal documents cited here do not explicitly require indemnity.

The G-TrialsSOP states that if the investigator is notified or becomes aware that a trial participant intends to make a claim against the institution or sponsor for injuries arising as a result of participating in a clinical trial undertaken at the institution (or any of the satellite sites under supervision by the institution in a teletrial), the investigator must promptly notify the following parties in writing that such an action is intended:

• The institution’s authority
• The coordinating principal investigator (CPI)/principal investigator (PI)/associate investigator, as relevant
• The sponsor

In addition, if the institution is notified or becomes aware that a trial participant intends to make a claim for compensation against the institution or sponsor for injuries arising as a result of participating in a clinical trial undertaken at the institution (or any of the satellite sites under supervision by the institution in a teletrial), the institution must promptly notify the institution’s insurer in writing that such an action is intended.

See AUS-39 for indemnity and injury compensation guidelines for commercially-sponsored trials.

Trial Participation

The G-NatlStmt states that it is generally appropriate to reimburse participants for the costs associated with taking part in research including travel, accommodations, and parking. Sometimes participants may also be paid for time involved. However, payment may not be disproportionate to the time involved, or include other incentives that encourage participants to take risks. Further, payment or reimbursement decisions should consider customs and practices of the community in which the trial will be conducted.

According to the G-ResearchPayment, any proposal for payment of participants should be considered by the ethics committee (EC) reviewing the research. The EC should be provided with a payment plan that includes:

• A rationale for the proposed payments
• The method and timing of any disbursements, including how they have been calculated, and
• Information about how prospective participants will be advised of the provision of payment

Payment of participants is ethically appropriate if it is equitable and proportionate to the burden of the research, and does not:

• Undermine a participant’s capacity to provide voluntary and informed consent
• Unduly influence a participant to accept a risk or burden that is greater than they would otherwise accept in everyday living or to compromise their fundamental values
• Unduly influence a participant to make false representations about or conceal information that is relevant to their eligibility for the research, their contribution to the research, or the risks related to participation

To minimize the likelihood of a payment acting as an undue influence, the G-ResearchPayment further indicates that payment of participants should generally be limited to reimbursement of documented expenses and remuneration for time and inconvenience. Payment may be offered as an incentive to participate in cases where the research offers little or no benefit to individuals or where the research requires the participation of target populations that are difficult to recruit. In these cases, adequate processes must be in place to promote valid consent. For more information and examples of payment models, see the G-ResearchPayment.

According to the AU-ICH-GCPs, payments to a participant should be prorated and not wholly contingent on completion of the trial by the participant.

Post-Trial Access

Per the G-NatlStmt, researchers must make clear to the participant if there are any intended therapeutic benefits from the trial, and if the treatment will be available only through participation in the trial. In addition, researchers must make it clear to the participant whether they will have access to the treatment or information they received after completion of the trial.

Insurance

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

Compensation

Injury or Death

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

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

Trial Participation

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

• Reimbursement of transportation, food expenses, or prior material provision
• Other types of compensation required, depending on the research project

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

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

Post-Trial Access

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

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

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

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

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

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

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

Further, ResNo563 states that for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining ANVISA registration. ResNo311, which amends ResNo38, also indicates that the sponsor or the contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil) should guarantee access to the post-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (CNS)). The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Study Medicine Supply Programs (see BRA-126 for form).

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

Quality Assurance/Quality Control

As per the TGR and the AU-ICH-GCPs, 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.

According to the AU-ICH-GCPs, the quality management system should use a risk-based approach that includes:

• Identifying processes and data that are critical to ensure participant protection and the reliability of trial results during protocol development
• Identifying risks to critical trial processes and data
• Evaluating the identified risks against existing risk controls
• Deciding which risks to reduce and/or 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
• Describing the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken in the clinical study report

The G-RBMgmtMntring provides further guidance on the application of risk-based trial processes, particularly as a reference to sponsors of non-commercial trials.

The AU-ICH-GCPs further indicates 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 generated, recorded, and reported in compliance with the protocol, the AU-ICH-GCPs, 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. The sponsor should implement a system to manage quality throughout all stages of the trial process, and QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. Any agreements between the sponsor and investigator, or with any other parties involved in the clinical trial, should be written, either within the protocol or in a separate agreement.

As per AUS-74, the Therapeutic Goods Administration (TGA) has adopted certain guidelines released by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), the European Medicines Agency (EMA), and the United States Food & Drug Administration (FDA) regarding quality management and technical aspects of clinical trials. See each of these documents for additional details:

· ICH Guideline E8 (R1) on General Considerations for Clinical Studies (AUS-76)

· Guideline on Strategies to Identify and Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products (AUS-77)

· Guideline on Clinical Trials in Small Populations (AUS-79)

· ICH E11(R1) Guideline on Clinical Investigation of Medicinal Products in the Pediatric Population (AUS-80)

· Use of Electronic Health Record Data in Clinical Investigations - Guidance for Industry (AUS-82)

· Considerations for the Use of Real-World Data and Real-World Evidence to Support Regulatory Decision-Making for Drug and Biological Products - Guidance for Industry (AUS-83)

· ICH Topic E 10 Choice of Control Group in Clinical Trials (AUS-84)

· ICH Topic E 9 - Statistical Principles for Clinical Trials (AUS-85)

See AUS-74 for more information on, as well as a list of, the international scientific guidelines adopted by the TGA.

Responsible Research Conduct

The G-CodeConduct outlines principles, responsibilities, and expectations for institutions and researchers to facilitate responsible research practices. Australian institutions must establish and maintain good governance and management practices for responsible research conduct. In addition, researchers must comply with the relevant laws, regulations, disciplinary standards, ethics guidelines, and institutional policies related to responsible research conduct. Compliance with the G-CodeConduct is a requirement to receiving funding from the National Health and Medical Research Council (NHMRC) or the Australian Research Council (ARC).

The G-CodeBreaches describes the preferred model for institutions to use to investigate and manage potential code breaches, to determine any corrective actions, and when a finding of research misconduct may be made. The Australian Research Integrity Committee uses the G-CodeBreaches as a guide for reviewing how NHMRC- and ARC-funded institutions manage potential code breaches.

The G-RptBreachGCP requires the sponsor to notify the reviewing ethics committee (EC) (Human Research Ethics Committee (HREC) in Australia) within seven (7) days of confirming a serious breach of good clinical practice (GCP). A serious breach is defined as one that is likely to affect to a significant degree: the safety or rights of a trial participant or the reliability and robustness of the data generated in the trial. Sponsors should also develop documented processes for managing serious breaches. The G-TrialsSOP notes that although all deviations or breaches of the protocol must be reported by the investigator to the sponsor, only serious breaches must be reported to the EC. Serious breaches should also be reported by the principal investigator (PI) to their institution, as they may have an impact on medico-legal risk, the responsible conduct of research, or adherence to contractual obligations.

The supplementary guidance G-RptBreachGCP should be read alongside the G-CodeConduct and the G-CodeBreaches.

Monitoring Requirements

As part of its QA system, the AU-ICH-GCPs 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, the AU-ICH-GCPs, 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 auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with its own SOPs and that the auditor’s observations are documented.

Per the G-TrialsSOP, the PI must ensure audit/inspection readiness throughout the study, have oversight of any audit or inspection of the trial at both primary and satellite sites, and ensure any deficiencies identified through audit or inspection are actively managed to ensure continuous improvement.

The TGR further states that the sponsor must provide a written assurance to comply with any trial-related requests by an authorized TGA officer(s), which includes allowing inspection of clinical trial sites. The PI is required to comply with requests and answer any questions the authorized officer(s) may have. According to the G-GCP-Inspect, clinical trial sites that have been notified of a GCP inspection should prepare for the inspection by:

· Ensuring their authorizing institution, trial sponsor, and clinical team are advised of the inspection (the G-GCP-Inspect notes that although the TGA does not require that the sponsor be informed, there is generally a requirement in the contract between the site and the sponsor to share this type of information)

· Ensuring access for the inspectors to clinical trial records and source documents is arranged for the time of the inspection

· Ensuring their IT processes allow them to grant view-only access to the inspectors

The G-GCP-Inspect adds that ECs and trial sponsors are not included in the scope of the TGA’s GCP inspection program. The site PI can invite the sponsor representative(s) to attend the inspection opening and closing meeting. See the Scope of Assessment section and the G-GCP-Inspect for more information on TGA inspections.

Premature Study Termination/Suspension

As per the G-CTHandbook, procedures following the TGA’s revocation of approval under the Clinical Trial Approval (CTA) scheme or a breach of the conditions of the Clinical Trial Notification (CTN) scheme would be determined on a case-by-case basis based on the impact on participants and their ongoing safety. The AU-ICH-GCPs states that if a trial is prematurely terminated or suspended, the sponsor should promptly inform the investigator(s), institution(s), the EC, and the TGA. The sponsor should provide the reason(s) for the termination or suspension. Additionally, as indicated in the G-CTHandbook, the sponsor must notify all sites in the case of a multicenter trial. A lead EC in a multicenter study will need to liaise with the sites and sponsor when determining which, if any, are affected and the actions they need to apply.

According to the G-TrialsSOP, if a trial is prematurely terminated or suspended for any reason, the investigator must:

• Promptly inform the sponsor, EC, research governance officer, associate investigator, any satellite site, and the TGA by providing a detailed written explanation of the premature termination or suspension
• Promptly inform the trial participant and the participant’s primary care physician where the trial participant has consented, of the termination or suspension and, if applicable, of the investigational product (IP) and dose that was administered
• Assure appropriate therapy and follow up for the participant’s continued care

As per the G-NatlStmt, if an institution or EC considers that suspension of research is necessary, the instruction to stop should come from the management of the institution. Where ethics approval for a research project is suspended:

• The institution must ensure that the researcher promptly suspends the research and makes arrangements to meet the needs of participants, such as ensuring that appropriate counselling support or the provision of standard care continues
• The research may not be resumed unless: (i) the research is modified to provide sufficient protection or participants or address the concerns that led to the suspension; or (ii) the researcher establishes to the satisfaction of the EC that continuation of the research will not compromise participants’ welfare; and (iii) the institution authorizes the continuation of the research

The G-NatlStmt further indicates that if ethics approval for a research project is withdrawn, the researcher must promptly halt the research, make arrangements to meet the needs of participants, and notify the institution that these steps have been taken.

