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

Central Drugs Standard Control Organization

As set forth in the 2019-CTRules and the Hdbk-ClinTrial, the Central Drugs Standard Control Organization (CDSCO) is the regulatory authority responsible for clinical trial oversight, approval, and inspections in India. In accordance with the provisions of the 2019-CTRules, the Drugs Controller General of India (DCGI) heads CDSCO, and is responsible for granting permission for clinical trials to be conducted and for regulating the sale and importation of drugs for use in clinical trials. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

According to IND-59, CDSCO functions under the Directorate General of Health Services (DGHS), which is part of the Ministry of Health and Family Welfare (MOHFW). Per IND-59 and IND-47, as the Central Drug Authority, CDSCO is responsible for approving new drugs, conducting clinical trials, establishing drug standards, overseeing the quality of imported drugs, providing expert advice, and coordinating the state licensing authorities who regulate the manufacture, sale, and distribution of drugs.

Per the DCA-DCR, the Drugs Technical Advisory Board (DTAB) and the Drug Consultative Committee (DCC) advise the DCGI. IND-16 states that the DTAB, a statutory board, is composed of technical experts who advise the central and state governments on technical drug matters and on making rules. The DCC, a statutory committee, consists of central and state drug control officials who advise the central and state governments and the DTAB to ensure drug control measures are enforced throughout India.

Further, as indicated in the Hdbk-ClinTrial, Subject Expert Committees (SECs) comprise experts representing the relevant therapeutic areas that are responsible for reviewing the submitted clinical trial applications, investigators’ brochures, and study protocols. The 2019-CTRules and Order13Jan20 further note that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with specialization in relevant fields to evaluate scientific and technical drug-related issues. In accordance with the 2019-CTRules and with the approval of the MOHFW, Order13Jan20 establishes the terms of reference that CDSCO will use to constitute the SECs from the groups/panels of approximately 550 medical experts with specialization in relevant fields, including the existing members of the SECs from various government medical colleges and institutions. Additionally, per Notice31Jan24, CDSCO’s SEC Division is responsible for conducting meetings to evaluate IND proposal submissions. Refer to Scope of Assessment section for additional

Please note: India is party to the Nagoya Protocol on Access and Benefit-sharing (IND-29), 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 IND-45.

Contact Information

According to IND-58 and IND-70, CDSCO contact information is as follows:

Central Drugs Standard Control Organization
Directorate General of Health Services (DGHS)
Ministry of Health and Family Welfare
Government of India
FDA Bhavan, ITO, Kotla Road
New Delhi 110002
India
Phone: +91-11-23216367 (CDSCO)/23236975
Fax: +91-11-23236973
E-mail: dci@nic.in

Overview

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

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

Clinical Trial Review Process

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

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

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

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

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

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

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

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

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

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

Inspection

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

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

Priority Submissions

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

New Drugs for Rare Diseases Submissions

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

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

Optimized Analysis Procedure Reviews

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

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

Drug & Biological Product Registration/Post-Registration

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

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

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

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

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

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

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

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

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

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

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

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

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

See the Submission Process and Submission Content sections for details.

DDCM & IP Substantial Modifications by Risk Assessment

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

Overview

In accordance with the 2019-CTRules and the Hdbk-ClinTrial, the Drugs Controller General of India (DCGI), who heads the Central Drugs Standard Control Organization (CDSCO), is responsible for reviewing and approving clinical trial applications for all new drugs, investigational new drugs (INDs), and imported drugs to be registered in India. Additionally, per the 2019-CTRules, the G-ICMR, and IND-31, the DCGI and a DCGI-registered ethics committee (EC) must approve a clinical trial application prior to the sponsor (also known as applicant) initiating the trial, except in the case of non-regulatory academic/research clinical trials that only require EC approval. Refer to the Scope of Review section for detailed information on non-regulatory academic/research clinical requirements. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

As per the 2019-CTRules and the Hdbk-ClinTrial, the scope of the DCGI assessment includes a review of applications for IND and new drug clinical trials, global clinical trials (GCTs), and post marketing studies (Phases I-IV). Per Notice18Feb20, which clarifies information provided in IND-31, the 2019-CTRules are only applicable to new drugs and investigational new drugs. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2019-CTRules defines a “new drug” as:

• A drug, including active pharmaceutical ingredients or phytopharmaceutical drugs, that has not been used in the country to any significant extent
• A drug that has already been approved by the DCGI and is now proposed to be marketed with modified or new claims
• A fixed dose combination of two (2) or more drugs, individually approved for earlier specific claims, and which are now proposed to be combined for the first time in a fixed ratio, or, if the ratio of ingredients in an already marketed combination is proposed to be changed
• A modified or sustained release form of a drug, or novel drug delivery system of any drug approved by the DCGI
• A vaccine, recombinant Deoxyribonucleic Acid (r-DNA)-derived product, living modified organism, monoclonal antibody, cell, or stem cell derived product, gene therapeutic product, or xenografts intended to be used as a drug

Per the 2019-CTRules and IND-31, the above listed drugs, excluding the modified/sustained drug forms and biological drug products, will be deemed new for four (4) years from the date of first approval. The modified/sustained drug forms and biological products including vaccines should always be viewed as new drugs. See also IND-6 for additional information on the revised definition of “new drug” under the 2019-CTRules.

The 2019-CTRules defines an IND as a new chemical or biological entity or a product having therapeutic indication but that has never been tested on human beings, and as also noted in IND-31, has not been approved as a drug for marketing in any country.

In addition, according to IND-31, the DCGI review and approval process may be conducted in parallel with the institutional or independent EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm that the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (See the Scope of Review section for more information.)

Clinical Trial Review Process

As set forth in the 2019-CTRules and the Hdbk-ClinTrial, the DCGI is responsible for reviewing and approving clinical drug applications. The evaluation timeline is dependent upon whether the investigational drugs under review are developed outside India, or discovered, researched, and manufactured in India. (Refer to the Timeline of Review section for detailed CDSCO timeline information.)

Per the Hdbk-ClinTrial, upon receipt of an application (via Form CT-04 which is found in the 2019-CTRules), a CDSCO official is responsible for conducting the initial administrative review. If the application is deemed complete, the official forwards the application along with a summary of the evaluation and a statement referring the proposal to a Subject Expert Committee (SEC) for further technical review. If the proposal is not accepted by the SEC, the sponsor may request additional consideration of the proposal by the Technical Committee. Otherwise, only the SEC’s recommendations are required for the DCGI (CDSCO) to issue a final decision to the Technical or Apex Committee. Additionally, per Notice31Jan24, CDSCO’s SEC Division is responsible for conducting meetings to evaluate IND proposal submissions. See the Submission Process section for CDSCO submission requirements.

Per the Hdbk-ClinTrial, SECs are usually comprised of six (6) experts representing various therapeutic areas, including pharmacologists/clinical pharmacologists, and medical specialists. However, Order13Jan20, issued in accordance with the 2019-CTRules, indicates that SECs will be comprised of eight (8) medical experts, specifically one (1) pharmacologist and seven (7) medical specialists. Per the Hdbk-ClinTrial, SECs are responsible for advising CDSCO with in-depth evaluations of non-clinical data (including pharmacological and toxicological data) and clinical trial data (Phases I-IV) provided by the sponsors for approval. The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with specialization in relevant fields to evaluate scientific and technical drug-related issues.

Additionally, per Order13Jan20, SECs will evaluate and advise the DCGI on proposals in various categories for the approval of new drug and clinical trial applications. These include the following: new drug substances of chemical and biological origin including vaccines and r-DNA derived products; subsequent approval of new drug and biological products including vaccines and r-DNA derived products already approved in the country; global clinical trials; fixed dose combinations of two (2) or more drugs to be introduced for the first time in the country; causality analysis, drug safety, or any other technical matter requiring expert advice in the opinion of the Ministry of Health and Family Welfare (MOHFW) or the DCGI. See Order13Jan20 for the complete terms of reference required to constitute SECs.

Once an SEC has completed its review, the Hdbk-ClinTrial indicates that the committee sends its comments via email to CDSCO. CDSCO will then compile any written SEC comments requiring sponsor clarification or modification and sends this feedback to the sponsor. The sponsor must submit a written reply to CDSCO, which is also sent to the SEC for review.

Following receipt of the sponsor’s response, the DCGI (CDSCO) will issue a final decision by official communication (permission, rejection, or resubmission) to the Technical or Apex Committee. In the case of a sponsor’s request for reconsideration, CDSCO will review the resubmitted application and send it to the SEC again, or, to the Technical Committee per the sponsor’s request. Following the SEC’s review, the DCGI (CDSCO) will send a final decision to the Technical or Apex Committee. If CDSCO rejects the reconsideration request, the agency will send a letter to the sponsor to communicate this decision. Refer to the Hdbk-ClinTrial for additional timeline information.

Per the 2022-CTRules-3rdAmdt, which amends the 2019-CTRules, upon obtaining approval from the DCGI, the sponsor must notify CDSCO via Form CT-06A (see 2022-CTRules-3rdAmdt) prior to initiating the clinical trial. The DCGI will then record the information provided on this form and it will become part of the official record known as the approval of the DCGI. The DCGI grants permission to initiate a clinical trial via either Form CT-06 (see 2019-CTRules) or as an automatic approval via Form CT-4A (see 2019-CTRules). 2022-CTRules-3rdAmdt further states that when the DCGI approves a clinical trial of a new drug already approved outside India per the 2019-CTRules, the sponsor must also notify CDSCO via Form CT-06A, and this record will become part of the official record known as the guaranteed approval of the DCGI.

Per the 2019-CTRules, the DCGI’s permission to initiate a clinical trial granted via either Form CT-06 or as an automatic approval via Form CT-4A will remain valid for two (2) years from the date of its issue, unless extended by the DCGI as noted in the 2019-CTRules and IND-31.

In addition, per the 2019-CTRules, an investigator should not implement any deviations from or changes to the protocol without the sponsor’s agreement and after obtaining the EC’s prior review and documented approval or favorable opinion of the amendment. All protocol amendments should be submitted to the DCGI in writing along with the EC approval letter. Similarly, the G-ICMR indicates that the EC must review and approve any protocol amendments, major deviations, or violations prior to those changes being implemented.

The 2019-CTRules explains that the exception to this requirement is when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature. In this case, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should be notified of administrative or logistical changes or minor amendments in the protocol within 30 days.

The Hdbk-ClinTrial and the 2019-CTRules also note that application reviews should be based on the following evaluation parameters:

• Assessment of risk versus benefit to the patients
• Innovation vis-à-vis existing therapeutic option
• Unmet medical need in the country
• Safety/dosage/investigational tests (e.g., pharmacogenetic tests)
• Any additional information or study(ies) needed before marketing approval for inclusion in package insert/ summary product characteristic (SmPC) post marketing

See IND-46 for additional information on conducting clinical trials in India. For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

(See the Submission Process and Submission Content sections for detailed submission requirements.)

Waiving Local Clinical Trials

As delineated in the 2019-CTRules and IND-31, the DCGI, with the approval of the Central Government, may waive the requirement to conduct a local trial for a new drug already approved outside India. Order7Aug24, in accordance with Rule 101 in the 2019-CTRules, further specifies that the United States, the United Kingdom, Japan, Australia, Canada, and the European Union are the countries for which the DCGI may waive a local clinical trial for applications requesting permission to conduct a clinical trial and for applications requesting permission to import or manufacture new drugs in the following new drug categories:

• Orphan drugs for rare diseases
• Gene and cellular therapy products
• New drugs used in pandemic situations
• New drugs used for special defense purpose
• New drugs having significant therapeutic advance over the current standard care

The 2019-CTRules explains that for applications to request permission to import or manufacture a new drug, a local clinical trial may be waived if the following conditions are met:

• The new drug is approved and marketed in the countries specified by the DCGI in Order7Aug24, and no major unexpected serious adverse events have been reported, or
• The DCGI has already granted permission to conduct a Global Clinical Trial with the new drug that is currently ongoing in India and this new drug has also been approved for marketing in one (1) of the countries to be specified by the DCGI in Order7Aug24, and
• There is no probability or evidence, on the basis of existing knowledge, of any difference in the metabolism of the new drug by the Indian population, or any factor that may affect the pharmacokinetics, pharmacodynamics, and safety and efficacy of the new drug, and
• The applicant has committed in writing to conducting a Phase IV clinical trial to establish the new drug’s safety and efficacy per the DCGI-approved formulation

For countries that do not meet the waiver eligibility requirements, the 2019-CTRules states that these applications must be approved by the DCGI within 90 working days from the date of application receipt. Refer to the Manufacturing & Import section for detailed information on import requirements for new drugs already approved outside of India. See also IND-6 for additional information on local clinical trial waivers to import or manufacture new drugs under the 2019-CTRules.