Quality Assurance/Quality Control

As set forth in LawNo14.874 and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil adopted per ResNo945, the sponsor is responsible for the implementation and maintenance of quality assurance (QA) and quality control (QC) systems, based on standard operating procedures (SOPs), in order to ensure that research is conducted and data is generated, documented, and reported in compliance with the protocol, good clinical practices (GCP), and other applicable regulatory requirements. The sponsor is responsible for QC during each stage of data processing, with a view to ensuring its reliability and correct processing; and for maintaining the quality and integrity of research data, even if some or all functions have been transferred to a contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil). Per BRA-28, the CRO should also implement a QA/QC plan.

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

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

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

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

Monitoring Requirements

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

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

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

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

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

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

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

See ResNo926 for information on ANVISA’s inspection requirements for research centers to obtain a Certification of Good Practices to conduct bioavailability/bioequivalence drug studies.

Premature Study Termination/Suspension

Pursuant to LawNo14.874, the sponsor is responsible for promptly communicating to the investigators involved, the executing institution, and ANVISA regarding the reasons for the suspension or premature termination of the research, where applicable. ResNo945 further explains that, at any time, the sponsor may suspend or cancel a (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) or approved clinical trial, provided that the appropriate justifications are submitted, as well as a plan for monitoring the participants, if the clinical trial has been initiated. Per ResNo945 and the G-DDCMAmdmts, once a DDCM has been cancelled, no clinical trials related to it may be continued in the country. If a DDCM or clinical trial is canceled for safety reasons, the sponsor must describe the reasons for the cancellation and present the measures to minimize/mitigate risk to the clinical trial participants in compliance with the requirements detailed in the AESafetyManual. Per ResNo945 and the G-DDCMManual, suspensions and cancellations must be filed with ANVISA, in the form of a secondary petition attached to the corresponding DDCM. ResNo945 and the G-DDCMAmdmts also note that the petition must be submitted within 15 business days following the decision to suspend or cancel a DDCM or clinical trial.

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

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

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

Electronic Data Processing System

When using electronic trial data handling systems, the sponsor must ensure and document that the electronic data processing system conforms to its established requirements for completeness, accuracy, reliability, and consistent intended performance, and that standard operating procedures (SOPs) are maintained for using these systems. Refer to the AU-ICH-GCPs for additional information.

The Therapeutic Goods Administration (TGA) has adopted the United States Food & Drug Administration (FDA)’s Use of Electronic Health Record Data in Clinical Investigations - Guidance for Industry (AUS-82). For more information, see AUS-82.

Records Management

According to the G-CodeConduct and the G-DataInfoMgt, institutions must provide access to facilities for the safe and secure storage and management of research data, records, and primary materials.

The G-DataInfoMgt requires that institutional policy include guidance for managing research data and primary materials that addresses the following:

• Ownership, stewardship, and control
• Storage, retention, and disposal
• Safety, security, and confidentiality
• Access by interested parties

Furthermore, institutional policies on ownership of, and access to, databases and archives must require that:

• Researchers are informed of relevant confidentiality agreements and restrictions on the use of research data
• Computing systems are secure
• Information technology personnel understand their responsibilities for network security and access control
• Those holding primary material, including electronic material, understand their responsibilities for security and access

The G-CodeConduct and the G-DataInfoMgt further state that researchers must retain clear, accurate, secure, and complete records of all research including research data and primary materials. Additionally, the G-NatlStmt indicates that when multiple researchers are collaborating on the collection, storage, and/or analysis of data or information, they should agree to the arrangements for custodianship, storage, retention, and destruction of those materials, as well as the rights of access, rights to analyze/use and re-use the data or information, and the right to produce research outputs based upon them.

According to the G-TrialsSOP, the investigator must maintain adequate source documents and trial records, including all key observations on each of the trial participants. The investigator must also store all trial related documents in a study master file (SMF) and take measures to prevent accidental or premature destruction of these documents. In the case of a teletrial, the SMF is stored at the primary site, and the principal investigator (PI) must have control of all essential documents and records generated by the investigator(s), institution, and satellite site(s) before, during, and after the trial. The PI must also establish the maintenance rules of the SMF and relationship between the primary site’s SMF and any satellite site study files. For more information on the SMF, see the G-TrialsSOP.

As set forth in the annotated AU-ICH-GCPs, the TGA requires that the sponsor retain records for 15 years following the completion of a clinical trial. However, product liability is the overriding consideration, and the sponsor should be able to produce records at any time, including possibly beyond the life of a product, in the event of an adverse event claim. The sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

The TGA has adopted the European Medicines Agency (EMA)’s Guideline on the Content, Management and Archiving of the Clinical Master File (Paper and/or Electronic) (AUS-75). For more information on the clinical trial master file, see AUS-75.

Data Management Plan

According to the G-NatlStmt and the G-DataInfoMgt, researchers should create a data management plan, which should be developed as early as possible in the research process and should include details regarding:

• Physical, network, system security, and any other technological security measures
• Policies and procedures
• Contractual and licensing arrangements and confidentiality agreements
• Training for members of the project team and others, as appropriate
• The form in which the data or information will be stored
• The purposes for which the data or information will be used and/or disclosed
• The conditions under which access to the data or information may be granted to others
• What information from the data management plan, if any, needs to be communicated to potential participants

The G-NatlStmt states that in the data management plan, researchers should also clarify whether they will seek extended or unspecified consent for future research, or permission from a review body to waive the requirement for consent. In addition, the security arrangements specified in the plan should be proportional to the risks of the research project and the sensitivity of the information.

In accordance with the G-NatlStmt, researchers must comply with all relevant legal and regulatory requirements that pertain to the data or information collected, used, or disclosed as well as the conditions of the consent provided by participants. Data, information, and biospecimens used in research should be disposed of in a manner that is safe and secure, consistent with the consent obtained and any legal requirements, and appropriate to the research design.

The G-NatlStmt indicates that in the absence of justifiable ethical reasons and to promote access to the benefits of research, researchers should collect and store data, or information generated by research projects, in such a way that they can be used in future research projects. A justification must be provided when a researcher believes there are valid reasons for not making data or information accessible. More details are provided in the G-NatlStmt.

In addition, for details related to secondary use and sharing of data or information, see the G-NatlStmt.

Electronic Data Processing System

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

Records Management

As delineated in ResNo945, the sponsor must be responsible for storing clinical trial data for a period of five (5) years after the last approval of a registration request for registration in Brazil. ResNo945 and BRA-28 also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, or a marketing application receives the last approval. Per BRA-28, the sponsor should also inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.

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

Responsible Parties

Per AUS-70, the PrivacyAct regulates how certain health service providing organizations collect and handle personal information, including health information. It also includes provisions that generally allow an individual to access information held about them.

According to the PrivacyAct, agencies and organizations as defined in the PrivacyAct must comply with the Act and the Australian Privacy Principles (APP), found in Schedule 1, and are referred to as APP entities.

Data Protection

Per the PrivacyAct’s APP, an APP entity must have a clearly expressed and up-to-date policy about the management of personal information by the entity. Individuals must have the option of not identifying themselves or of using a pseudonym, and an APP entity must not collect sensitive information about an individual unless the individual consents to the collection of the information.

The APP outline further requirements for the consideration of personal information privacy; the collection of personal information; dealing with personal information; the integrity of personal information; and access to, and correction of, personal information. For the full list of APP, see Schedule 1 of the PrivacyAct.

Consent for Processing Personal Data

The PrivacyAct’s APP indicate that if an APP entity holds personal information about an individual that was collected for a particular purpose, the entity must not use or disclose the information for another purpose unless consent is obtained from the individual. There are limited exceptions to this requirement, which can be found in Schedule 1 of the PrivacyAct.

AUS-70 notes that in certain circumstances, the PrivacyAct permits the handling of health information and personal information for health and medical research purposes, where it is impracticable for researchers to obtain individuals' consent, recognizing: the need to protect health information from unexpected uses beyond individual healthcare, and the important role of health and medical research in advancing public health. To promote these ends, the Office of the Australian Information Commissioner (OAIC) approved the National Health and Medical Research Council (NHMRC)’s legally binding guidelines, G-PrivacyAct95 and G-PrivacyAct95A, which researchers must follow when handling health information for research purposes without individuals' consent. The guidelines also assist ethics committees (ECs) (known as the Human Research Ethics Committees in Australia) in deciding whether to approve research applications. The guidelines are:

• G-PrivacyAct95, which sets out procedures that ECs and researchers must follow when personal information is disclosed from a federal agency for medical research purposes
• G-PrivacyAct95A, which provides a framework for ECs to assess proposals to handle health information held by organizations for health research (without individuals' consent). It ensures that the public interest in the research activities substantially outweighs the public interest in the protection of privacy

See the PrivacyAct, the G-PrivacyAct95, and the G-PrivacyAct95A for more information.

Responsible Parties

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

Per CD-ANPD-No18, which regulates the performance of the person responsible for processing data, the person in charge is appointed by the controller and operator to act as a communication channel between the controller, data subjects, and the National Data Protection Authority (Autoridade Nacional de Proteção de Dados (ANPD)). The person in charge may be a natural person, member of the organizational structure of the processing agent or external to it, or a legal entity, and must be able to communicate with the holders and with the ANPD, clearly, precisely, and in Portuguese. Additionally, the exercise of activity of the person in charge does not presuppose registration with any entity or any specific certification or professional training. See CD-ANPD-No18 for details on the activities and duties of the person in charge and how conflicts of interest are handled. Refer to G-CD-ANPD-No18 for additional guidance and good practices for data processing agents. See also BRA-116 and BRA-119 for additional information.