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).

Central Drugs Standard Control Organization

As per the 2019-CTRules, IND-43, and IND-42, a sponsor (also known as applicant) is responsible for a paying a fee to the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), to submit a clinical trial application. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

The 2019-CTRules and IND-43 specify that Form CT-04 should be accompanied by one (1) of the following officially mandated fees:

• 3,00,000 Rupees for Phase I (human) clinical trials
• 2,00,000 Rupees for Phase II (exploratory) clinical trials
• 2,00,000 Rupees for Phase III (confirmatory) clinical trials
• 2,00,000 Rupees for Phase IV clinical trials
• 50,000 Rupees for reconsideration of application for permission to conduct clinical trial

According to the 2019-CTRules, the sponsor must also submit a fee of 5,000 Rupees per product with an application for permission to manufacture or import the investigational product (IP) to be used in a clinical trial.

In addition, the 2019-CTRules states that no fee is required to be paid along with the clinical trial application if a trial is being conducted by an institution or an organization wholly or partially funded or owned by the Central Government of India or one of India’s state government institute(s).

See also IND-31 for additional information on CDSCO fee requirements.

In addition, IND-24 indicates that for applications submitted to the National Single Window System (NSWS) portal (IND-3), users should pay any required fees directly to CDSCO or any other ministry/department/state responsible for processing the application via the NSWS portal (IND-3). At this time, however, per IND-14, only a few CDSCO steps and processes (e.g., medical device related registration, manufacturing/import applications and drug manufacturing/import applications) have been moved to the NSWS portal (IND-3).

Payment Instructions

As described in the 2019-CTRules and IND-43, payment must be made electronically via the Bank of Baroda, Kasturba Gandhi Marg, New Delhi-110001, any other Bank of Baroda branch, or any other bank approved by the Ministry of Health and Family Welfare (MOHFW) via the State Bank of India’s SBIePay payment gateway, which is accessed from the SUGAM portal (IND-59). The payment should be credited to: Head of Account, 0210-Medical and Public Health, 04-Public Health, 104-Fees and Fines per the 2019-CTRules, also known as the head of Fees & Fines, according to IND-42.

According to IND-43 and IND-42, once the user validates the payment information in the SUGAM portal (IND-59), the payment request is redirected to the SBIePay payment gateway. When the payment is submitted, the bank payment gateway will confirm that the payment was successful, and the user will be redirected to the online payment status page in the SUGAM portal (IND-59) to view the e-Challan (payment receipt).

IND-43 and IND-42 also specify that the online payment will take two (2) to three (3) days to be credited to the National Portal of India’s Payment & Account Office. Therefore, users are requested to initiate online payments at least three (3) days prior to submitting an application to CDSCO. Refer to IND-43 and IND-42 for detailed fee requirements and online payment instructions via the SUGAM portal (IND-59).

(Note: Although the fees listed in IND-43 are correct, the SUGAM portal (IND-59) and associated documentation as well as CDSCO’s Pre-Screening Checklist (IND-32) have not yet been aligned with the 2019-CTRules in terms of referencing the new application form (CT-04). However, the ClinRegs team is regularly monitoring the CDSCO website for new developments and will post the most current sources as they become available.)

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

As delineated in the 2019-CTRules and IND-31, India has a decentralized process for the ethical review of clinical trial applications, and requires ethics committee (EC) approval for each trial site. Because there is no national EC in the country, ECs are based at either institutions/organizations, or function independently, and must meet the requirements set forth in the 2019-CTRules and the G-ICMR. Prior to initiating and throughout the duration of a trial, every trial site must be overseen by an EC registered with the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO). (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.)

Ethics Committees for Biomedical and Health Research

Per the 2019-CTRules, CDSCO requires institutions that intend to conduct biomedical and health research to have an EC that reviews and oversees this type of research study. In addition, CDSCO has also established a separate registration and monitoring system for ECs that review biomedical and health research. See the Scope of Review section for additional information on biomedical and research study requirements.

Ethics Committee Composition

Pursuant to the 2019-CTRules and the G-ICMR, an institutional/independent EC should be multidisciplinary and multi-sectorial, representing a mixed gender and age composition. ECs that review clinical trial applications and those that review biomedical and health research share the same composition criteria including affiliations, qualifications, member specific roles and responsibilities, as well as terms of reference and review procedures.

The 2019-CTRules and the G-ICMR state that an EC should appoint from among its members a chairperson (from outside the institution) and a member secretary (generally from inside the institution). The other members should represent a balance of affiliated and non-affiliated medical/non-medical and scientific/non-scientific persons, including the lay public. Per the 2019-CTRules and the G-ICMR, preferably 50% of the members should not be affiliated with the institution.

As per the 2019-CTRules and the G-ICMR, the composition should include the following:

• Chairperson from outside the institute (Vice Chairperson (optional))
• One (1) to two (2) basic medical scientists (preferably one (1) pharmacologist)
• One (1) to two (2) clinicians from various institutions
• Legal expert(s) or retired judge
• One (1) social scientist/representative of non-governmental voluntary agency
• One (1) philosopher/ethicist/theologian
• One (1) lay person from the community
• Member secretary (Alternative Member secretary optional)
• One (1) member whose primary area of interest/specialization is non-scientific
• At least one (1) member independent of the institution/trial site

Additionally, per the 2019-CTRules, EC members are required to:

• Be familiar with key clinical regulatory requirements as delineated in the 2019-CTRules and the G-ICMR that reference both the Declaration of Helsinki (IND-63) and the most recently updated International Council for Harmonisation’s Guideline for Good Clinical Practice E6(R2) (IND-41)
• Have post-graduate qualifications and experience in their fields if representing basic medical scientists/clinicians
• Represent the specific patient group as much as possible based on the research area requirement

Terms of Reference, Review Procedures, and Meeting Schedule

As delineated in the 2019-CTRules and the G-ICMR, EC members should be made aware of their roles and responsibilities. The terms of reference should also include a statement on terms of appointment including duration and conditions; policy for removal/replacement; resignation procedure; meeting frequency; payment of processing fee to EC for review; honorariums to members and invited experts; maintenance of EC documentation and communication records, etc. Each committee should specify these terms in its own standard operating procedures (SOPs) that should be made available to each member.

In addition, per the 2019-CTRules and the G-ICMR, members should have no conflict of interest, and should voluntarily withdraw from the EC while making a decision on an application if a proposal evokes a conflict of interest. The G-ICMR indicates the term of membership is generally two (2) to three (3) years, and may be extended.

In terms of training, the G-ICMR also specifies each member must:

• Provide a recent signed Curriculum Vitae (CV) and training certificates on human research protection and good clinical practice (GCP) guidelines, if applicable
• Either be trained in human research protection and/or GCP at the time of induction into the EC, or undergo training and submit training certificates within six (6) months of appointment (or as per institutional policy)
• Be willing to undergo training or update their skills/knowledge during their tenure as an EC member

Further, if required, the 2019-CTRules and the G-ICMR, state subject experts could also be invited to offer their views, which must be recorded; however, the experts would not have any voting rights. Only members independent of the trial and the trial sponsor (also known as applicant) should vote/provide opinions in study related matters. In addition, all records must be safely maintained after the completion or termination of the study for at least five (5) years from the date of the trial’s completion or termination (both hard and soft copies).

The G-ICMR specifies that all EC members should review all proposals. Members should be given at least one (1) week to review the proposal and related documents, except in the case of expedited reviews. The Member Secretary should screen the proposals for their completeness and categorize them into three (3) types according to risk level: exemption from review, expedited review, or full committee review. An investigator cannot decide that a protocol falls in the exempted category without an EC review. Per the 2019-CTRules and the G-ICMR, a minimum of five (5) members is required for the quorum.

For detailed EC procedures and information on other administrative processes, see the 2019-CTRules, the G-ICMR, and IND-5. See also IND-27 and IND-28 for the Indian Council of Medical Research (ICMR)’s research conduct policies.

Overview

New National System of Ethics in Research with Human Beings

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

National Research Ethics Authority

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

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

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

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

National Research Ethics Commission (CONEP)

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

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

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

CONEP-Designated Protocol Reviews

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

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

CONEP Review Pathways

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

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

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

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

Role in Clinical Trial Approval Process

National Research Ethics Authority

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

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

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

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

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

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

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

National Research Ethics Commission (CONEP)

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

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

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

Foreign Research

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

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

Multicenter Research

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

See ResNo346 for additional multicenter protocol processing information.

Exemption from Review

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

Overview

The primary scope of information assessed by ethics committees (ECs) relates to maintaining and protecting the rights, safety, and well-being of all research participants, especially those in vulnerable populations, in accordance with the requirements set forth in the 2019-CTRules, the G-ICMR, the G-Children, the Declaration of Helsinki (IND-63), and the International Council for Harmonisation's Guideline for Good Clinical Practice E6(R2) (IND-41). (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these populations).

The 2019-CTRules and the G-ICMR also state that ECs must ensure an independent, timely, and competent review of all ethical aspects of the research protocols. They must act in the interests of the potential research participants and the communities involved by evaluating the possible risks and expected benefits to participants, and they must verify the adequacy of confidentiality and privacy safeguards. Per the G-Children, ECs providing opinions on studies involving children should also include members with pediatric expertise. The expert(s) may be permanent EC members or invited as subject experts to provide advice and be consulted on an ad-hoc basis.

See also the G-AI-BiomedRes for EC review guidelines for biomedical and health research proposals involving artificial intelligence-based tools and technologies.

Role in Clinical Trial Approval Process

As per the 2019-CTRules, the G-ICMR, and IND-31, the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), and a DCGI-registered EC must approve a clinical trial application prior to the sponsor (also known as applicant) initiating the trial, except in the case of non-regulatory academic clinical trials that only require EC approval. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) According to IND-31, the DCGI review and approval process may be conducted in parallel with the EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2019-CTRules, the Hdbk-ClinTrial, and IND-31 specify that an EC must grant a separate approval for each trial site to be used, and the DCGI must be informed of each approval. A trial may only be initiated at each respective site after obtaining an EC approval for that site. The 2019-CTRules and IND-31 further state that if a site does not have an EC, it may obtain approval from another site’s EC provided that it is located within the same city or within a radius of 50 kilometers of the trial site. The DCGI should be notified of the EC’s approval within 15 working days of the approval being granted per the 2019-CTRules. Per the 2019-CTRules and IND-31, the EC of each site should notify the DCGI of its approval and provide a copy within 15 working days of making this decision. Refer to IND-36 for the Indian Council of Medical Research (ICMR)’s EC clinical trials application form.

During a clinical trial, per the 2019-CTRules, an investigator should not implement any deviations from or changes to the trial protocol without agreement by the sponsor and after obtaining the EC’s prior review and documented approval or favorable opinion of the amendment. All protocol amendments should be submitted to the DCGI in writing along with the EC’s approval letter.

The 2019-CTRules further states that the exception to this requirement is when it is necessary to eliminate an immediate hazard to the trial participant or when the changes involved are only logistical or administrative in nature. In this case, the EC as well as the DCGI must be notified immediately of all such exceptions. The DCGI should also be notified of administrative or logistical changes or minor amendments in the protocol within 30 days.

As delineated in the 2019-CTRules, ECs also have a continuing responsibility to monitor approved clinical trials and biomedical and health research studies to ensure ethical compliance throughout the study duration.

For all studies, the G-ICMR indicates that ECs must review and approve any protocol amendments, major deviations, or violations at regular intervals.

There is no stated expiration date for an EC approval in the 2019-CTRules or the G-ICMR. However, per the 2019-CTRules, in the event that an EC revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator as well as to the DCGI.

Per the 2019-CTRules, the EC must also maintain data, record, registers and other documents related to the functioning and review the clinical trial for a period of five (5) years after completion of the study. For detailed EC review procedures and information on other administrative processes, see the 2019-CTRules, the G-ICMR, IND-5, and IND-27. See also IND-36 for the EC clinical trial application form, and IND-52 for other commonly used EC review forms.

The G-ICMR further states that research during humanitarian emergencies and disasters can be reviewed by an EC through an expedited review and scheduled/unscheduled full committee meetings, and this may be decided by the member secretary on a case-by-case basis depending on the urgency and need. If an expedited review is done, full ethical review should follow as soon as possible. The EC should also closely monitor the conduct and outcome of research. See Section 12.5 of the G-ICMR for additional information on EC review requirements during humanitarian emergencies.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Academic Clinical Trials

As defined by the 2019-CTRules, an academic clinical trial is a clinical trial of a drug already approved for a certain claim and initiated by any investigator, academic or research institution for a new indication or new route of administration, or, new dose or new dosage form, where the results of such a trial are intended to be used only for academic or research purposes and not for seeking DCGI approval or regulatory authority approval in any country for marketing or commercial purpose.

The 2019-CTRules and IND-31 specify that an academic clinical trial does not require DCGI approval as long as the following conditions are met:

• The trial is approved by the EC, and
• The data generated is not intended for submission to the DCGI

In addition, per the 2019-CTRules and IND-31, the EC should inform the DCGI about the academic trials it has approved and cases where there could be an overlap between the clinical trial for academic and regulatory purposes. If the DCGI does not comment to the EC within 30 days from receiving EC notification, it should be presumed that DCGI permission is not required. See also IND-6 for additional information on academic trial approval requirements.

IND-25 further explains that a drug import license is not required for EC-approved academic trials that will be using a permitted drug formulation with a new indication, a new route of administration, a new dose, or a new dosage form. See the Manufacturing & Import section for detailed information.

Biomedical and Health Research

According to the 2019-CTRules and the G-ICMR, biomedical and health research is defined as studies that include basic research, applied and operational research, or clinical research designed primarily to increase scientific knowledge about diseases and conditions (physical or socio-behavioral); their detection and cause; and evolving strategies for health promotion, prevention, or the amelioration of disease and rehabilitation.

As discussed in Notice15Sept19 and Chapter IV of the 2019-CTRules, any institution or organization that intends to conduct biomedical and health research involving human participants is required to have an EC to review and oversee the conduct of such research before the study is initiated and throughout its duration. See also IND-28 for ICMR’s biomedical and health research conduct policies, and IND-6 for additional information on the regulation of biomedical and health research under the 2019-CTRules.

The EC must also be registered with the designated authority within the Ministry of Health and Family Welfare (MOHFW)’s Department of Health Research (DHR). Refer to the Oversight of Ethics Committees section for detailed registration requirements.

Multicenter Research

As delineated in the G-ICMR, in a multicenter research study, all of the participating study sites are required to obtain approval from their respective ECs. Each EC may conduct a separate review, or the ECs may decide to designate a main EC, with the others choosing to accept its decision. The study sites also typically follow a common protocol to avoid duplication of effort, wastage of time, and issues arising with communication between committees.

Per the G-ICMR, in the event that sites choose to have separate EC reviews, the following requirements must be met:

• The participating site ECs/Secretariats should establish communication with one another
• If any EC does not grant approval for a study at a site, the reasons must be shared with other ECs and should be considered
• The EC can suggest site-specific protocols and informed consent modifications as per local needs

A separate review may be requested for studies with a higher degree of risk, clinical trials, or intervention studies where conduct may vary depending on the site, or, for any other reason that requires closer review and attention. See the G-ICMR for additional participating site requirements when a primary EC is selected for common EC review.

Per the G-ICMR, when the multicenter research study designates one (1) main EC, the nominated EC members that represent the participating sites may attend the meeting of the elected EC. The designated EC should also be in India and be registered with the relevant authority (either the DCGI or the DHR depending on the type of study). In addition, the decision to conduct a common review is only applicable for ECs in India. In the case of international collaboration for research and approval by a foreign institution, the local participating study sites would be required to obtain approval from a local EC. Refer to the G-ICMR for detailed information on multicenter studies that use the common review practice and involve international collaborations.

The G-ICMR further notes that the local site requirements (e.g., informed consent, research implementation and its monitoring) may be performed by the local EC, which would require good communication and coordination between the researchers and the EC secretariats representing the participating sites.

See the G-MultictrResRev for additional guidelines on streamlining the ethics review process for multicenter biomedical and health research studies conducted by the ICMR or its network of institutions.

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.

As indicated in the G-ICMR, ethics committees (ECs) may charge a reasonable fee to cover the expenses related to optimal functioning to conduct reviews. EC members may also be given reasonable compensation for their time attending EC meetings, and every institution should allocate adequate funds to ensure the smooth functioning of the EC.

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 2019-CTRules and IND-31, all ethics committees (ECs) that review drug clinical trials are required to register with the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), prior to reviewing and approving a clinical trial protocol. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) As delineated in Notice15Sept19 and Chapter IV of the 2019-CTRules, all ECs that review biomedical and health research studies are required to register with the designated authority within the Ministry of Health and Family Welfare (MOHFW)’s Department of Health Research (DHR). According to IND-50, the DHR’s Office for Ethics Committee Registration has been designated as the entity responsible for coordinating and monitoring registrations for ECs overseeing biomedical and health research in India. This office will receive applications for registration of ECs and will review and make decisions on EC registrations/re-registrations.

See also IND-69 for an application submission checklist to re-register ECs. Refer to IND-49 for a list of registered ECs, and IND-48 for a list of re-registered ECs.

Registration, Auditing, and Accreditation

Registration Provisions for Clinical Trial Ethics Committees

As specified in the 2019-CTRules and Notice1Aug18, ECs that intend to review clinical trial research protocols must submit Form CT-01 via the SUGAM portal (IND-59) to register with the DCGI. The DCGI, in turn, will review the application within 45 working days from the date of receipt and, if satisfied with the information provided, grant the EC's registration request via Form CT-02. Per 2022-CTRules-3rdAmdt, provided that no communication has been received from the DCGI within the stated period of 45 working days, the EC registration will be deemed granted by the DCGI, and such registration will be regarded as legally valid for all purposes and the applicant will be authorized to initiate a clinical trial in accordance with these rules. 2022-CTRules-3rdAmdt further states that once the EC has obtained provisional approval from the DCGI per the 2019-CTRules, the committee must also notify CDSCO via Form CT-02A, which will become part of the official record known as the guaranteed registration of the DCGI.

Per the 2019-CTRules and IND-53, the EC registration will remain valid for a period of five (5) years from the date of issue, unless suspended or cancelled sooner. The EC may apply for registration renewal via the IND-59 using Form CT-01 and should include all additional required documentation 90 days prior to the registration’s expiration date. The registration will remain in force until the DCGI passes a new registration order as long as the application is received within the specified 90-day deadline. Following the DCGI’s review of the application and inspection report, if any, and provided that there are no changes to the documentation included in the original application, the EC’s request for registration renewal will be granted within 45 working days from the date of application receipt. See also IND-42 and IND-43 for detailed fee requirements and online payment instructions via IND-59.

The 2019-CTRules also states that if the EC fails to comply with any of the registration conditions, the DCGI may, after giving the EC an opportunity to show cause as to why such an order should not be passed, prepare an order in writing to suspend or cancel the EC registration for such period as deemed necessary. The suspended or cancelled EC can appeal to the DCGI within the period specified in the show cause notice, and, after consideration, the DCGI may respond by taking one (1) or more of the following actions:

• Withdraw the notice
• Issue a warning to the EC describing the deficiency or defect observed during an inspection
• Reject the results of the clinical trial
• Suspend for a specified period or cancel the registration, or
• Debar its members to oversee any future trial for a specified period

The aggrieved EC may file an appeal to the Government of India (Central Government) within 60 working days. The Central Government may subsequently pass an order in response to the appeal within 60 working days from the date of the appeal filing.

The EC must also allow CDSCO officials to enter the committee premises to inspect any records, data, documents, or other materials related to a clinical trial. The EC must provide adequate replies to any queries raised by the inspecting authority in relation to the conduct of the trial as noted in the 2019-CTRules.

Registration Provisions for Biomedical and Health Research Ethics Committees

As explained in Notice15Sept19 and IND-51, ECs planning to review biomedical and health research studies are initially required to register on the DHR’s National Ethics Committee Registry for Biomedical and Health Research (NECRBHR) website (IND-51). The NECRBHR facilitates the receipt and processing of application submissions and assists the DHR’s Office of Ethics Committee Registration. An authorized signatory/responsible person must complete the EC Applicant Registration Form (IND-38) and submit it online on the NECRBHR website (IND-51). Once the NECRBHR verifies the application and approves the account registration, the applicant will receive an email with login instructions to apply electronically via the DHR’s NAITIK portal (IND-54). See IND-66 for a checklist of NECRBHR registration requirements.

Per the 2019-CTRules, the EC must submit an application to the NECRBHR using Form CT-01 along with the required information and documentation specified in Table 1 of the Third Schedule of the 2019-CTRules. Upon receipt of the application, the DHR’s Office of Ethics Committee Registration (designated authority) must grant provisional registration to the EC for a period of two (2) years. Final registration will be granted to the EC on Form CT-03 when the DHR has completed its review of the application and the associated documentation. The final registration will remain valid for a period of five (5) years from the date of its issue, unless suspended or cancelled sooner.

The EC may also apply to request registration renewal using Form CT-01 along with the specified documentation at least 90 days prior to the final registration’s expiration date. The final registration will remain in force until the DHR completes its review of the renewal application provided that the following conditions are met:

• The DHR does not require the EC to provide a new set of documents
• There have been no changes in the submitted documents since the final registration was granted, and
• The EC submits a certificate to the DHR validating that the documents have not changed

Following a review of the registration renewal application and further inquiry to confirm there have been no documentation changes, the DHR will renew the EC’s registration on Form CT-03 within 45 working days from the date of application receipt. The renewed registration will remain valid for five (5) years from the date of its issue, unless suspended or cancelled sooner.

The 2019-CTRules further states that if the EC fails to comply with any of the registration conditions, the DHR may, after giving the EC an opportunity to show cause as to why such an order should not be passed, prepare an order in writing to suspend or cancel the EC registration for such period as deemed appropriate. The suspended or cancelled EC can appeal to the DHR, and after consideration, the DHR may respond by taking one (1) or more of the following actions:

• Issue a warning to the EC describing the deficiency or defect observed, which may adversely affect the rights or well-being of the study participants
• Suspend the EC for a specified period or cancel the registration, or
• Debar its members from overseeing any future biomedical health research for a specified period

The aggrieved EC may file an appeal to the Government of India (Central Government) within 45 working days. In response to the appeal, as deemed necessary, and after giving the EC an opportunity to be heard, the Central Government may subsequently pass an order considered appropriate to the case.

(Note: The registration provisions for biomedical and health research ECs in Notice15Sept19 and IND-51 have not yet been aligned with the 2019-CTRules in terms of explaining the application submission process. The 2019-CTRules does not specify that the application submission process is electronic as is stated in Notice15Sept19 and IND-51. Further, only Notice15Sept19 and IND-51 specify that the DHR’s Office of Ethics Committee Registration is the designated authority. However, the ClinRegs team is regularly monitoring the CDSCO website for new developments and will post the most current sources as they become available.)

Additional Provisions for Clinical Trial and Biomedical and Health Research Ethics Committees

In addition to requiring all ECs to register with the relevant regulatory authority (the DCGI or the DHR), the G-ICMR specifies that ECs should be encouraged to seek recognition, certification, and accreditation from established national and international bodies (e.g., the SIDCER-FERCAP Foundation, the Association for the Accreditation of Human Research Protection Programs (AAHRPP), CDSCO, and the Quality Council of India through National Accreditation Board for Hospitals and Healthcare Providers (NABH), etc.). Although voluntary, the G-ICMR states that these certifications and accreditations should be continually updated to help with quality assurance and quality improvement and ensure that ECs comply with best practices to protect research participants.