Data Protection

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

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

The LGPD also provides a definition for sensitive personal data or information that encompasses health related considerations. Sensitive personal data refers to personal data about racial or ethnic origin; religious belief; political opinion; union membership or organization of a religious, philosophical, or political nature; data relating to health or sexual life; and genetic or biometric data, when linked to a natural person.

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

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

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

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

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

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

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

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

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

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

In addition, per CD-ANPD-No19, establishes the procedures and rules applicable to international data transfer operations for countries or international organizations that provide a level of personal data protection adequate to that provided for in the LGPD, upon recognition of adequacy by the ANPD; or, when the controller verifies compliance with the principles, rights of the holder, and the data protection regime in the form of specific contractual clauses for a given transfer; standard contractual clauses; or global corporate standards as provided for in the LGPD and CD-ANPD-No19. Refer to Chapter V of the LGPD, CD-ANPD-No19, and BRA-118 for detailed international data transfer requirements.

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

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Children/Adolescents

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

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

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

Obtaining Consent

In all Australian clinical trials, valid consent is required from each participant in accordance with the requirements set forth in the AU-ICH-GCPs and the G-NatlStmt. According to the AU-ICH-GCPs, if requirements specified in the G-NatlStmt appear to differ from those specified in the AU-ICH-GCPs, the Therapeutic Goods Administration (TGA) recommends compliance with the G-NatlStmt.

As per the AU-ICH-GCPs, the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (known as a Human Research Ethics Committee in Australia) and kept on file before the trial commences. (See the Required Elements section for details on what should be included in the form.)

According to the G-TrialsSOP, the principal investigator (PI) for any research project retains overall responsibility for ensuring a participant’s consent has been obtained in the correct manner prior to the participant’s entry into the project. This includes where consent is obtained from participants at satellite sites in a teletrial. The PI can delegate the duty for obtaining consent to a suitably qualified associate investigator at the PI’s discretion, but the PI remains responsible for any delegated activity. Furthermore, the investigator must ensure that institutional authorization is obtained, inclusive of approval by an appropriate EC, for all written information and any other media used to provide information to potential participants prior to their usage to obtain consent from any participant.

The AU-ICH-GCPs states that the investigator must provide detailed research study information to the participant or legal representative/guardian. The ICF content should be as non-technical as practical and understandable to the participant or legal representative/guardian. The G-TrialsSOP further indicates that the ICF and relevant EC-approved participant information documents can be provided in person, by telehealth, or by telephone and email or weblink. If informed consent is obtained by telephone, this must be recorded on the ICF and in the participant’s health and medical record, and/or source document, stating (as an example): “The protocol was discussed with [participant’s name] via telephone on [DD/MM/YYYY].”

According to the G-TrialsSOP, e-consent may be the preferable option for teletrials, as consent signatures can be obtained contemporaneously at both primary and satellite sites. For more information on obtaining consent using telehealth, see the G-TrialsSOP.

As per the AU-ICH-GCPs, the ICF content should be clearly presented orally, or in a written language that is easy to understand, and commensurate with the age and comprehension level of the research participant. The participant and legal representative/guardian should also be given adequate time to consider whether to participate. According to the G-NatlStmt, information should also be presented to potential participants in ways that help them make informed choices. To this end, the researcher should take into account cultural and language barriers, the need for accurate and reliable translation, the participant’s educational background, the participant’s age and maturity level, and whether there is a visual, hearing, or communication impairment. See AUS-65 for researcher guidance on how to talk to potential participants.

Furthermore, as delineated in the G-TrialsSOP, the PI or delegate must assess the potential participant’s understanding of what they are agreeing to, that they are aware of the purpose of the study, what will be involved, and any risks that may exist. The participants must demonstrate that they fully understand the implications of decisions that may be made within the course of the research.

Per the G-NatlStmt, where a potential participant lacks the capacity to consent, a person or appropriate statutory body exercising lawful authority for the potential participant should be provided with relevant information and decide whether the individual will participate. That decision must not be contrary to the individual’s best interests. Researchers should bear in mind that the capacity to consent may fluctuate, and even without that capacity, people may have some understanding of the research and the benefits and burdens of their participation. Additionally, within some communities, decisions about participation in research may involve not only individuals but also properly interested parties such as formally constituted bodies, institutions, families, or community elders. See the Emergencies, Vulnerable Populations, Children/Minors, Prisoners, and Mentally Impaired sections for additional information about these populations.

As per the AU-ICH-GCPs, 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 representative(s) from liability for negligence. Per the G-NatlStmt, no person should be subject to coercion or pressure in deciding whether to participate in a trial.

The G-NatlStmt indicates that consent may be:

• Specific – limited to the specific project under consideration
• Extended – given for the use of data or tissue in future research projects that are: (i) an extension of, or closely related to, the original project; or (ii) in the same general area of research (for example, genealogical, ethnographical, epidemiological, or chronic illness research)
• Unspecified – given for the use of data or tissue in any future research

The G-NatlStmt further states that when unspecified consent is sought, its terms and wide-ranging implications should be clearly explained to potential participants. When such consent is given, its terms should be clearly recorded. Subsequent reliance, in a research proposal, on existing unspecified consent should describe the terms of that unspecified consent. See the G-NatlStmt for more information on consent to future use of data and tissue in research. Additionally, see the Consent for Specimen section for more information on consent related to use of tissue in research.

Re-Consent

According to the AU-ICH-GCPs and the G-TrialsSOP, any change in the ICF that is relevant to the participant’s consent should be approved by the 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. The G-TrialsSOP further specifies that unless there is a significant safety concern, ECs will not usually require that participants be recontacted immediately since there are potential implications related to blinding. If approved by the EC, continued consent may be obtained verbally and recorded in the participant’s medical records and relevant documents. Re-consent may also be obtained by telephone if approved by an EC.

The G-NatlStmt notes that in some research, consent may occasionally need to be renegotiated or confirmed, especially where projects are complex or long-running, or participants are vulnerable. Research participants should be told if there are changes to the terms to which they originally agreed and given the opportunity to continue their participation or withdraw.

Language Requirements

Pursuant to the G-NatlStmt, methods for presenting research information to participants should take into account the need for accurate and reliable translation into the participant’s first language or dialect, as well as culture and its effects on the communication process. According to the G-TrialsSOP, in cases where translation is required, a professional interpreter should facilitate the process.

Documenting Consent

The AU-ICH-GCPs and the G-TrialsSOP state that the participant or legal representative(s)/guardian(s) and the investigator(s) must sign and date the ICF. Where the participant is unable to read or the legal representative/guardian is unable to read, an impartial witness should be present during the entire informed consent discussion. After the following steps have occurred, the witness should sign and date the ICF attesting that the information in the ICF was accurately explained to, and apparently understood by the participant or legal representative/guardian:

• The written ICF and any other written information to be provided to the participant is read and explained to the participant or legal representative/guardian
• The participant or legal representative/guardian has orally consented to the participant’s involvement in the trial, and has 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.

The G-TrialsSOP further indicates that where consent is obtained by telehealth or telephone, once the ICF is signed and dated by both the participant and the investigator (and any other person present, for example an interpreter), the participant must select the statement identifying that consent was obtained by telehealth or telephone with the name of the investigator. Similarly, the investigator must select the statement identifying that consent was obtained by telehealth or telephone with the name of the participant. For more information on informed consent documentation, see the G-TrialsSOP.

According to the G-NatlStmt, consent may be expressed orally, in writing, or by some other means (such as return of a survey or conduct implying consent), depending on the nature, complexity, and level of risk of the research, and the participant’s personal and cultural circumstances.

Waiver of Consent

The G-NatlStmt specifies that although voluntary consent is a requirement for every trial, the EC may approve an alteration to the consent requirements. Limited disclosure to participants of the aims and/or methods of research may be justifiable. However, only an EC can review and approve research that involves active concealment or planned deception or aims to expose illegal activity.

Per the G-NatlStmt, it may be appropriate to use an opt-out approach for participant recruitment when obtaining explicit consent is neither practical nor feasible. An opt-out approach is a method used in the recruitment of research participants where information is provided to the potential participant regarding the research and their involvement, and where their participation is presumed unless they take action to decline to participate. An EC may approve the use of an opt-out approach for research if the study satisfies all of the following conditions:

• It involves only low risk to participants
• The public interest in the proposed activity substantially outweighs the public interest in the protection of privacy
• The research activity is likely to be compromised if the participation rate is not near complete, and the requirement for explicit consent would compromise the necessary level of participation
• Reasonable attempts are made to provide participants with appropriate plain language information explaining the nature of the information to be collected, the purpose of collecting it, and procedure to decline participation or withdraw from the research
• A reasonable time period is allowed between the provision of information to prospective participants and the use of their data so that an opportunity for them to decline to participate is provided before the research begins
• A mechanism is provided for prospective participants to obtain further information and decline to participate
• The data collected will be managed and maintained in accordance with relevant security standards
• There is a governance process in place that delineates specific responsibility for the project and for the appropriate management of the data
• The opt-out approach is not prohibited by state, federal, or international law

According to the G-NatlStmt, only an EC may grant a waiver of consent for research using personal information in medical research, or personal health information. However, other review bodies may grant a waiver of consent for other research. In order to help maintain public confidence in the research process, each institution must make publicly accessible summary descriptions of all its research projects for which consent has been waived.