Overview

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

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

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

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

Regulatory Submission

Primary Petitions

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

ResNo945 provides the following additional DDCM submission requirements:

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

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

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

Secondary Petitions

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Electronic Filing

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

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

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

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

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

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

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

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

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

Ethics Review Submission

National Research Ethics Authority

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

National Research Ethics Commission (CONEP)

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

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

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

Overview

In accordance with the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, the sponsor (also known as the applicant) is required to submit a clinical trial application to the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), to obtain authorization to conduct a clinical trial in India. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) The investigator must also obtain ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. According to IND-31, the DCGI review and approval process may be conducted in parallel with the EC review for each clinical trial site. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

For specific guidelines regarding gene therapy and stem cell therapy clinical trial submissions, see G-GeneThrpy and G-StemCellRes.

Regulatory Submission

SUGAM Pre-Submission Registration

As explained in IND-42, CDSCO created the SUGAM portal (IND-59) to be used by applicants to apply for no objection certificates (NOCs), licenses, registration certificates, permissions, and approvals. Once submitted, applicants can track their applications, respond to queries, and download CDSCO issued permissions. According to IND-20, importers, Indian agents, foreign enterprises that hold an Indian subsidiary, and corporate users can register on the SUGAM portal (IND-59).

Per IND-42, users are required to complete a registration form requesting access to the SUGAM portal (IND-59) along with uploading the required identification (ID) documentation. IND-42 specifies that the authorized signatory/responsible person in an organization should complete the registration form. After registration is approved, the user is required to submit hard copies of identification (ID), proof of undertaking, and address to the CDSCO office. Registration will be approved by CDSCO only after evaluation of the submitted documents. IND-20 further notes that the email ID provided in the registration form should be an official email ID as all correspondence with CDSCO via the SUGAM portal (IND-59) will be completed using this registered email ID. Additionally, IND-20, the user will receive login credentials on the registered email ID after completion of the verification process from the CDSCO office. For detailed registration instructions, see IND-42 and IND-20.

NSWS Portal Pre-Submission Registration

Per Notice1Jan24, CDSCO launched the National Single Window System (NSWS) portal (IND-3) that will eventually serve as a one-stop shop for all approvals, licenses, registrations, and clearances. IND-24 further explains NSWS portal (IND-3) is a digital platform that is designed to integrate the services provided by various ministries, departments, and states thereby enabling users to identify and apply for regulatory approvals and registrations per their business requirements in a single location. According to IND-14, once the implementation process is completed, various regulatory documents including approvals, applications, and records will be accessible via the NSWS portal (IND-3). At this time, however, per Notice1Jan24 and Notice16Jan24, only a few CDSCO steps and processes (e.g., medical device related registration, manufacturing/import applications, and drug manufacturing/import applications) have been moved to the NSWS portal (IND-3). Per IND-24, while the NSWS portal (IND-3) does not charge a fee for registration, users are required to pay any fees required by CDSCO or any other ministry/department/state to process applications submitted for approval via the NSWS portal (IND-3).

IND-24 indicates that to access the NSWS portal (IND-3) services, users are required to sign up by registering with an email address and mobile phone, and then creating a business profile. As explained in IND-61, to complete the business profile, users are required to have a tax identification number known as a Permanent Account Number (PAN)). According to IND-33, a PAN is issued by the Income Tax Department within the Indian Ministry of Finance. Both domestic and foreign users can apply for a PAN using the appropriate application form.

Per IND-62 and IND-64, the user’s PAN will need to be verified using Digital Signature Certificate (DSC) for the created business profile. The steps involved in this process include adding authorized signatory information, registering the DSC, and verifying the PAN details against the registered DSC. IND-62 and IND-64 also note that users will need to have emBridge software installed on their computers to serve as a connecting link between the NSWS portal (IND-3) and DSC. Please refer to IND-62 and IND-64 for detailed instructions on completing this registration process which is required to apply for approval and registrations. See also IND-4 for a complete list of NSWS portal (IND-3) user guides.

Submissions

As indicated in the Notice15Jan18, all clinical trial application submissions must be submitted electronically via CDSCO’s SUGAM portal (IND-59). Refer to IND-42 for instructions on uploading forms and related documentation via the SUGAM portal (IND-59).

Per IND-7, CDSCO has introduced a new protocol for the submission of regulatory affairs related documents to facilitate the transition from hard copy to soft copy document submission. As explained in Notice12Oct23 and IND-7, effective immediately, CDSCO’s Clinical Research Unit (CRU) Division is requesting that stakeholders submit bulky dossiers, documents, query replies, and similar materials in soft copy format. The soft copies should be submitted in PDF format and ideally less 20 MB on a CD or pen drive to the CRU Division or submitted via email to cru.division@cdsco.nic.in. The files will then be forwarded to the appropriate Division along with the stakeholder’s cover letter.

The DCA-DCR delineates that English should be used for specific documents included in the clinical trial application submission. For the informed consent form and patient information sheet, English and/or the vernacular language of the participant(s) should be used. English should also be used for the package inserts.

In addition, per Notice31Jan24, CDSCO’s Subject Expert Committee (SEC) Division is responsible for conducting meetings to evaluate investigational new drug (IND) proposals. Applicants are requested to submit a copy of their proposal presentation only to the appropriate SEC division via the SUGAM portal (IND-59) after receiving an invitation letter from CDSCO, and well in advance of the scheduled meeting.

Ethics Review Submission

As indicated in the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, India requires all clinical trials of drugs involving human participants to be reviewed by a DCGI-registered EC. Because the submission process at individual institutional ECs will vary, applicants should review and follow their institution’s specific requirements. The G-ICMR also specifies that investigators should submit research proposals as soft or hard copies to the EC Secretariat for review in the prescribed format and required documents as per EC standard operating procedures (SOPs).

Regulatory Authority Requirements

Clinical Drug Development Dossier (DDCM)

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

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

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

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

Specific Clinical Trial Dossier (DEEC)

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

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

Substantial IP Modifications

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

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

Substantial Protocol Amendments

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

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

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

Optimized Analysis Procedure (Reliance) Submissions

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

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

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

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

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

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

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

Ethics Committee Requirements

National Research Ethics Authority

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

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

National Research Ethics Commission (CONEP)

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

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

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

Clinical Protocol

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

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

For complete protocol requirements, refer to OMREC and OSNo001.

Regulatory Authority Requirements

As per the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35, documentation must be submitted to the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), as part of the approval process for investigational new drugs (INDs) will depend upon the type of application, phase of the study, stage in drug development process, and/or objective of the study. Information that may be required is included in the lists below (Note: Each of the items listed below will not necessarily be found in all sources, which provide overlapping and unique elements):

• Form CT-04 (the clinical trial application form including sponsor (also known as applicant) name; sponsor nature/constitution and contact information; clinical trials site contact information and details; contact information for person responsible for compensation payment, if any; correspondence address; new drug/investigational new drug name(s) and details (i.e., therapeutic class, dosage form, composition, and indications); clinical trial phase; protocol number with date; and ethics committee (EC) and investigator names)
• Treasury Challan receipt demonstrating payment of corresponding fee or transaction ID
• Chemical and pharmaceutical information
• Animal pharmacology data
• Animal toxicology data
• Human clinical pharmacology data
• Active ingredient information (for INDs and global clinical trials (GCTs))
• Formulation data (for INDs and GCTs)
• Therapeutic class (for INDs and GCTs)
• Regulatory status in India and in other countries
• Proposed study status in other participating countries and any approvals, withdrawals, discontinuation of approval, etc. (for GCTs)
• Affidavit stating study has not been discontinued in any country (for GCTs)
• Prescribing information
• Testing protocol(s) for quality control testing
• Clinical study protocol
• Dosage form
• Justification and schematic diagram/flow chart proposed study and design (for INDs and GCTs)
• Number of patients globally (for GCTs) and number of patients to be enrolled from India (for INDs and GCTs)
• Details of all sites selected and assessment for suitability of sites and investigators (with contact details)
• EC registration status of the selected sites
• Relevance of study, investigational drug, or any specific study aspects to the health care needs of India
• Innovation vis-à-vis existing therapeutic options
• Unmet medical need in the country (as applicable)
• Any India-specific safety/dosage concerns/investigational tests to be done
• Clinical study reports should be submitted per the International Council for Harmonisation (ICH) Common Technical Document (CTD) (IND-68)
• Protocol safety measures per toxicological studies; early clinical studies, approved product insert for marketed product, and published literature
• Investigator’s Brochure (IB)
• Investigational Medicinal Products Dossier (IMPD) (for (GCTs))
• Affidavit stating the IB information is correct and based on facts (for GCTs)
• Source of bulk drugs (for INDs)
• Treasury Challan with Application for Grant of License to Import New Drug or Investigational New Drug for Clinical Trial or Bioavailability or Bioequivalence Study or for Examination, Test and Analysis (CT-16) (IND-11) (for GCTs)
• Sponsor authorization letter (for GCTs)
• Details of biological specimens to be exported and the online application for export no objection certificate (NOC) for biological samples on the SUGAM portal (IND-59) (for GCTs) (See IND-1 for the application form to request a NOC to export biological samples) (Refer to the Specimens topic for more information on specimen import/export)
• Case Report Form (CRF)
• Informed consent form (ICF) and patient information sheet (See Required Elements section for additional information)
• Investigator(s) undertaking
• EC approvals (if available)
• Clinical study report(s)
• Investigator list in India and site address

See the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35 for detailed DCGI application submission requirements. See also IND-22 for details on the IND-59 approval process for GCTs and IND-31 for clinical trial FAQs. (Note: The Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Refer to the 2019-CTRules and IND-31 to obtain detailed submission requirements for applications to conduct a clinical trial using an already approved new drug with a new indication, a new dosage form/new route of administration, a modified release dosage form, or a new drug with an additional strength.

Ethics Committee Requirements

Each institutional EC has its own application form and clearance requirements, which can differ significantly regarding the number of copies to be supplied and application format requirements. However, per the G-ICMR, the requirements listed below are basically consistent and shared by all of the Indian ECs:

• Cover letter to the Member Secretary
• Type of review requested
• Application form for initial review (IND-39)
• Informed consent document (in English and the local language(s)) including translation and back translation certificates, if applicable
• Case record form/questionnaire
• Recruitment procedures (e.g., advertisement, notices) if applicable
• Patient instruction card, diary, etc., if applicable
• IB (as applicable for drugs, biological, or device trials)
• Details of funding agency/sponsor and fund allocation, if applicable
• Investigators’ Curriculum Vitaes (CVs)
• Conflict of interest statement, if applicable
• Good Clinical Practice (GCP) training certificate for investigators (preferably within last five (5) years)
• Any other research ethics/other training evidence, if applicable as per EC standard operating procedures (SOPs)
• List of ongoing research studies undertaken by the principal investigator, if applicable
• Investigator’s undertaking statement with all participating investigator signatures
• Regulatory permissions (as applicable)
• Relevant administrative approvals (such as Health Ministry’s Screening Committee (HMSC) approval for international trials)
• Institutional Committee for Stem Cell Research (IC-SCR) Registration (IND-72), if applicable
• Memorandum of Understanding (MoU) in case of studies involving collaboration with other institutions, if applicable
• Clinical trial agreement between the sponsors, investigator, and the head of the institution(s), if applicable
• Clinical trial registration documentation (preferable)
• Insurance policy (it is preferable to have the policy as well as the insurance certificate) for study participants indicating conditions of coverage, date of commencement and date of expiry of coverage of risk (if applicable)
• Indemnity policy, clearly indicating the conditions of coverage, commencement date, and expiry date of risk coverage (if applicable)
• Any additional document(s), as required by EC (such as other EC clearances for multicentric studies)
• Protocol

Furthermore, the ICMR has prepared a generic application for initial review (IND-39) that may be used by the EC. The form is also included in the bulleted list above.

Clinical Protocol

As delineated in the 2019-CTRules, the Hdbk-ClinTrial, and the G-ICMR, the clinical study protocol should include the following elements:

• Title page
• Table of contents
• Brief summary (See G-ICMR)
• Study rationale
• Study objective
• Study design and methodology
• Study population
• Justification of inclusion/exclusion of vulnerable populations (See G-ICMR)
• Participant eligibility and recruitment procedures
• Study assessments
• Study conduct stating the types of activities that would be included (e.g., medical history, type of physical examination, etc.)
• Study treatment
• Ethical consideration
• Study monitoring and supervision
• Investigational product management (See Investigational Products topic for detailed coverage of this subject)
• Data analysis
• Undertaking by the Investigator statement
• Appendices

The G-ICMR also mentions the following requirements:

• Study duration
• Justification for placebo, benefit-risk assessment, plans to withdraw; if standard therapies are to be withheld, justification for the same
• Informed consent procedure and sample of the patient/participant information sheet and informed consent forms including audiovisual recording, if applicable, and informed consent for stored samples
• Plan to maintain the privacy and confidentiality of the study participants
• Adverse events/adverse drug reactions
• For research involving more than minimal risk, an account of management of risk or injury
• Proposed compensation, reimbursement of incidental expenses and management of research related injury/illness during and after research period
• Provision of ancillary care for unrelated illness during the duration of research
• Account of storage and maintenance of all data collected during the trial
• Plans for publication of results while maintaining confidentiality of participants’ personal information/identity

For detailed information on these elements, see the 2019-CTRules, the Hdbk-ClinTrial, and the G-ICMR.

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

Based on the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, the review and approval of a clinical trial application by the Drugs Controller General of India (DCGI), head of the Central Drugs Standard Control Organization (CDSCO), is dependent upon obtaining ethics committee (EC) approval from a DCGI-registered EC prior to initiating a study. (Note: The DCGI is commonly referred to as the Central Licensing Authority in the Indian regulations.) According to IND-31, the DCGI review and approval process may be conducted at the same time as the EC review for each clinical trial site, except in the case of non-regulatory academic clinical trials that only require EC approval. However, per the 2019-CTRules and the Hdbk-ClinTrial, CDSCO must confirm the EC approvals for each participating site have been obtained per the protocol prior to approving the initiation of the study. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

Regulatory Authority Approval

As specified in the 2019-CTRules and IND-31, upon receipt of a clinical trial application , the DCGI has 90 calendar days to evaluate the application for a new drug or an investigational new drug; 90 calendar days to evaluate a new drug already approved outside India; and 30 days to evaluate a drug discovered, researched, and manufactured in India. Per the Hdbk-ClinTrial, upon receipt of an application, a CDSCO official conducts the initial administrative review. If the application is deemed complete, within four (4) weeks following receipt, the official forwards the application along with a summary of their evaluation and a statement referring the proposal to a Subject Expert Committee (SEC) for further technical review.

The 2019-CTRules further notes that the DCGI may, when required, constitute one (1) or more of these expert committees or group of experts with the specialization in relevant fields to evaluate scientific and technical drug-related issues. The committee/group may submit its recommendations within 60 days from the date of the request. See the Scope of Assessment section for more information on SEC composition and review processes.

Once the SEC has completed its review, the Hdbk-ClinTrial indicates that the committee sends its comments via email to CDSCO. CDSCO will then compile any written SEC comments requiring sponsor (also known as applicant) clarification or modification and send this feedback to the sponsor within one (1) week of receipt. The applicant must submit a written reply to CDSCO within four (4) weeks of receiving the comments, which will, in turn, be sent to the SEC for review.

Following receipt of the sponsor’s response, the DCGI (CDSCO) will issue a final decision by official communication (permission, rejection, or resubmission) to the Technical or Apex Committee within 15 days. In the case of a sponsor’s request for reconsideration, CDSCO will review the resubmitted application and send it to the SEC again or to the Technical Committee per the sponsor’s request. Following the SEC’s review, the DCGI (CDSCO) will send a final decision to the Technical or Apex Committee within 15 days. If CDSCO rejects the reconsideration request, the agency will send a letter to the sponsor to communicate this decision. Refer to the Hdbk-ClinTrial for additional timeline information.

See also IND-22 for details on the SUGAM portal (IND-59) approval process for global clinical trials, and IND-46 for additional information on conducting clinical trials in India.

Per the 2022-CTRules-3rdAmdt, which amends the 2019-CTRules, provided that no communication has been received from the DCGI within the stated period of 90 working days, permission to conduct all new drug or investigational new drug clinical trials as well as clinical trials for new drugs already approved outside India will be deemed granted by the DCGI. This permission will be regarded as legally valid for all purposes and the applicant will be authorized to initiate a clinical trial in accordance with these rules. Similarly, per the 2019-CTRules and IND-31, if the DCGI does not respond within 30 days to applications for drugs developed in India, the sponsor may conclude that permission to conduct the trial has been granted. Refer to the Scope of Assessment section for information on obtaining a waiver for an already approved drug. See also the Manufacturing & Import section for detailed information on import requirements for new drugs already approved outside of India.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

(See also the Submission Process and Submission Content sections for detailed submission requirements.)

Ethics Committee Approval

As per IND-9, the EC review and approval process, which occurs at the same time as the DCGI review and approval, generally takes from four (4) to six (6) weeks. Many study sites also have scientific review committees (SRCs) review the scientific justification of the study. Once the SRC approves the study, it is submitted to the EC for its review and approval.

The G-ICMR indicates that EC members should be given enough time (at least one (1) week) to review the proposal and related documents, except in the case of expedited review. While all EC members should review all submitted proposals, each EC may adopt different procedures for protocol review per their standard operating procedures.

Overview

New National Ethics System of Ethics in Research with Human Beings

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

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

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

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

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

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

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

Clinical Trial Agreement

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

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

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

Clinical Trial Registration

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

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

Overview

As set forth in the 2019-CTRules, the Hdbk-ClinTrial, the G-ICMR, and IND-31, a clinical trial can only commence in India after the sponsor (also known as applicant) receives permission from the Drugs Controller General of India (DCGI) and approval from the respective ethics committees (ECs). The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations. According to the 2019-CTRules and IND-31, non-regulatory clinical trials intended for academic/research purposes only require institutional EC approval. (See the Scope of Review section for additional details). There is no waiting period required following the sponsor’s receipt of these approvals. (Note: the Hdbk-ClinTrial has not yet been updated to fully align with the 2019-CTRules.)

The 2022-CTRules-3rdAmdt, which amends the 2019-CTRules, further indicates that once the sponsor obtains approval from the DCGI for a new drug, an investigational new drug, or a new drug already approved outside India, the sponsor must notify CDSCO via Form CT-06A prior to initiating the clinical trial. The DCGI will then record the information provided on the form and it will become part of the official record known as the automatic approval of the DCGI.

In addition, per the 2019-CTRules and IND-31, the sponsor is required to obtain approval from the DCGI to manufacture or import investigational products (IPs) and to obtain an import license for the shipment of IPs to be used in the trial. (See the Manufacturing & Import section for additional information.)

As explained in the 2019-CTRules and IND-31, the EC should notify the DCGI about the academic trials it has approved and about cases where there could be an overlap between a clinical trial for academic and regulatory purposes. If the DCGI does not provide comments to the EC within 30 days from receiving EC notification, then it should be presumed that DCGI permission is not required.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Clinical Trial Agreement

According to the 2019-CTRules, the sponsor must have an agreement with the investigator, which is to be provided to the EC. Furthermore, the investigator must sign an undertaking to conduct the trial in accordance with the protocol, good clinical practice guidelines, and all applicable requirements, among other things. For more details, see Table 4 (Third Schedule) in the 2019-CTRules.

Clinical Trial Registration

Per the 2019-CTRules, the G-ICMR, and IND-31, it is mandatory for all sponsors to register their clinical trials, including academic trials, with the Indian Council of Medical Research (ICMR)’s Clinical Trials Registry - India (CTRI) (IND-57) before initiating a study. Refer to the Scope of Review and Submission Process sections for further information on academic trials.

According to IND-56, registrants are advised to factor in a minimum of 10 to 15 working days for trial review, verification, and validation and the submission must indicate “Not Yet Recruiting” for the trial’s status. A REF number is issued to those registrants who have successfully submitted a trial to IND-57.

In addition, per IND-10, the ICMR has agreed to adopt the United Nation’s recommendations to register and publicly disclose results from all funded or supported clinical trials. The ICMR, along with other participating healthcare bodies, plans to develop and implement policies that require all trials they fund, co-fund, sponsor, or support to be registered in a publicly available registry. All study results will also be released within specified timeframes on the registry or through scientific journal publications.

See the 2019-CTRules, the Hdbk-ClinTrial, IND-32, and IND-35 for detailed DCGI application submission requirements.

Safety Reporting Definitions

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

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

Safety Reporting Requirements

Investigator Responsibilities

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

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

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

Sponsor Responsibilities

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

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

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

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

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

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

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

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

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

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

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

Ethics Committee Responsibilities

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

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

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

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

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

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

Other Safety Reports

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

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

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

Form Completion & Delivery Requirements

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

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

Safety Reporting Definitions

In accordance with the 2019-CTRules, the G-ICMR, and IND-42, the following definitions provide a basis for a common understanding of India’s safety reporting requirements:

• Adverse Event (AE) – Any untoward medical occurrence (including a symptom/disease or an abnormal laboratory finding) during treatment with a pharmaceutical product in a patient or a human participant not necessarily related to the treatment
• Adverse Drug Reaction (ADR) – a noxious and unintended response at doses normally used or tested in humans (in cases of approved pharmaceutical products); a noxious and unintended response at any dose(s) (in cases of new unregistered pharmaceutical products); an untoward medical occurrence seemingly caused by overdosing, abuse/dependence and interactions with other medicinal products (in clinical trials)
• Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – an AE or ADR that is associated with death, in-patient hospitalization (in case the study was being conducted on outpatients), prolongation of hospitalization (in case the study was being conducted on in-patients), persistent or significant disability or incapacity, a congenital anomaly or birth defect, or is otherwise life threatening. Per IND-42, Important Medical Events may be considered SAEs when they may jeopardize the patient or subject and may require medical or surgical intervention to prevent one (1) of the outcomes listed in this definition
• Unexpected Adverse Drug Reaction – an ADR, the nature or severity of which is not described in the informed consent/information sheet or the applicable product information, such as an investigator’s brochure (IB) for the unapproved investigational product (IP) or package insert/summary of product characteristics for an approved product (G-ICMR)

Safety Reporting Requirements

Per the 2019-CTRules, the sponsor (also known as applicant) and the investigator must forward any SAE/SADR report, after due analysis, within 14 days of the occurrence to the Drugs Controller General of India (DCGI), the ethics committee (EC) Chairman, and the head of the institution where the trial is being conducted. (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

In the event of an SAE/SADR resulting in death, per the 2019-CTRules, the sponsor or the representative and the investigator must forward the SAE/SADR reports to the DCGI within 14 days of knowledge of this occurrence. The 2019-CTRules and IND-42 also indicate that the EC is also required to forward its report along with its opinion on financial compensation, if any, to be paid by the sponsor or the representative, to the DCGI within 30 days of the incident.

See Table 5 of the 2019-CTRules for details on the data elements required for reporting SAEs/SADRs that occur during a clinical trial.

See the Insurance & Compensation section for additional information on sponsor compensation requirements.

Investigator Responsibilities

As indicated in the 2019-CTRules, the G-ICMR, and IND-42, the investigator must report all SAEs/SADRs to the DCGI, the sponsor or the representative, and the EC, within 24 hours of occurrence. Per the 2019-CTRules, in the event that the investigator fails to report any SAE/SADR within the stipulated period, the investigator is then required to provide reasons for the delay to the DCGI along with the SAE/SADR report for the DCGI’s approval.

In addition, per the G-ICMR, the investigator must submit a report to the DCGI explaining how the SAE/SADR was related to the research within 14 days. According to the 2019-CTRules, the investigator must also promptly report to the EC all changes in the clinical trial activities and all unanticipated problems involving risks to human research participants or others.

Form Completion & Delivery Requirements

As per Notice25Feb21, the investigator, the sponsor or the representative, and the EC must report all SAEs electronically via the SUGAM portal (IND-59). However, follow-up reports pertaining to SAE reports submitted prior to March 14, 2021, will continue to be accepted in paper form. Refer to IND-59 for the SUGAM user manual and video tutorials. See also IND-42 for instructions on how to submit SAE reports (referred to as Due Analysis Reports) via IND-59.

The G-ICMR further states that the investigator may report SAEs/SADRs to the EC through email or fax communication (including on non-working days). Refer to IND-37 for the Indian Council of Medical Research (ICMR)'s EC Serious Adverse Event Reporting Format (Clinical Trials).