As stated in the G-NatlStmt, an EC may waive the requirement for consent if the study satisfies all of the following conditions:

• Involvement in the research carries no more than low risk to participants
• The benefits from the research justify any risks of harm associated with not seeking consent
• It is impracticable to obtain consent (for example, due to the quantity, age, or accessibility of records)
• There is no known or likely reason for thinking that participants would not have consented if they had been asked
• There is sufficient protection of their privacy
• There is an adequate plan to protect the confidentiality of data
• There is, where practicable, a plan for making information arising from the research available to participants in cases where the results have significance for their welfare
• The possibility of commercial exploitation of derivatives of the data or tissue will not deprive the participants of any financial benefits to which they would be entitled
• The waiver is not prohibited by state, federal, or international law

See the G-NatlStmt for more information on conditions for the opt-out approach or waiving consent.

Obtaining Consent

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

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

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

Re-Consent

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

Language Requirements

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

Documenting Consent

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

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

Waiver of Consent

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

Based on the AU-ICH-GCPs and the G-NatlStmt, both the informed consent discussion and the written informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia) should include the following statements or descriptions, as applicable (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• That the trial involves research
• The purpose of the trial
• The trial treatment(s) and the probability for random assignment to each treatment
• The trial procedures to be followed, including all invasive procedures
• The participant's responsibilities
• Those aspects of the trial that are experimental
• The reasonably foreseeable risks or inconveniences to the participant and, when applicable, to an embryo, fetus, or nursing infant
• The reasonably expected benefits, including to the wider community. When there is no intended clinical benefit to the participant, the participant should be made aware of this
• The alternative procedure(s) or course(s) of treatment that may be available to the participant, and their important potential benefits and risks
• The compensation and/or treatment available to the participant in the event of trial-related injury, including provision of services to participants adversely affected by the research
• The amounts and sources of funding for the research, as well as financial or other relevant declarations of interests of researchers, sponsors, or institutions
• The anticipated prorated payment, if any, to the participant for participating in the trial
• The anticipated expenses, if any, to the subject for participating in the trial
• That participation in the trial is voluntary and that the participant may refuse to participate or withdraw from the trial, at any time, without penalty or loss of benefits to which the subject is otherwise entitled
• Any implications of withdrawal from the trial, and whether it will be possible to withdraw data
• How the research will be monitored
• That the monitor(s), the auditor(s), the ethics committee (EC), and the regulatory authority(ies) will be granted direct access to the participant's original medical records for verification of clinical trial procedures and/or data, without violating the confidentiality of the participant, to the extent permitted by the applicable laws and regulations and that, by signing a written informed consent form, the participant or legal representative/guardian is authorizing such access
• That records identifying the participant will be kept confidential and, to the extent permitted by the applicable laws and/or regulations, will not be made publicly available. If the results of the trial are published, the participant’s identity will remain confidential
• That the participant or legal representative/guardian will be informed in a timely manner if information becomes available that may be relevant to the participant's willingness to continue participation in the trial
• The person(s) to contact for further information regarding the trial and the rights of trial participants, and whom to contact in the event of trial-related injury
• Contact details of a person to receive complaints and of the researchers
• The foreseeable circumstances and/or reasons under which participation in the trial may be terminated
• The expected duration of participation in the trial
• The approximate number of participants involved in the trial
• The likelihood and form of dissemination of the research results, including publication
• Any other relevant information, including research-specific information required under other chapters of the G-NatlStmt

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

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

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

Overview

In accordance with the AU-ICH-GCPs and the G-NatlStmt, Australia’s ethical standards protect participants’ rights and promote respect for human beings, research merit and integrity, justice, and beneficence. The G-NatlStmt further recognizes that state or territory authorities may have additional statutes regarding the use of human tissues, guardianship, and illegal and unprofessional conduct. Furthermore, a participant’s rights must be clearly addressed in the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia).

The Right to Participate, Abstain, or Withdraw

As stated in the AU-ICH-GCPs and the G-NatlStmt, the participant or the legal representative/guardian should be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled. The G-TrialsSOP further specifies that participants may withdraw their consent at any time without giving a reason.

Per the G-NatlStmt, the participant should be informed of any implications of withdrawal and whether it is possible to withdraw data.

The Right to Information

As per the AU-ICH-GCPs and the G-NatlStmt, a potential research participant or the 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 AU-ICH-GCPs and the G-NatlStmt, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. Privacy is also subject to national, state, and territory laws, including the PrivacyAct. As per the G-TrialsSOP, if telehealth is used, all measures must be taken to ensure privacy and confidentiality of the participant’s identity.

See the Personal Data Protection section for more details on personal information collection and handling requirements.

The Right of Inquiry/Appeal

The AU-ICH-GCPs and the G-NatlStmt state that the research participant or the legal representative/guardian should be provided with contact information for the individual responsible for addressing trial-related inquiries and/or rights.

AUS-45 provides information on who the participant or the legal representative/guardian may contact regarding a concern with the clinical trial. The options include contacting the researcher(s) directly, the ethics committee (EC) (known as Human Research Ethics Committee in Australia), the institution, the healthcare complaints entity in the state or territory, or the National Health and Medical Research Council (NHMRC). Concerns may also be reported to the Therapeutic Goods Administration (TGA). See AUS-45 for more information on the types of concerns that may be reported to each party.

See the G-NatlStmt for more information on institutional requirements for receipt of complaints.

The Right to Safety and Welfare

The AU-ICH-GCPs (which upholds the Declaration of Helsinki (AUS-52)) and the G-NatlStmt clearly state that a research participant’s right to safety and protection of 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.

Overview

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

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

The Right to Privacy and Confidentiality

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

The AU-ICH-GCPs states that in emergency situations, when prior consent of the participant is not possible, the consent of the legal representative/guardian, if present, should be requested. When prior consent of the participant is not possible, and the legal representative/guardian is not available, enrollment of the participant should require measures described in the protocol and/or elsewhere, with documented approval/favorable opinion by the ethics committee (EC) (known as the Human Research Ethics Committee in Australia), to protect the rights, safety, and well-being of the participant and to ensure compliance with applicable regulatory requirements, including the G-NatlStmt. Per the AU-ICH-GCPs, 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.

The G-NatlStmt recognizes that in emergency care research, recruitment into a research project often must be achieved rapidly. Where the research involves emergency treatment and meets the G-NatlStmt’s requirements for research involving people highly dependent on medical care, consent for the research may be waived. See the Vulnerable Populations section for more information on people highly dependent on medical care, and the Documentation Requirements section for more details on waiver of consent.

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

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

Overview

The AU-ICH-GCPs characterizes vulnerable populations as those who may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation in a clinical trial, or of a retaliatory response for 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, residents of nursing homes, unemployed or impoverished persons, patients in emergency situations, homeless persons, nomads, refugees, minors, and those incapable of giving consent. Per the G-NatlStmt, people who may be involved in illegal activities, Aboriginal and Torres Strait Islander peoples, ethnic minority groups, and people in other countries are other groups for which specific ethical considerations are required.

People Highly Dependent on Medical Care

According to the G-NatlStmt, research involving people who are highly dependent on medical care may be approved where:

• It is likely that the research will lead to increased understanding about, or improvements in, the care of this population
• The requirements of relevant jurisdictional laws are taken into account
• Either: 1) any risk or burden of the proposed research to this particular participant is justified by the potential benefits, or 2) where participants have capacity to consent, any risk or burden is acceptable to them and justified by the potential benefits of the research

The G-NatlStmt indicates that when a researcher is also the treating health professional, it should be considered whether an independent person should seek the consent of potential participants who are highly dependent on medical care. In addition, the participant and/or the participant’s relatives and an authorized representative should be informed of the participant’s inclusion in the research and of the option to withdraw from it without any reduction in quality of care.

The G-NatlStmt states that when neither the potential participant nor the legal representative/guardian can consider the proposal and give consent, an ethics committee (EC) (known as the Human Research Ethics Committee in Australia) may, having taken account of relevant jurisdictional laws, approve a research project without prior consent if:

• There is no reason to believe that, were the participant or legal representative/guardian to be informed of the proposal, the participant would be unwilling to consent
• The risks of harm to individuals, families, or groups linked to the participant, or to their financial or social interests, are minimized
• The project is not controversial and does not involve significant moral or cultural sensitivities in the community

And, where the research is interventional, these additional conditions apply:

• The research supports a reasonable possibility of benefit over standard care
• Any risk or burden of the intervention to the participant is justified by its potential benefits
• Inclusion in the research project is not contrary to the interests of the participant

The G-NatlStmt further provides specific requirements related to conducting research on participants in terminal care, which is characterized by the short remaining life expectancy of the participants and their vulnerability to unrealistic expectations of benefits. Terminal care research should be designed so that the benefits of research justify any burden, discomfort, or inconvenience to the participants; the prospect of benefit from research participation is not exaggerated; the needs and wishes of participants to spend time as they choose are respected; and the entitlement of those receiving palliative care to participate is recognized.

Aboriginal and Torres Strait Islander Peoples

The G-NatlStmt states that research involving Aboriginal and Torres Strait Islander Peoples must be reviewed and approved by an EC and include assessment and advice from: people who have networks with and/or knowledge of Aboriginal and Torres Strait Islander Peoples; and people familiar with the culture and practices of the relevant Aboriginal and Torres Strait Islander community(ies). In addition, the researcher should ensure the following:

• Research methods are respectful and acknowledge the cultural distinctiveness of participating Aboriginal and Torres Strait Islander communities and groups
• There is evidence of support for the research project from relevant Aboriginal and Torres Strait Islander communities or groups and the research methodology engages with their social and cultural practices
• The research methods provide for mutually agreed mechanisms for recruitment, information provided about the research, notification of participants’ consent and of research progress, and final reporting
• Procedures and actions have been taken to monitor and, where appropriate, minimize any potential negative consequences of the proposed research

For more information on research involving Aboriginal and Torres Strait Islander Peoples, see the G-AboriginalEthic, the G-EthicsRsrchTrackII, and the G-AIATSISCode.

People in Dependent Groups

The G-NatlStmt cautions that dependent or unequal relationships that might compromise the voluntary character of a participant’s decision should be considered. Examples of such relationships include caregivers and people with chronic conditions/disabilities; health care professionals and their patients; teachers and their students; prison authorities and prisoners; governmental authorities and refugees; employers/supervisors and their employees (including members of police and Defense Forces); and service-providers and especially vulnerable communities to whom the services are provided. Where potential participants are especially vulnerable or powerless, consideration should be given to the appointment of a participant advocate.

Per the G-NatlStmt, when a researcher and potential participant have a pre-existing relationship, it should be considered whether an independent person should seek the consent of the participant.

People Who May Be Involved in Illegal Activities

The G-NatlStmt provides specific requirements related to conducting research on participants who may be involved in illegal activities. Research that is intended to study or expose, or likely to expose, illegal activity should be reviewed and approved by an EC. Researchers should be satisfied that participants who are subject to criminal justice processes are aware that the research may discover illegal activity and do not have unrealistic expectations of benefit from their participation. Finally, research designed to expose illegal activity should only be approved where the illegal activity bears on the discharge of a public responsibility or the fitness to hold public office, the risks are justified by the benefits, and the research meets the other requirements in the G-NatlStmt.

People in Other Countries

The G-NatlStmt states that research involving people in other countries must be reviewed and approved by an EC and comply with the G-NatlStmt. The research design, protocol, and consent process should take into consideration the local cultural values, yet still result in participants being treated with no less respect and protection than what is provided in the G-NatlStmt. Additional details are provided in the G-NatlStmt.

Overview

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

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

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

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

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

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

Indigenous Peoples

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

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

The FamLawAct defines a child as a person who is under 18 years of age. Per AUS-71, different states or territories may have specific legislation about a parent/guardian providing consent to medical treatment for a minor; otherwise, the FamLawAct has provisions that may apply.

According to AUS-71, children under 16 cannot give legal consent, which must be given by a parent/guardian, but they can and should be involved in the decision. Young people over 16 can give legal consent to medical treatment; however, they usually cannot provide legal consent to participate in research until they are 18. Nonetheless, some ethics committees (ECs) (known as Human Research Ethics Committees in Australia) do allow mature young people under 18 to give their consent for some kinds of research.

The AU-ICH-GCPs states that minors should be informed to the extent compatible with their maturity and understanding, and if capable, they should sign and personally date the informed consent form (ICF) (also referred to as a participant information sheet and consent form (PICF) in Australia). In accordance with the G-NatlStmt, consent requirements for conducting clinical trials follow the general requirements listed in the Required Elements section.

The G-NatlStmt states before including a child or young person in research, researchers must establish that there is no reason to believe that such participation is contrary to that child's or young person's best interest. Furthermore, a child or young person's refusal to participate in research should be respected wherever the child or young person has the capacity to give consent to that same research. Where a child or young person lacks this capacity, the child or young person’s refusal may be overridden by the judgement of the parent/guardian as to what is in the child's best interest.

The G-NatlStmt indicates that an EC may approve research to which only the child or young person consents if it is satisfied that:

• The child or young person is mature enough to understand the relevant information and give consent
• The research involves low risk
• The research aims to benefit children or young people
• The child or young person is estranged or separated from the parent/guardian and the researcher ensures the child or young person’s safety, security, and well-being in the research conduct; or it would be contrary to the best interests of the child or young person to seek consent from the parent/guardian, and the researcher ensures the child or young person’s safety, security, and well-being in the research conduct

In addition, as stated in the G-NatlStmt, children and young people who are not of sufficient maturity to consent should only participate in clinical studies when: the research is likely to advance knowledge about the health or welfare of, other matters relevant to, children and young people; or their participation is indispensable to the conduct of the research. When considering the inclusion of children and young people in research, the researchers and EC must consider their level of maturity to ensure adequate protections for their welfare.

Assent Requirements

AUS-71 indicates that when a parent/guardian gives consent for their child to take part in a clinical trial, researchers may also ask the child for their permission or agreement, also referred to as assent. The researchers must do this in an age-appropriate manner. Both the parent/guardian and the child should have the chance to ask any questions before agreeing to participate and at any time during a trial. In order for a child to provide their consent or assent they must:

• Understand the research process
• Understand the purpose of the trial
• Be told what they are expected to do or what will happen to them during the trial

AUS-71 further states that children should be able to express their views and any worries they might have about participating in a trial, and have their questions answered. Children should always be given information in a form that they can understand. Additionally, AUS-80 indicates that refusal to assent or withdrawal of assent by a child should be respected. Over the course of a clinical study, it may be necessary to reassess the assent of a child in recognition of their advancing age, evolving maturity, and competency, especially for long-term studies or studies that may require sample retention. During clinical studies, it is required to obtain adequate informed consent for continued participation from pediatric participants once a child reaches the age of legal consent. Local regulations related to confidentiality and privacy of pediatric participants must be followed.

Furthermore, the G-NatlStmt states that except in cases involving standing parental consent, specific consent must be obtained from the child or young person whenever the child or young person has the capacity to make this decision, and either one (1) parent, except when the EC decides that the risks require the consent of both parents, or the child or young person’s parent/guardian.

Per the G-NatlStmt, researchers must respect the developing capacity of children and young people to be involved in decisions about participation in research. The child or young person's particular level of maturity has implications for whether consent is necessary and/or sufficient to authorize participation. However, it is not possible to attach fixed ages to each level of maturity, which may vary from child to child. The following guidelines on maturity and corresponding capacity to consent are provided:

• Infants, who are unable to take part in discussion about the research and its effects
• Young children, who are able to understand some relevant information and take part in limited discussion about the research, but whose consent is not required
• Young people of developing maturity, who are able to understand the relevant information but whose relative immaturity means that they remain vulnerable; the consent of these young people is required, in addition to consent from a parent or guardian
• Young people who are mature enough to understand and consent, and are not vulnerable through immaturity in ways that warrant additional consent from a parent or guardian

See the G-NatlStmt for more information on consent and assent involving children and young people.

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

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

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

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

Assent Requirements

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

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

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

As per the G-NatlStmt, studies involving pregnant women, fetuses, and neonates require additional safeguards to ensure that the research assesses the risks to the pregnant women, fetuses, and neonates. The wellbeing and care of the woman who is pregnant and of her fetus always takes precedence over research considerations, and research involving a fetus or fetal tissue should be conducted in a manner that maintains a clear separation between the woman’s clinical care and the research. Additionally, research should be designed to minimize pain or distress for the fetus, include steps for monitoring for signs of fetal pain or distress, and include steps for suspending or ceasing the research if necessary.

In accordance with the G-NatlStmt, consent requirements for conducting clinical trials follow the general requirements listed in the Required Elements section. However, except for therapeutic innovative therapy cases, the process of providing information and obtaining consent for participating in research should be clearly separate from clinical care if the woman is pregnant and the fetus is in utero. Further, per the G-NatlStmt, the woman should be informed of the following:

• That she should consider whether to seek consent to the proposed research from any other person (e.g., the other parent)
• Whether it is possible to store the fetus or fetal tissues for later use in research
• That she is free to withdraw her consent to the research at any time, whether before or after a termination or other loss of a fetus
• Whether there is potential for commercial application of outcomes of the research, including the development of cell lines
• That she will not be entitled to a share in the profits of any commercial applications
• Whether fetal organs or stem cell lines developed from them will be exported to another country

In addition, the G-NatlStmt states that if, for research purposes, fetal cells are to be derived from the fetal tissue and stored or propagated in tissue culture, or tissues or cells are to be used in human transplantation, the woman's consent is required. Others whom the woman identifies may also need to be involved in decisions about these matters.

For requirements related to assisted reproductive technology, including research involving the creation of human embryos using precursor cells from a human embryo or a human fetus, see the G-EthicsART.

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

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

The G-NatlStmt refers to prisoners and prison authorities as an example of people who may be in dependent or unequal relationships.

Per the G-NatlStmt, a research study involving people in dependent or unequal relationships (such as prisoners) should, wherever possible, invite prospective participants to discuss their participation with someone who is able to support them in making their decision. If prospective participants are especially vulnerable, researchers should consider appointing a participant advocate.

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

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

Cognitive Impairment, Intellectual Disability, or Mental Illness

The G-NatlStmt discusses the requirements for research involving participants with cognitive impairment, intellectual disability, and mental illness together, noting that many of the ethical issues they raise about research participation are similar. An ethics committee (EC) (known as Human Research Ethics Committee in Australia) must review and approve research involving such participants, except where the research uses collections of non-identifiable data and involves negligible risk.

Per the G-NatlStmt, the research design should take into account factors that may affect the capacity to receive information, to consent to the research, or to participate in it. Additionally, care should be taken to determine whether the participant’s cognitive impairment, intellectual disability, or mental illness increases the susceptibility to some forms of discomfort or distress. Ways of minimizing effects of this susceptibility should be described in the research proposal.

As delineated in the G-NatlStmt, the participant must consent if the participant has the capacity, or the participant’s legal representative/guardian must consent on behalf of the participant. Where a legal representative/guardian has given consent, the researchers still must explain to the participant what the research is about and what participation involves. If the participant recovers the capacity to consent, the researcher should offer the opportunity to continue participation or withdraw. Refusal or reluctance to participate in a research project should be respected.

The G-NatlStmt states that if the participant’s impairment, disability, or illness is temporary or episodic, researchers should seek consent when the condition does not interfere with the capacity to give consent. This consent should occur in the presence of a witness who is familiar with the participant, is independent from the research, and understands the research’s merits, risks, and procedures.

Research Involving Unconscious Persons

The G-NatlStmt states when prior consent is not possible for research involving unconscious persons, consent should be provided by the participant’s legal representative/guardian. However, relevant jurisdictional laws must be taken into account. Because of their extreme vulnerability, unconscious persons should be excluded from all but minimally invasive research, or in research designed both to be therapeutic for them and to improve treatment for the condition from which they suffer.