Interim and Annual Progress Reports

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

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

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

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

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

Final Report

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

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

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

Other Reporting Requirements

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

Interim and Annual Progress Reports

As described in the 2019-CTRules and IND-31, the Drugs Controller General of India (DCGI), who heads the Central Drugs Standard Control Organization (CDSCO), requires the sponsor (also known as applicant) to submit a six (6)-month status report for each clinical trial electronically via the CDSCO’s SUGAM portal (IND-59). The report should clarify whether the trial is ongoing, completed, or terminated. In the case of termination, detailed reasons for such termination must be communicated to the DCGI within 30 working days of the termination. In addition, per the 2019-CTRules, an ethics committee (EC) may periodically request study progress reports from the investigators.

As delineated in the 2019-CTRules, sponsors are also required to submit an annual status report for the clinical trial to the DCGI.

The 2019-CTRules further specifies that in cases where trials have been prematurely discontinued for any reason, including a lack of commercial interest in pursuing the new drug application (NDA), the sponsor should submit a summary report within three (3) months. The summary report should provide a brief description of the study, the number of participants exposed to the drug, dose/duration of exposure, details of adverse drug reactions, if any, and the reason for the study’s discontinuation or non-pursuit of the NDA.

See IND-35 for a Checklist of Notification for Annual Status Report documentation requirements to be included in a global clinical trial application.

Final Report

The final report should comply with the format and content guidelines listed in the 2019-CTRules as follows:

• Title page
• Study synopsis (1 to 2 pages)
• List of abbreviations and definitions
• Table of contents
• EC approval letter(s)
• Study team introduction
• Study objective
• Investigational plan
• Trial participants
• Efficacy evaluation
• Safety evaluation
• Discussion and overall conclusion
• List of references
• Appendices

See the 2019-CTRules for more detailed information on preparing the final report.

See IND-35 for a checklist of documentation requirements to be included in a global clinical trial application pertaining to end of clinical trial notification.

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

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

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

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

As per the 2019-CTRules and the G-ICMR, a sponsor (also known as applicant) is defined as an individual, a company, or an institution that takes responsibility for the initiation, management, or financing of a clinical study. The G-ICMR further states that an investigator who independently initiates and takes full responsibility for a trial automatically assumes the role of a sponsor. The 2019-CTRules also indicates that the sponsor may appoint a contract research organization (CRO).

Overview

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

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

Foreign Sponsor Responsibilities

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

Data Safety and Monitoring Board

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

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

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

Multicenter Studies

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

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

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

Overview

As stated in the 2019-CTRules, all investigators must possess appropriate qualifications, training, and experience, and should conduct the trials in compliance with Good Clinical Practices (GCPs) and Good Laboratory Practices (GLPs). (See GCLP for the G-ICMR for Good Clinical Laboratory Practices (GCLP), IND-31 for additional laboratory requirement information, and IND-76 for international GCLP guidelines. Investigators should also have access to investigational and treatment facilities as relevant to the protocol.

Per the 2019-CTRules, prior to entering into an agreement with the investigator(s)/institution(s) to conduct a study, the sponsor (also known as applicant) should provide the involved parties with the protocol and an up-to-date investigator’s brochure and allow them sufficient time to review this documentation. The sponsor must also define and allocate all study-related duties and responsibilities to the respective identified person(s) and organization(s) prior to initiating the study.

In addition, per Notice2Dec19, the Central Drugs Standard Control Organization (CDSCO) is preparing a comprehensive database of clinical trial sites and investigators involved in the conduct of global clinical trials in different therapeutic categories by collecting information from various sources. The first phase includes an Excel spreadsheet of sites and investigators involved in global clinical trials (IND-26).

See also IND-28 for the Indian Council of Medical Research (ICMR)’s research conduct policies.

Foreign Sponsor Responsibilities

No information is currently available on foreign sponsor responsibilities.

Data and Safety Monitoring Board

While there are no general requirements for establishing a Data Safety Monitoring Board (DSMB), the G-Children recommends that a DSMB be strongly considered for research involving children in emergency situations.

Multicenter Studies

As delineated in the G-ICMR, in the case of multicenter research studies, all of the participating study sites are required to obtain approval from their respective ethics committees (ECs), which includes the option of each site choosing to accept the review/approval of a primary EC. The study sites also typically follow a common protocol to avoid duplication of effort, wastage of time, and communication issues. See the G-ICMR for additional participating site requirements when a primary EC is selected for common EC review. Also, see the Scope of Review section for additional details.

Further, per the G-ICMR, if a multicenter trial is going to be conducted, the sponsor may organize a coordinating committee or select coordinating investigators. The sponsor must also conduct training for investigators in ethics, GCPs, standard operating procedures (SOPs), and study protocols.

Insurance

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

Compensation

Injury or Death

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

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

Trial Participation

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

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

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

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

Post-Trial Access

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

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

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

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

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

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

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

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

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

Insurance

The G-ICMR specifies that the sponsor (also known as applicant) should provide insurance coverage or a provision in the budget for possible compensation for trial-related injuries. The G-ICMR also states that it is preferable to have the insurance certificate and the policy for study participants. Further, the policy should explain the conditions of coverage, date of commencement, and expiration date for risk coverage (if applicable). In addition, institutional mechanisms must be established to allow for insurance coverage of trial-related or unrelated illnesses (ancillary care).

The 2019-CTRules states that the ethics committee (EC) also requires a copy of the insurance policy or details regarding compensation for participation and for serious adverse events (SAEs) occurring during the study as part of its submission review process.

With regard to indemnity coverage, the G-ICMR states that an indemnity policy must be included in the documentation for EC review. The policy should clearly indicate the conditions of coverage, date of commencement, and coverage expiration date, if applicable.

Compensation

Injury or Death

In accordance with the 2019-CTRules and the G-ICMR, the sponsor is responsible for providing compensation to research participants and/or their legal heir(s) in the event of trial-related injuries, permanent disability, or death. Per the G-ICMR, in the event the investigator/institution becomes the sponsor in a clinical trial, it is the host institution’s responsibility to provide compensation for research-related injury or harm as determined by the ethics committee (EC).

The 2019-CTRules further notes that the sponsor is responsible for compensating the research participant and/or the legal heir(s) if the trial-related injury, death, or permanent disability to a participant is specifically related to any of the following reasons:

• Adverse effects of an investigational product (IP)
• Any trial procedures involved in the study
• A violation of the approved protocol, scientific misconduct, or negligence by the sponsor, the representative, or the investigator
• Failure of the IP to provide the intended therapeutic effect where, the standard care, though available, was not provided to the participant per the protocol
• Not providing the required standard care, though available to the participant per the protocol in the placebo-controlled trial
• Adverse effects due to concomitant medication excluding standard care, necessitated as part of the approved protocol
• Adverse effect on the child in-utero due to a parent’s participation in a trial
• Any clinical trial procedures involved in the study leading to a serious adverse event (SAE/serious adverse drug reaction (SADR)

Per the 2019-CTRules and the G-ICMR, the sponsor must also ensure that participants who suffer any trial-related injuries be provided with free medical treatment for such injuries as long as required per the opinion of the investigator (and the EC per the G-ICMR), or until such time it is established that the injury is not related to the clinical trial, whichever is earlier. Per the 2019-CTRules, if the sponsor or the representative fails to provide medical management, the Drugs Controller General of India (DCGI), after a hearing, must issue a written order to suspend or cancel the study or restrict the sponsor, including the representative, from conducting any further clinical trials or taking any other action for such period deemed appropriate for this case. (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

In the case of a trial-related injury, the 2019-CTRules and IND-31 state that the sponsor is required to provide complete medical management and compensation to the participant within 30 days of receiving an order from the DCGI. In the event of permanent injury or death, the sponsor is required to provide compensation to the participant or to the legal representative/guardian within 30 days of receiving the DCGI’s order. According to IND-31, compensation and medical management requirements are also applicable in the case of injury or death occurring during an academic trial.

The 2019-CTRules explains that in the case of an SAE resulting in death, the DCGI must constitute an independent expert committee to review the incident and make its recommendations to the DCGI for the cause of death and to provide a quantum of compensation. The sponsor or the representative and the investigator must forward their reports, after due analysis, to the DCGI and the head of the institution where the trial was conducted within 14 days of the occurrence. The EC must forward its report along with its opinion on financial compensation, if any, to be paid by the sponsor or the representative within 30 days of receiving the investigator’s report. The DCGI, in turn, must forward the sponsor, investigator, and EC reports to the expert committee chairperson. Following its review, the expert committee must make its recommendations to the DCGI as to the cause of the SAE resulting in death and the quantum of compensation within 60 days from receiving the DCGI’s submission. The DCGI must then consider the expert committee’s recommendations and issue an order within 90 days to the sponsor or the representative specifying the quantum of compensation required to be paid within 30 days of receiving the order.

In the case of an SAE/SADR resulting in permanent disability or any injury other than death, the 2019-CTRules indicates that the sponsor or the representative and the investigator must forward their reports, after due analysis, to the DCGI, the EC chairperson, and the head of the institution where the trial has been conducted within 14 days of the occurrence. The EC, after due analysis, must forward its report along with its opinion on financial compensation, if any, to the DCGI within 30 days of the event occurrence. The DCGI, in turn, must determine the cause of the injury and issue an order, with the option to constitute an independent expert committee, within 60 days of receipt of the report. The DCGI must issue an order within 90 days of receiving the report indicating the quantum of compensation to be paid by the sponsor or the representative within 30 days of receipt of this order.

In the case of an injury not being permanent in nature, per the 2019-CTRules, compensation should be commensurate with the participant’s loss of wages.

Per the 2019-CTRules, in the event that a sponsor or the representative fails to provide compensation to a research participant for trial-related injuries, or to the legal heir(s) in case of death, the DCGI must, after giving an opportunity to show cause why such an order should not be passed by a written order, suspend or cancel the clinical trial, or restrict the sponsor or the representative from conducting any further clinical trials in India or taking any other action deemed fit given the circumstances.

See the 2019-CTRules and the G-ICMR for detailed information on terms of compensation payment.

Trial Participation

The G-ICMR explains that participants may also be compensated for their time and other expenses (e.g., loss of wages, food supplies, and travel). The EC should approve all payments, reimbursement, and medical services provided. Per the G-ICMR, participants should not be required to pay for any expenses incurred beyond routine clinical care and which are research related including patient work-ups, or interventions associated with treatment. If there are provisions, participants may receive additional medical services at no further cost.

Post-Trial Access

The 2019-CTRules and IND-31 explain that the investigator may recommend the sponsor provide post-trial access to the investigational product (IP) free of cost to the participant for such period as deemed necessary by the investigator and the EC. The sponsor must obtain DCGI approval to initiate this plan. The investigator’s recommendation will be based on the following conditions:

• If the trial is being conducted for an indication for which no alternative therapy is available, and the IP has been determined to be beneficial
• The participant or the legal representative/guardian has consented in writing to use the post-trial IP, and has certified and declared in writing, along with the investigator, that the sponsor must have no liability for post-trial use of the IP

See also IND-6 for additional information on post-trial access to IPs under the 2019-CTRules.

Additionally, per the G-ICMR, the benefits accruing from research should be made accessible to individuals, communities and populations whenever relevant. The EC should consider the need for an a priori agreement between the researchers and sponsors regarding the following:

• Efforts should be made to communicate the findings of the research study to the individuals/communities wherever relevant
• The research team should make plans wherever applicable for post-research access and sharing of academic or intervention benefits with the participants, including those in the control group
• Post-research access arrangements or other care must be described in the study protocol so that the EC may consider such arrangements during its review

G-ICMR further states that if an investigational drug is to be given to a participant post-trial, appropriate regulatory approvals should be in place. In studies with restricted scope, such as student projects, post study benefit to the participants may not be feasible, but conscious efforts should be made by the institution to take steps to continue to support and give better care to the participants.

Quality Assurance/Quality Control

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

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

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

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

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

Monitoring Requirements

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

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

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

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

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

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

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

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

Premature Study Termination/Suspension

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

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

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

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

Quality Assurance/Quality Control

In accordance with the 2019-CTRules and the G-ICMR, the sponsor (also known as applicant) 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, Good Clinical Practices (GCPs), and all applicable laws and regulations.