The G-TrialsSOP notes that as per the Declaration of Helsinki (AUS-52), for research involving participants who are physically or mentally incapable of giving consent (e.g., unconscious patients/participants), the study must be relevant to the physical or mental condition of the participant(s) that prevents them from being able to consent to participate in the study.

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

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

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

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

According to the AU-ICH-GCPs and the G-TrialsSOP, an investigational product (IP) is defined as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial. This includes a product with a marketing authorization when used or assembled (formulated or packaged) in a different way from the approved form; when used for an unapproved indication; or when used to gain further information about an approved use.

In Australia, IPs are also referred to as unapproved therapeutic goods. As per the G-CTHandbook and AUS-47, an unapproved therapeutic good includes:

• Any medicine, biological, or medical device not entered on the Australian Register of Therapeutic Goods (ARTG) (AUS-22), including any new formulation, strength or size, dose, name, indications, directions for use or type of container of a medicine already in the ARTG
• Any therapeutic good already in the ARTG to be used in a manner not covered by the existing ARTG entry

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

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

Manufacturing

As specified in the TGAct, the TGR, and the G-CTHandbook, the Therapeutic Goods Administration (TGA) authorizes the manufacture of investigational products (IPs) in Australia. As per AUS-47 and AUS-49, the sponsor provides manufacturer and/or active ingredient information to the TGA in the clinical trial application under one (1) of the two (2) regulatory schemes—the Clinical Trial Notification (CTN) scheme or the Clinical Trial Approval (CTA) scheme. AUS-49 indicates that as part of a CTN scheme application involving a medicine or biological, the sponsor must provide either the TGA-issued good manufacturing practice (GMP) license, the GMP certification (for overseas manufacturers), or a relevant exemption.

Pursuant to TGManuf, Australia adopted the Pharmaceutical Inspection Co-operation Scheme (PIC/S) Guide to Good Manufacturing Practice for Medicinal Products, PE 009-16 (AU-PIC-S-GMP-Guide) regarding the manufacture of therapeutic goods. Per the AU-PIC-S-GMP-Guide, the holder of a manufacturing authorization must manufacture IPs to ensure that they are fit for their intended use, comply with the requirements of the clinical trial authorization, and do not place participants at risk due to inadequate safety, quality, or efficacy. The production of IPs involves added complexity in comparison to marketed products and therefore requires personnel with a thorough understanding of, and training in, the application of GMP to IPs. For manufacturers to be able to apply and comply with GMP for IPs, cooperation between manufacturers and sponsors of clinical trials is required.

Additionally, the principles of the AU-PIC-S-GMP-Guide on certification by an authorized person and batch release also apply to IPs for human use. Although the ultimate responsibility for the performance of a medicinal product over its lifetime, as well as its safety, quality, and efficacy, lies with the marketing authorization holder, the authorized person is responsible for ensuring that each individual batch has been manufactured and checked in compliance with national requirements in accordance with the requirements of the marketing authorization and with GMP.

See the AU-PIC-S-GMP-Guide for detailed manufacturing requirements. Additionally, see AUS-73 for the TGA’s summary of the changes in version 16 of the AU-PIC-S-GMP-Guide.

Import

The G-CTHandbook and AUS-47 indicate that IPs may be imported and held under the direct control of the sponsor (importer) until the IPs are the subject of a notification to the TGA under the CTN scheme or an approval under the CTA scheme. The IPs must be kept in a warehouse or other properly secured area. There is no requirement for the CTN or CTA process to have been completed prior to importation of the clinical trial goods.

Per AUS-47, importers are advised to contact other relevant agencies, as there may be further restrictions on importation imposed through other legislation.

Other Considerations

AUS-47 states that Australian clinical trial product importers/manufacturers are not required to provide the TGA with six (6) monthly reports under regulation 47B of the TGR. However, the TGA can require information or documents relating to the supply (including quantity) of therapeutic goods that are exempt under the CTN scheme or approved under the CTA scheme.

Manufacturing

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

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

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

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

Import

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

Additionally, as described in ResNo945 and the G-DDCMManual, if a company is interested in importing IP(s) prior to DDCM approval, the sponsor must attach a declaration of commitment along with the DDCM documentation stating that the IP will only be distributed to research centers after the DDCM and DEEC are approved and ANVISA’s authorization is published in the DOU. In the event ANVISA rejects the DDCM, the corresponding DEEC, and prior import of the IP(s) authorization, the sponsor must submit a petition to amend the DDCM process informing ANVISA of the destination or destruction of the IP(s). This document must be submitted to ANVISA within a maximum period of 60 business days from the publication of the DDCM rejection and respective DEEC, and must contain information on the destination given to the IPs including their respective quantities compatible with what was previously imported. ResNo945 further states that changing the import purpose of goods and products is prohibited without ANVISA’s authorization. Any change to the IP information contained in the DI may only be made upon request to ANVISA’s clinical research technical area. Furthermore, the use of any IP imported by means of a DI prior to the approval of the DDCM and DEEC petition published in the DOU, constitutes a health violation and subjects the offender to the penalties provided for in LawNo6.437, and in specific health regulations, without prejudice to applicable civil and criminal sanctions.

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

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

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

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

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

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

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

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

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

Advanced Therapy Products

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

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

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

Investigator’s Brochure

According to the AU-ICH-GCPs, the sponsor is responsible for providing the investigators with an investigator’s brochure (IB). 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.

According to the G-TrialsSOP, where the investigator contributes to the content and development of the IB, the investigator must ensure the IB follows the outline in the AU-ICH-GCPs. The AU-ICH-GCPs requires the IB to cover 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 (pharmacokinetics, metabolism, and pharmacodynamics; safety and efficacy; and regulatory and post-marketing experiences)

• Summary of data and guidance for the investigator(s)

See Section 7 of the AU-ICH-GCPs for detailed content guidelines.

Quality Management

As specified in the AU-ICH-GCPs, the sponsor must ensure that the products are manufactured in accordance with Good Manufacturing Practice (GMP). Furthermore, the sponsor must maintain a Certificate of Analysis to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.

Per the AU-PIC-S-GMP-Guide, GMP ensures that products are consistently produced and controlled to the quality standards appropriate to their intended use and as required by the clinical trial authorization. A pharmaceutical quality system designed, set up, and verified by the manufacturer or importer should be described in written procedures, taking into account the guidance in Chapter 1 or Part I of the AU-PIC-S-GMP-Guide. Manufacturers should maintain documentation including specifications and instructions; the IP order; manufacturing formulae and processing instructions; packaging instructions; and batch records. The product specifications and manufacturing instructions may be changed during development, but full control and traceability of the changes should also be maintained. The product specification file should be continually updated as development of the product proceeds, ensuring appropriate traceability to the previous versions.

See the AU-PIC-S-GMP-Guide for more details on quality system and documentation requirements.

Investigator's Brochure

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

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

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

Quality Management

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

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

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

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

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

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

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

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

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

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

International GMP Compliance

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

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

Investigational product (IP) labeling in Australia must comply with the requirements set forth in the G-CTHandbook, the AU-ICH-GCPs, and the AU-PIC-S-GMP-Guide. Per the AU-PIC-S-GMP-Guide, as annotated by the G-CTHandbook, the following information must be included on the IP label:

• Sponsor’s name, address, and phone number. The main contact details for information on the product, clinical trial, and emergency unblinding must be an Australian contact
• Pharmaceutical dosage form, route of administration, and quantity of dosage units. For closed blinded trials, the labeling should include a statement indicating “placebo or [name/identifier] + [strength/potency]”
• The batch and/or code number to identify the contents and packaging operation
• A trial reference code, which should identify the particular trial site, unless provided elsewhere or its absence can be justified. The trial reference code used should also identify the Australian trial sponsor, unless provided as the main contact or its absence can be justified
• The trial participant identification number/treatment number
• Investigator’s name. The name of the principal investigator should appear on the label unless already included in a trial reference code or unless its absence can be justified
• Directions for use
• “For clinical trial use only” or similar wording
• The storage conditions
• The period of use (use-by date, expiry date, or re-test date as applicable) in month/year format and in a manner that avoids any ambiguity
• “Keep out of reach of children” except when the product is not taken home by participants

The G-CTHandbook recognizes that in exceptional circumstances, it may not be possible to meet the requirements of Annex 13 of the AU-PIC-S-GMP-Guide for labeling IPs. In this case, the sponsor must contact the Therapeutic Goods Administration (TGA) (see AUS-23) if they wish to request a departure from the requirements of Annex 13.

In addition, the AU-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.

Per the G-CTHandbook, labeling is a manufacturing step under the TGAct. However, an exemption from the requirement to hold a manufacturing license may apply to certain persons identified within the TGR, to allow relabeling of the IP with name and address of the new sponsor. If there is a change of Australian trial sponsor, the clinical trial medication should be relabeled appropriately with the details of the new trial sponsor at the time of transfer. See the G-CTHandbook for more details on these manufacturing exemptions.

Additional details on IP labeling are provided in the G-CTHandbook and the AU-PIC-S-GMP-Guide.

Investigational product (IP) labeling in Brazil must comply with the requirements set forth in ResNo945, the G-DDCMManual, RegNo136, the G-BiolProdManual, and the International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945. As described in the RegNo136 and the G-BiolProdManual, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging (Note: Each of the items listed below will not necessarily be found in both sources, which provide overlapping and unique elements):

• Name, address, and telephone number of sponsor, contract research organization (CRO) (clinical research representative organization (CRPO) in Brazil), or investigator (the main contact for information about the product, clinical trial and emergencies)
• Presentation, pharmaceutical form, route of administration, quantity of dosage units, and the drug name/identifier and concentration/potency in the case of open studies
• Batch and/or product identification code
• Clinical trial reference code
• Clinical trial participant identification code, and where relevant, the visit number
• Investigator name, if not included in earlier contact information
• Instructions for use (reference may be made to an explanatory pamphlet or other document that guides the trial participants or person administering the IP
• Storage conditions
• Period of use (use limit date, expiration date or retest date, as applicable), considering, at least, in the month/year format, and in a way that avoids any ambiguity
• Warning phrases in capital letters such as: “For clinical trial use only” or “EXCLUSIVE USE IN CLINICAL TRIALS”
• “KEEP OUT OF REACH OF CHILDREN”, except when the IP is for use in trials in which the product is not taken home by clinical trial participants

RegNo136 further explains that the labeling information must appear on the primary and secondary packaging, unless the IP is packaged as follows:

• Provided inside a primary package, together with the secondary package, and the secondary package contains the labeling data, or
• The primary packaging is a blister or small units, such as ampoules, on which the labeling information cannot be displayed, and requires the outer packaging to be provided with a label containing this information

Additionally, as described in RegNo136, when the primary IP packaging is always combined with the secondary packaging, the secondary packaging should contain the following:

• Name of the sponsor, CRO, or investigator
• Presentation, route of administration (may be excluded for oral solid dosage forms), dosage, and in the case of open trials, the name/identifier of the IP and strength/potency
• Batch and/or code number to identify the contents and packaging operation
• A trial reference code allowing identification of the trial, site, investigator, and sponsor if not given elsewhere
• The trial participant identification number/treatment number and where relevant, the visit number

As delineated in RegNo136, if the primary container takes the form of blister packs or small units, such as ampoules, and cannot be displayed, the outer packaging should be provided bearing a label with this information. However, the primary container should bear the following information:

• Name of the sponsor, CRO, or investigator
• Route of administration (may be excluded for oral solid dosage forms), dosage, and, in the case of open trials, name/identifier and concentration/potency
• Batch and/or code number for identifying the content and packaging operation
• Clinical trial reference code for study, site, investigator, and sponsor identification, if not provided elsewhere
• Trial participant identification number/treatment number and where relevant, the visit number

In addition, per RegNo136, the labeling information must be in the language of the country where the clinical trial takes place, however, other languages ​​may be included. By comparison, the G-BiolProdManual indicates that all of the text labeling must be written in Portuguese. RegNo136 and the G-BiolProdManual further note that symbols, pictograms, and warnings may also be included on both the primary and outer packaging. Also, the primary contact’s address and telephone number for IP or clinical trial information, and for emergency unblinding, need not appear on the label when the trial participant has been provided with a leaflet or card containing this information and has been instructed to keep this contact in their possession at all times. ResNo945 further states that the sponsor must ensure the IP, modified active comparator drug, or placebo be coded and labeled in a manner that protects blinding, if applicable, and characterizes them as products under clinical investigation. According to BRA-28, the sponsor should also ensure that the IP(s) (including active comparator(s) and placebo, if applicable) is characterized as appropriate to the stage of development of the product(s), is manufactured in accordance with any applicable good manufacturing practice (GMP), and is coded and labelled in a manner that protects the blinding, if applicable. The IP(s) coding system should include a mechanism that permits rapid IP(s) identification in case of a medical emergency but does not permit undetectable breaks of the blinding.

As explained in RegNo136 and the G-BioProdManual, additional information, warnings, or handling instructions may also be displayed. The additional label must indicate the new expiration date and repeat the batch number. The additional label may be superimposed over the old expiration date but may not be superimposed over the original batch number for quality control reasons. This operation may only be carried out at a duly authorized manufacturing site. If duly justified, the operation may be carried out in a location authorized by the sponsor, a pharmacist, or other authorized health professional. This operation may also be carried out at the research site under the supervision of the clinical trial center pharmacist, or another health professional, in accordance with national regulations, or when this is not possible, by the clinical trial monitor(s), who must be adequately trained. Furthermore, this operation must be carried out in accordance with GMP principles, standard and specific operating procedures, and under contract, if applicable, and must be verified by a second person. Additional labeling must be adequately documented in the test documentation and batch records.

Supply, Storage, and Handling Requirements

As stated in the AU-ICH-GCPs, the sponsor must supply the investigator(s) with the investigational product(s) (IPs)). The G-CTHandbook and AUS-47 indicate that Therapeutic Goods Administration (TGA) approval through the Clinical Trial Approval (CTA) scheme or notification through the Clinical Trial Notification (CTN) scheme must occur prior to supplying the IP(s) to the trial site(s).

The AU-ICH-GCPs specifies that the sponsor must ensure the following:

• Timely delivery of the IP(s)

• Records maintained for IP document shipment, receipt, disposition, return, and destruction

• A system for retrieving or disposing of IP(s) and documenting this retrieval or disposal

• Written procedures including instructions for IP handling and storage, adequate and safe receipt of the IP(s), dispensing of the IP(s), retrieval of unused IP(s), return of unused IP(s) to the sponsor, and disposal of unused IP(s) by the sponsor
• IP product quality and stability over the period of use
• IP manufactured according to any application of the Good Manufacturing Practice (GMP)
• Proper coding packaging, and labeling of the IP(s)
• Acceptable IP handling and storage conditions and shelf-life

In addition, the AU-ICH-GCPs states that the IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage. Refer to the AU-ICH-GCPs for detailed sponsor-related IP requirements.

As per the G-TrialsSOP, responsibility for IP management and accountability at the trial site rests with the principal investigator (PI). However, the PI may delegate responsibility for IP management to the site pharmacist or, where a pharmacist is not available or involved, to an appropriately qualified person. The site pharmacist or the appropriately qualified person will undertake IP management at the primary site and/or the satellite site in a teletrial. The investigator, pharmacist, or appropriately qualified non-pharmacist must ensure the IP is used only in accordance with the approved protocol and confirm IP certification and all relevant trial approvals/notifications are in place before releasing the IP for dispensing to participants. Refer to the G-TrialsSOP for detailed investigator-related IP requirements.

The AU-PIC-S-GMP-Guide indicates that the manufacturer or sponsor’s representative should destroy IPs only with prior written authorization by the sponsor. The arrangements for destruction of IPs must be described in the protocol. Any related arrangement between the sponsor and manufacturer should be defined in their technical agreement. Destruction of unused IPs should be carried out only after reconciliation of delivered, used, and recovered products and after investigation and satisfactory explanation of any discrepancies upon which the reconciliation has been accepted.

Record Requirements

According to the G-TrialsSOP, the investigator, pharmacist, or appropriately qualified non-pharmacist must maintain records of all IP management aspects. These records at a minimum should include: shipping documents; date of each transaction; quantities; batch/serial numbers; expiration dates/retest dates (if applicable); temperature logs showing the storage conditions of the IP throughout the trial period; the set of unique code numbers assigned to the IP and to the trial participant; and record of destruction/return.

As set forth in the AU-ICH-GCPs, the sponsor must retain essential documents for 15 years following completion of the trial. The sponsor should inform the investigator(s) and institution(s) in writing when record retention is needed and when the trial-related records are no longer needed. Per the AU-PIC-S-GMP-Guide, documents which are part of the product specification file must be retained for at least five (5) years. If the sponsor and the manufacturer are not the same entity, the sponsor must make appropriate arrangements with the manufacturer to fulfil the sponsor’s requirement to retain the clinical trial master file. Arrangement for retention of such documents and the type of documents to be retained should be defined in an agreement between the sponsor and manufacturer.

Supply, Storage, and Handling Requirements

As delineated in LawNo14.874, medicines should be packaged, stored, and disposed of in accordance with the applicable regulations. As specified in ResNo945 and the G-DDCMManual, the investigational products (IPs) must be stored in a protected area, under the sponsor’s control, and may only be distributed to the locations where they will be used following the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s approval of the clinical trial applications (Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM))) and Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) petitions published in the Official Gazette of the Union (Diário Oficial da União (DOU)). If a company is interested in importing IP(s) prior to DDCM approval, along with the DDCM documentation, the sponsor must submit a declaration of commitment to distribute to clinical trial centers and use IPs only after authorization from the corresponding DDCM and DEEC, when import is authorized prior to publication of the approval/rejection in the DOU. The sponsor is also responsible for acquiring a sufficient quantity of the IP and other supplies to be used in the clinical trial, and may only distribute them to the institutions informed in the approved Clinical Trial Submission Form (FAEC) (BRA-22) and authorized by the research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)).

Additionally, per ResNo945, the sponsor is responsible for the final disposal of medicines and products that were not used in the clinical trial. ResNo945 and the G-DDCMManual further state that in the event ANVISA rejects the DDCM and corresponding DEEC, and the IP(s) were imported prior to approval, the sponsor must submit a petition to amend the DDCM process with a document informing ANVISA of the destination or destruction of the IP(s). This document must be submitted to ANVISA within a maximum period of 60 business days from the publication of the DDCM rejection and respective DEEC, and must contain information on the destination given to the IPs including their respective quantities compatible with what was previously imported.

The International Council for Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), which Brazil has adopted per ResNo945, also states that the sponsor is responsible for supplying the investigator(s)/institution(s) with the IP(s). The sponsor should not supply an investigator/institution with the IP(s) until the sponsor obtains all required documentation (e.g., approval/favorable opinion from EC (CEP) and ANVISA). The sponsor should also ensure that written procedures include instructions that the investigator/institution should follow for the handling and storage of IP(s) for the trial and documentation thereof. The procedures should address adequate and safe receipt, handling, storage, dispensing, and retrieval of unused product from participants, and return of unused IP(s) to the sponsor (or alternative disposition if authorized by the sponsor and in compliance with the applicable regulatory requirement(s)).