Monitoring Requirements

As per the 2019-CTRules, the sponsor must permit clinical trial site inspections by the Drugs Controller General of India (DCGI)-authorized officers. The officers may enter the premises and clinical trial site with or without prior notice to inspect, search, or seize any record, statistical result, document, investigational drug, and other related material. The sponsor must also reply to inquiries raised by the inspecting authority in relation to the conduct of the trial. (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

In addition, as part of its QA system, the 2019-CTRules notes that investigator(s) may provide periodic study progress reports (PSUR), or regulatory officials or sponsor-designated authorized representatives may provide monitoring and internal audit reports to the ethics committee (EC) to support its recurring clinical trial reviews. An audit certificate may be issued, if available.

Furthermore, the 2019-CTRules requires the investigator to sign an undertaking indicating agreement to maintain adequate and accurate records and to make those records available for audit or inspection by the sponsor, the EC, the Central Licensing Authority, or their authorized representatives, in accordance with regulatory provisions and GCP guidelines. The investigator must agree to fully cooperate with any study-related audit conducted by regulatory officials or authorized representatives of the sponsor.

See IND-35 for a checklist of PSUR documentation requirements to be included in a global clinical trial application, and IND-34 for the DCGI’s GCP Inspection Checklist.

Premature Study Termination/Suspension

As delineated in the 2019-CTRules, when the sponsor fails to comply with any provisions of the DCA-DCR and the 2019-CTRules, the DCGI may, after giving an opportunity to show cause and after affording an opportunity of being heard, by an order in writing, implement one (1) or more of the following actions:

• Issue a warning in writing describing the deficiency or defect observed during inspection or otherwise which may affect adversely the right or well-being of a trial participant or the validity of clinical trial conducted
• Reject the results of the clinical trial
• Suspend for such period as considered appropriate or cancel the permission granted in Form CT-06 or in Form CT-4A
• Debar the investigator or the sponsor, including the representatives, from conducting any clinical trial in the future for such period as considered appropriate by the DCGI

The sponsor or the representative may appeal the DCGI’s decision within 60 working days of receipt of the order.

Further, per the 2019-CTRules, in case of studies prematurely discontinued for any reason, including lack of commercial interest in pursuing the new drug application, the sponsor should submit a summary report within three (3) months. The summary report should provide a brief description of the study, the number of patients exposed to the drug, dose and duration of exposure, details of adverse drug reactions, if any, and the reason for discontinuation of the study or non-pursuit of the new drug application.

The 2019-CTRules also indicates that in case of termination of any clinical trial the detailed reasons for such termination must be communicated to the DCGI within 30 working days of such termination.

See IND-35 for a checklist of premature study termination documentation requirements to be included in a global clinical trial application.

Electronic Data Processing System

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

Records Management

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

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

Electronic Data Processing System

No information is currently available on electronic data processing systems.

Records Management

Per the 2019-CTRules, the sponsor (known as applicant) must keep a record of new drugs manufactured and persons to whom the drugs have been supplied for clinical trial or bioavailability and bioequivalence study or for examination, testing, and analysis. In addition, the 2019-CTRules indicates that the licensed sponsor must maintain records of any imported new drug or substance that indicates the quantity of drug imported, used, and disposed of in any manner including related documentation.

See the Scope of Review section for information on ethics committee management of clinical trial related records.

Responsible Parties

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

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

Data Protection

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data

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

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

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

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

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

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

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

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

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

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

Consent for Processing Personal Data of Children/Adolescents

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

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

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

Responsible Parties

For the purposes of data protection regulation in India, the ITAct, the ITActAmend, and the IT-SPDIRules delineate responsibilities of the “body corporate.” The body corporate as defined by the ITAct, the ITActAmend, and the IT-SPDIRules refers to any company including a firm, sole proprietorship, or other association of individuals engaged in commercial or professional activities. The IT-SPDIRules further explains that the body corporate or any person on its behalf is the entity responsible for collecting, receiving, possessing, storing, dealing with, or handling personal information, including sensitive personal data and information. (Note: In ClinRegs, the “body corporate” is referred to as “sponsor,” but the requirements may apply to other parties as well).

Data Protection

Data protection in India is currently regulated by the ITAct, the ITActAmend, and the IT-SPDIRules. Per the IT-SPDIRules, the sponsor (or the “body corporate”) must provide a privacy policy for the handling of or dealing with this personal information including sensitive personal data or information. The IT-SPDIRules defines sensitive personal data or information as information relating to password(s); financial information; physical, physiological, and mental health condition(s); sexual orientation; medical records and history; and biometric information. The sponsor must ensure that this policy is available for view by the information providers under a lawful contract. The policy must be published on the sponsor’s or its representative’s website and provide the following:

• Clear and easily accessible statements of its practices and policies
• The type of personal information including sensitive personal data or information collected
• The purpose of collection and usage of such information
• Disclosure of information including sensitive personal data or information
• Reasonable security practices and procedures

Please refer to the IT-SPDIRules for detailed requirements on implementing security practices and procedures and collecting, disclosing, and transferring sensitive personal data or information.

See also IND-65 for more detailed information on India’s data protection requirements.

Pursuant to the G-LabValidTest, laboratory validation testing is used to ensure that laboratory test data and results are accurate, consistent, and precise, and may include tests that are conducted using residual, archived, unlinked, and anonymous biological samples such as blood, urine, tissue, cells, saliva, DNA, etc. The G-LabValidTest indicates that if the biological samples are linked to different types of personal identifiers (name, address, etc.) or with health-related data (chronic illnesses, prior hospital stays), and other types of potentially sensitive data (travel history, family history), there is a risk for breach of confidentiality and such samples are not recommended for laboratory validation testing without ethics committee (EC) approval. The investigator undertaking laboratory validation testing must also keep the EC informed regarding use of leftover, archived, or anonymous samples. The laboratories involved in the validation of tests/methods, may be exempted from ethical approval when using leftover archived and anonymized samples.

See also the G-AI-BiomedRes for data privacy and confidentiality guidelines in biomedical and health research involving artificial intelligence-based tools and technologies.

Additionally, the Digital Personal Data Protection Act, 2023 was enacted on August 11, 2023, with an effective date to be determined by the Indian Government. The ClinRegs team will update the Personal Data Protection section when more information becomes available.

Consent for Processing Personal Data

As set forth in the IT-SPDIRules, the body corporate or its representative must obtain consent in writing through letter, fax, or email from the provider of the sensitive personal data or information regarding the purpose of usage before collection of such information. The IT-SPDIRules further states that while collecting information directly from the information provider, reasonable steps must be taken to ensure that the information provider receives details regarding the following:

• The fact that the information is being collected
• The purpose for which the information is being collected
• The intended recipients of the information; and
• The name and address of the agency that is collecting the information, and the agency that will retain the information

Per the IT-SPDIRules, the body corporate or its representative, must provide an option to the information provider to withhold the requested data or information prior to the collection of information including sensitive personal data or information. The information provider must, at any time, also have the option to withdraw consent given earlier to the sponsor or the sponsor’s representative. This withdrawal of consent must be sent in writing.

Obtaining Consent

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

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

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

Re-Consent

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

Language Requirements

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

Documenting Consent

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

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

Waiver of Consent

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

Obtaining Consent

In all Indian clinical trials, a freely given, written informed consent is required to be obtained from each participant to comply with the requirements set forth in the 2019-CTRules, the G-ICMR, and the G-Children.

As per the 2019-CTRules and the G-ICMR, prior to beginning a clinical trial, the investigator is required to obtain ethics committee (EC) approval for the informed consent form (ICF) and the patient information sheet. This documentation must also be supplied to the Drugs Controller General of India (DCGI), prior to the trial’s initiation. The ICF and patient information sheet are ultimately integrated into one (1) document referred to as the ICF. (See the Required Elements section for details on what should be included in the form.) (Note: The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.)

The 2019-CTRules, the G-ICMR, and the G-Children specify that investigator(s) should provide detailed study information to the research participant or the legal representative/guardian. The ICF content should be briefly and clearly presented orally, and in writing, and in a manner that is easy to understand, commensurate with the comprehension level of the participants, and without coercion or unduly influencing a potential participant to enroll in the trial. Per the G-ICMR, the ICF language should not only be scientifically accurate and simple, but should also be sensitive to the participant’s social and cultural background. In addition, the participant or the legal representative/guardian, should be given adequate time to consider whether to participate. The consent should also be given voluntarily and not be obtained under duress or coercion of any sort or by offering any inducements.

The G-ICMR also states that, in the case of differently abled participants, such as those with physical, neurological, or mental disabilities, appropriate methods should be used to enhance the participants’ understanding (e.g., Braille for the visually impaired).

As delineated in the 2019-CTRules, investigator(s) must obtain an audio-video (AV) recording of the informed consent process for vulnerable participants in clinical trials for a new chemical or molecular entity, including the procedure of providing information to the participant and their understanding of the consent. This AV recording should be retained in the investigator’s files. In cases where clinical trials are conducted on anti-human immunodeficiency virus (HIV) and anti-leprosy drugs, the investigator(s) must only obtain an audio recording of the informed consent process. The investigator(s) is also required to retain the audio recording for their records.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Re-Consent

According to the G-ICMR and the G-Children, investigator(s) are required to renew the informed consent of each participant if there are any changes in the ICF related to the study conditions or research procedures, or if new information becomes available during the trial.

Per the G-ICMR and the G-Children, re-consent is applicable in cases in which a participant regains consciousness from an unconscious state and/or recovers mental capacity to understand the research study. If such an event is expected, then procedures to address this circumstance should be explained clearly in the ICF.

The G-ICMR and the G-Children explain that re-consent is required in the following situations:

• New information pertaining to the study becomes available that has implications for the participant(s) or that changes the benefit and risk ratio
• A research participant who is unconscious regains consciousness or suffered loss of mental competence and regains the ability to understand the research implications
• A child becomes an adult during the study, or the parent/legal guardian have changed
• Research requires a long-term follow up or an extension
• There is a change in treatment modality, procedures, site visits, data collection methods, or tenure of participation which may impact a participant’s decision to continue in the research
• There is possibility of identity disclosure through data presentation or photographs (this should be camouflaged adequately) in an upcoming publication
• Future research may be carried out on stored biological samples if not anonymized

The partner/spouse may also be required to give additional re-consent in some of the above cases.

Language Requirements

As stated in the 2019-CTRules and the G-ICMR, the ICF should be written in English and/or in a vernacular language that the participant is able to understand.

Documenting Consent

The G-ICMR and the G-Children specify that the participant or the participant’s legal representative/guardian must sign and date the ICF. If the participant is incapable of giving an informed consent, the legal representative/guardian should sign and date the ICF. Where the participant or the legal representative/guardian is illiterate, verbal consent should be obtained in the presence of and countersigned by an impartial witness.

Per the G-ICMR, if the participant or the legal representative/guardian cannot sign, a thumb impression must be obtained. In addition, the investigator(s) who administers the consent should also sign and date the ICF. As stated in the G-ICMR and the G-Children, when written consent as a signature or thumb impression is not possible, verbal consent may be taken with the EC’s approval, in the presence of an impartial witness who should sign and date the consent document, or through an AV recording. Per the G-ICMR, the ICF may also be administered and documented electronically, as long as the EC approves the process first.

As described in the G-ICMR, the following special situations may also arise in administering consent:

• The gatekeeper’s (a group’s head/leader or the culturally appropriate authorities), may provide permission on the group’s behalf in writing or audio/video recording and be witnessed
• Community consent is required for certain populations in order for participants to be permitted to participate in the research

According to the G-ICMR and the G-Children, a copy of the signed ICF and the patient information sheet should be given to the participant or the legal representative/guardian. Per the G-Children, the investigator should also keep a signed copy of the ICF.

Waiver of Consent

As specified in the G-ICMR and the G-Children, the investigator(s) can apply to the EC for a waiver of consent if the research involves less than minimal risk to participants and the waiver will not adversely affect the rights and welfare of the participants. In addition, per the G-ICMR, the EC may grant a waiver of consent in the following situations:

• Research cannot practically be carried out without the waiver and the waiver is scientifically justified
• Retrospective studies, where the participants are de-identified or cannot be contacted
• Research on anonymized biological samples/data
• Certain types of public health studies/surveillance programs/program evaluation studies
• Research on data available in the public domain, or
• Research during humanitarian emergencies and disasters, when the participant may not be in a position to give consent. An attempt should be made to obtain the participant’s consent as soon as possible

Refer to the Children/Minors section for information on waivers involving children.