BRA-28 further explains that the sponsor should:

• Ensure timely delivery of the IP(s) to the investigator(s)
• Take steps to ensure IP stability over the period of use
• Maintain sufficient quantities of the IP(s) to reconfirm specifications, if needed, and maintain records of batch sample analyses and characteristics. To the extent stability permits, samples should be retained either until the analyses of the trial data are complete or as required by the applicable regulatory requirement(s), whichever represents the longer retention period
• Determine acceptable storage temperatures, storage conditions (e.g., protection from light), storage times, reconstitution fluids and procedures, and devices for product infusion, if any. The sponsor should inform all involved parties (e.g., monitors, investigators, pharmacists, storage managers) of these determinations
• Ensure IP is packaged to prevent contamination and unacceptable deterioration during transport and storage
• Ensure the IP is manufactured according to any applicable good manufacturing practice (GMP) (see ResNo658 and RegNo136, which provides complementary GMP for IPs to be followed in addition to ResNo658)
• Ensure proper coding, packaging, and labeling of the IP(s)

Refer to BRA-28 for detailed sponsor-related IP requirements.

Record Requirements

Per BRA-28, the sponsor should comply with the following records requirements:

• Maintain records that document shipment, receipt, disposition, return, and destruction of the IP(s)
• Maintain a system for retrieving IPs and documenting this retrieval (e.g., for deficient product recall, reclaim after trial completion, and expired product recovery)
• Maintain a system for the disposition of unused IP(s) and for the documentation of this disposition

According to BRA-28, the sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related records are no longer needed. Sponsor-specific essential documents should also be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development.

In addition, per BRA-28, the investigator/institution and/or a pharmacist, or other appropriate individual who is designated by the investigator/institution, should also maintain records of the IP's delivery to the trial site, the inventory at the site, the use by each participant, and the return to the sponsor or alternative disposition of unused product(s). These records should include dates, quantities, batch/serial numbers, expiration dates (if applicable), and the unique code numbers assigned to the IP(s) and trial participants. Investigators should maintain records that document adequately that the participants were provided the doses specified by the protocol and reconcile all IP(s) received from the sponsor.

• Treat or prevent disease, ailment, defect, or injury
• Diagnose the condition of a person
• Alter the physiological processes of a person
• Test the susceptibility of a person to disease
• Replace or modify a person’s anatomy

As per OrdNo2201, ResNo504, ResNo441, and the G-BiolMatTransprt, a specimen is defined as any human biological material such as organs, tissues, cells, body fluids, excreta, and other fluids of human origin obtained from a single participant at a particular time. ResNo836 adds that these biological samples are intended to be used for laboratory or quality control tests.

Additionally, per ResNo504, human biological material is classified as Category A or B infectious biological material, or Category Risk Minimum. Category A includes materials where exposure can cause permanent disability or fatal disease to humans and animals. Category B includes those materials not listed in Category A such as samples suspected or known to contain infectious agents causing diseases in humans. Category Risk Minimum or “exempt human specimens” include biological materials from healthy individuals. Human biological materials must also be classified according to the World Health Organization (WHO)’s risk classification diagram available in the WHO’s Guidance on Regulations for the Transport of Infectious Substances (BRA-54).

The G-BiolMatTransprt also states that these materials are not considered hazardous if they are unlikely to cause disease in humans or animals. However, they are considered infectious substances, therefore dangerous materials, if through exposure to them, these substances can spread diseases.

The G-TrialsSOP indicates that to ensure the integrity of biological samples has been maintained, there should be evidence of the chain of custody from their point of collection through processing, storage, transport, through to disposal, with evidence of appropriate storage and transit conditions. Equipment used for processing and storage of samples (e.g., centrifuges, fridges, and freezers) should be maintained by suitably qualified persons and periodically inspected, cleaned, and calibrated to the relevant International Organization for Standardization (ISO) standard according to local policy and manufacturer’s manuals. Additionally, the investigator must ensure all study staff, who have cause to handle or ship biological substances, hold a current certificate in the International Air Transport Association (IATA) Approved, Civil Aviation Safety Authority (CASA) Certified Dangerous Goods Packaging Course. The investigator must also ensure that documentation (e.g., receipts, shipping records, order forms, and proformas) related to handling and shipment of biological specimens is maintained and filed in the respective site file.

Additional details on import and export requirements are provided in the G-CTHandbook, the G-TrialsSOP, the G-SpecExport, and AUS-24.

Import/Export

As set forth in ResNo208 (amending ResNo81) and ResNo172, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the import of human biological materials for clinical research purposes. ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) state that the import license will be carried out through the Integrated Foreign Trade System (SISCOMEX)’s Single Foreign Trade Portal (BRA-80) and express shipping. The following documentation is required to be submitted by the investigator and institution:

• Declaration from the importer with information on the Notice number (Special Notice (Comunicado Especial (CE)), Specific Special Notice (Comunicado Especial Específico (CEE)), Document for Import of Product(s) under investigation in the Clinical Drug Development Dossier (Dossiê de Desenvolvimento Clínico de Medicamento (DDCM)), or Dossier of Medical Device Clinical Investigation (DICD) issued by ANVISA
• Bill of lading cargo
• Commercial invoice
• 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 ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) for additional import documentation requirements. See the Manufacturing & Import section for details on how to submit an electronic import petition via ANVISA’s Solicita Electronic Petition Request System (BRA-56).

ResNo172 further states that ANVISA will analyze and release human biological samples intended for use in clinical research within 48 hours after arrival in Brazil, provided that the legal requirements are met. Refer to ResNo81 and ResNo172 for additional required items depending on the import method used.

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

As explained in ResNo504 and the G-BiolMatTransprt, the procedures for the import and export of human biological material should be determined by the biological material type and the mode of transport. Regardless of the mode of transport or material type, transport operations are required to be recorded and standardized through regularly updated written instructions. All documents and records of activities relating to human biological material transport equipment should be readily available to the health authorities, upon request. The biological material must be packed in a form that will preserve its integrity and stability and must be validated and approved by the supervisory technician. Per ResNo504, human biological material labeling should conform to the material type, risk classification, and specific requirements of the biological materials to be transported. The label for imported materials must be legible, understandable, and in English and Portuguese.

In addition to complying with ResNo504 and the G-BiolMatTransprt, human biological material transport should be conducted in accordance with legislation from applicable regulatory bodies including the Ministry of Transport (Ministério dos Transportes), the Ministry of Ports and Airports (Ministério dos Portos e Aeroportos), the National Land Transportation Agency (Agência Nacional de Transportes Terrestres (ANTT)), the National Civil Aviation Agency (Agência Nacional de Aviação Civil (Anac)), and the National Waterway Transport Agency (Agência Nacional de Transportes Aquaviários (ANTAQ)). Refer to the G-BiolMatTransprt for detailed import and export transport requirements.

Refer to ResNo504 and the G-BiolMatTransprt for detailed instructions on shipping biological materials within these categories. See also ResNo836 for detailed transport requirements relating to human cells and advanced therapy products, and BRA-97 for preparing reports on biobanking for research purposes.

Material Transfer Agreement

As set forth in LawNo14.874, human biological material and its associated information may be formally transferred to investigators, in accordance with the provisions of LawNo14.874 and other current regulations, through the execution of a Biological Material Transfer Agreement (Termo de Transferência de Material Biológico (TTMB)) and the presentation of proof of approval of the research project by the relevant ethical and regulatory bodies. OrdNo2201 defines a TTMB as a document duly approved by a research ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and CONEP (CEP/CONEP system) when requested by an investigator in a research project submission. The investigator uses the TTMB to receive stored human biological material with its associated information, and assumes responsibility for its safekeeping and use, for guaranteeing respect for the person and confidentiality, and for providing the biobank with the information obtained in their research.

LawNo14.874 further explains that the samples and components of the human biological material and associated information that have been transferred may not be passed on to third parties by the initial recipient institution, except when a new TTMB is signed between the original sending institution and the new recipient institution. The transfer of human biological material from the sending institution to the recipient must follow current health regulations, without prejudice to specific regulations for each type of biological material and the method of transport. The sending and storage of human biological material to a research center located outside the country is the responsibility of the sponsor and is subject to the following conditions:

• Compliance with national and international health legislation on the shipment and storage of biological material
• Guarantee of access and use of biological material and its data, for scientific purposes, to researchers and national institutions
• Compliance with national legislation, especially with regard to the prohibition of patenting and commercialization of biological material

OrdNo2201 also states that the transfer of stored human biological material is formalized through a specific term of transfer of responsibility between the legal representatives of the institutions involved. LawNo14.874 specifies that human biological material and its associated information used exclusively for a specific research purpose and stored in either a biorepository or a biobank, may be formally transferred to another biorepository or biobank in accordance with current regulations. In addition, OrdNo2201 specifies the sharing of stored human biological material and associated information between biobanks of partner institutions must follow the current regulations for the transportation, processing, and the use of human biological material applicable to the specimen. Additionally, the transfer of human biological material stored in a biobank to the biobank of another institution, depends on the approval of the ECs (CEPs) of the institutions involved.

• The research for which their biospecimens will be used and, where extended or unspecified consent is sought, and sufficient information is provided to meet the general requirements of consent
• How their biospecimens will be stored, used, and disposed of, including any processes to be adopted that respect their personal or cultural sensitivities
• The extent to which their biospecimens will be reasonably identifiable, and how their privacy and confidentiality will be protected
• Whether the biospecimen research is likely to provide information that may be important to their health or to the health of their blood relatives or their community; and, if such information is likely to be revealed, whether they have the choice to receive this information, whether they have the choice for it to be provided to their relatives or their community, and how these will be managed
• Whether their biospecimens and associated data may be distributed to other researchers, including those outside Australia
• Their right to withdraw consent for the continued use of their biospecimens or associated data in research, and any limitations that may be relevant to their withdrawal of consent
• Any relevant financial or personal interests that those engaged in the collection, processing, storage and distribution, and use of their biospecimens may have
• Any potential for commercial application of any outcomes of the research and how this will be managed and to whom the benefits, if any, will be distributed