See the G-ICMR, IND-5, and IND-27 for additional information on informed consent requirements.

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.

Per the 2019-CTRules, the G-ICMR, and the G-Children, 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 involves research and an explanation of its nature and purpose
• The expected duration of the participant’s participation
• Any benefits reasonably expected from the research to the participant or others; if no benefit is expected, the participant should be made aware of this
• The disclosure of specific appropriate alternative procedures or therapies available to the participant
• The mechanism by which confidentiality of records identifying the participant will be maintained and who will have access to the participant’s medical records
• An explanation about whom to contact for trial-related queries, participant rights, and in the event of any injury
• The policy on compensation and/or medical treatment(s) available to the participant in the event of a trial-related injury, disability, or death
• Participation is voluntary, the participant can withdraw from the study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled
• Any reasonably foreseeable risks or discomforts to the participant resulting from participation
• Approximate number of participants enrolled in the study

Additional requirements listed in the G-ICMR and the G-Children include:

• Foreseeable extent of information on possible current and future uses of the biological material and of the data to be generated from the research (e.g., storage period of sample/data; probability of material being used for secondary purposes; whether material is to be shared with others; participant’s right to prevent use of their biological sample(s) at any time during or after the study; risk of discovery of biologically sensitive information and provisions to safeguard confidentiality)
• Publication, if any, including photographs and pedigree charts
• Payment/reimbursement for participation and incidental expenses depending on the type of study
• Insurance coverage, if any, for research-related or other adverse events
• If there is a possibility that the research could lead to any stigmatizing condition (e.g., HIV and genetic disorders, provision for pre-test and post-test counseling)
• Post-research plan/benefit sharing for biological material research and/or if data leads to commercialization

Additional requirements listed in the 2019-CTRules include:

• The procedures to be followed, including all invasive procedures
• The investigational product (IP) may fail to achieve the intended therapeutic effect
• In the case of a placebo-controlled trial, the placebo administered to the participant(s) must not have any therapeutic effect
• The anticipated prorated payment, if any, to the participant for participating in the trial
• The participant’s responsibilities in participating in the trial
• 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
• The participant or the legal representative/guardian will be notified in a timely manner if significant new findings develop during the study which may affect the participant’s willingness to continue
• The particular treatment or procedure may involve risks to the participant (or to the embryo or fetus, if the participant is or may become pregnant), which are currently unforeseeable
• Additional costs to the participant that may result from participating in the study
• Any other pertinent information
• Clinical trial treatment schedule(s) and the probability for random assignment to each treatment

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

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see G-GeneThrpy and G-StemCellRes.

Overview

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

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

The Right to Participate, Abstain, or Withdraw

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

The Right to Information

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

The Right to Privacy and Confidentiality

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

The Right of Inquiry/Appeal

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

The Right to Safety and Welfare

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

Overview

In accordance with the 2019-CTRules and the G-ICMR, India’s ethical standards promote respect for all human beings and safeguard the rights of research participants. The G-ICMR upholds the Declaration of Helsinki (IND-63). The 2019-CTRules, the G-ICMR, and the G-Children state that a participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.

The Right to Participate, Abstain, or Withdraw

As stated in the 2019-CTRules, the G-ICMR, and the G-Children, the participant or the legal representative/guardian should be informed that participation is voluntary, the participant may withdraw from the research study at any time, and refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.

The Right to Information

As per the 2019-CTRules, the G-ICMR, and the G-Children, 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

As described in the 2019-CTRules, the G-ICMR, and the G-Children, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The 2019-CTRules also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identity and records of research participants.

The Right of Inquiry/Appeal

The 2019-CTRules, the G-ICMR, and the G-Children state that the research participant or the legal representative/guardian should be provided with contact information for the investigator(s) and the ethics committee (EC) to address trial-related inquiries and/or to appeal against a violation of the participant’s rights.

The Right to Safety and Welfare

The G-ICMR clearly states 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 G-ICMR and IND-27 for additional information on informed consent requirements. Refer to the Required Elements and Vulnerable Populations sections for additional information regarding requirements for participant rights.

See also the G-AI-BiomedRes for guidelines on safeguarding participants rights in biomedical and health research involving artificial intelligence-based tools and technologies.

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.

Children in Emergency Situations

Per the G-Children, research involving children in emergency situations should only be carried out when it is scientifically justified and cannot be conducted outside this setting. The ethics committee(s) (EC) should review and approve these studies as well as the proposed timeframe in which formal consent will be obtained. If consent cannot be obtained in an emergency, deferred consent is suggested. Deferred consent involves giving minimum information verbally, followed by full details and formal consent later. If the parent/legal guardian is unavailable or unable to give consent, another individual, such as the participant’s doctor or a person nominated by the healthcare provider, can give consent. However, the doctor or a person nominated by the healthcare provider may not be involved in the research. It is recommended that a Data Safety Monitoring Board (DSMB) be strongly considered for these types of studies. See the Children/Minors section for additional pediatric informed consent requirements.

Moreover, per the G-Children, if a child’s parent/legal guardian refuses to give consent once their child is stabilized, the child should not be included in the research, and no further research related procedures/data collection should be done. Additionally, the previously collected data obtained prior to the consent process should not be used without the parent's/legal guardian's permission.

Humanitarian Emergencies

As explained in the G-ICMR, during a humanitarian emergency or disaster, close attention should be paid to the effect of the emergency on perceptions of ethical questions, altered or increased vulnerabilities, provider-patient and researcher-participant relationships, and issues related to integrity of studies and ethical review processes. Obtaining valid informed consent in humanitarian emergencies is a challenge as the decisional capacity of the participants would be so low that they may not be able to differentiate between reliefs offered and research components. This should be very clearly distinguished during the informed consent process. Additional safeguards are required for participants due to their vulnerability, for example, counseling, psychological help, medical advice, and process of stakeholder consultation.

In addition, the G-ICMR indicates that the potential research participants might be under duress and traumatized. Researchers should be sensitive to this situation and are obligated to ensure that the informed consent process is conducted in a respectful manner. Researchers should strive to identify and address barriers to voluntary informed consent and not resort to inducements for research participation. The different roles of researchers, caregivers and volunteer workers must always be clarified, and potential conflict of interest declared. If research involves vulnerable individuals (such as minors), then the legal representative/guardian should give consent. Additional protections might be required in special cases, for example, children with untraceable or deceased relatives. In these situations, consent should be obtained from an individual who is not part of the research team who should be designated by the institution/agency conducting research.

For seeking a waiver of consent, the researchers should give the rationale justifying the waiver. The EC should approve such a waiver after careful discussion on the issue. Refer to the Documentation Requirements section for additional information on waivers of consent. When consent of the participant or the legal representative/guardian is not possible due to the situation, informed consent must be administered to the participant or the legal representative/guardian at a later stage, when the situation allows. However, this should be done only with the prior approval of the EC. See IND-5 for additional information on consent requirements during medical emergencies.

Overview

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

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

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

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

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

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

Indigenous Peoples

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

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

Overview

As set forth in the 2019-CTRules and the G-ICMR, in all clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The G-ICMR further describes vulnerable groups and individuals as those who may have an increased likelihood of incurring additional harm, as they may be relatively (or absolutely) incapable of protecting their own interests. According to the G-ICMR, vulnerable populations are characterized as individuals/communities with hierarchical relationships (e.g., prisoners, armed forces personnel, or staff and students at medical, nursing, or pharmacy academic institutions); economically and socially disadvantaged individuals (e.g., persons who are unemployed, abandoned, orphans, have language barriers, or cultural differences); persons below the poverty line; ethnic, religious, or sexual minority groups; tribal and marginalized communities; terminally ill patients or those suffering from stigmatizing or rare diseases; patients in emergency situations; institutionalized persons; homeless persons, nomads, or refugees; minors; women in special situations (e.g., pregnant or lactating women, those with poor decision-making powers, or poor access to healthcare); those with mental illness and cognitively impaired, differently abled, or mentally or physically disabled; or others incapable of personally giving consent.

See the G-ICMR for detailed safeguards that must be complied with when trials involving vulnerable populations are conducted. The G-ICMR also describes research principles that must be upheld during these trials and upholds the Declaration of Helsinki (IND-63). See also the G-AI-BiomedRes for guidelines on safeguarding participants rights in biomedical and health research involving artificial intelligence-based tools and technologies, especially those participants from underrepresented and vulnerable populations.

See the Children/Minors; Pregnant Women, Fetuses & Neonates; and Mentally Impaired sections for additional information about these vulnerable populations. See also IND-5 for additional information on consent requirements for vulnerable populations.

For specific guidelines regarding gene therapy and stem cell therapy clinical trials, see the G-GeneThrpy and the G-StemCellRes.

Terminally Ill Patients

Per the G-ICMR, terminally ill patients or patients seeking new treatments are vulnerable as they are ready to give consent for any intervention that could help them. The EC should carefully review protocols and recruitment procedures for these studies and comply with the following requirements:

• Additional monitoring should be done to detect any adverse event as soon as possible
• A benefit-risk assessment should be performed that considers the potential participant’s perception of benefits and risks
• Post-trial access to the medication

Indigenous Peoples

The G-ICMR states that research on tribal populations should only be conducted if it is of a specific therapeutic, diagnostic, and preventative nature with appropriate benefits to the tribal population. A competent administrative authority’s approval, such as the tribal welfare commissioner or the district collector, should be obtained prior to an investigator entering the area. Whenever possible, it is desirable to seek the help of government functionaries/local bodies or registered, non-governmental organizations who work closely with the tribal groups and have their confidence. The tribal leader, or other culturally appropriate authority may serve as the gatekeeper from whom permission to enter and interact should be obtained. A participant’s consent should be taken along as well as consulting with community elders and individuals who know the local language/dialect of the tribal population, and in the presence of appropriate witnesses. Additional precautions should be taken to avoid including children, pregnant women, and elderly people belonging to particularly vulnerable tribal groups. Benefit sharing with the tribal group should also be ensured for any research done using tribal knowledge that may have the potential for commercialization.

Elderly Persons

Permission to conduct clinical trials in geriatric patients must comply with the requirements listed in the Required Elements section. According to 2019-CTRules, geriatric patients should be included in Phase II and Phase III clinical trials at the sponsor’s (also known as the applicant’s) recommendation, in the following circumstances:

• The disease intended to be treated is typically a disease of aging
• The population to be treated is known to include substantial numbers of geriatric patients
• There is specific reason to expect that conditions common in the elderly are likely to be encountered
• The new drug is likely to alter the geriatric patient’s response (with regard to safety or efficacy) compared with that of the non-geriatric patient

Persons in Dependent Groups

As indicated in the G-ICMR, while reviewing protocols involving participants who are engaged in subordinate or dependent relationships, the ethics committee (EC) must ensure the following:

• Participant enrollment is specifically relevant to the research questions and is not merely a matter of convenience
• Extra efforts are required to ensure the autonomy of these individuals is respected, and that they are able to freely decide to participate or deny consent and/or later withdraw from the study without fear of any negative repercussions on their care
• Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol

Sexual Minorities and Sex Workers

Per the G-ICMR, sexual minorities and sex workers require additional protections as they are more vulnerable to privacy, confidentiality, stigma, discrimination, and exploitation issues during a research study. Research proposals should ensure the dignity of these participants is protected and that they have access to quality healthcare. Investigators should consult the community, if possible, prior to the proposal being finalized. It is also advised that a representative of the sexual minority group/lesbian/gay/bisexual and transgender (LGBT) community attend the EC meeting as a special invitee/member.

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-ICMR, children are individuals who have not obtained the legal age of consent, which is 18.

As stated in the G-ICMR, the 2019-CTRules, and the G-Children, in the case of pediatric clinical trials, participants are legally unable to provide written informed consent, and are dependent on their parents/legal guardians to assume responsibility for their participation in a research study.

However, as specified in the 2019-CTRules, all pediatric participants should be informed to the extent compatible with the child’s understanding, and if capable, the pediatric participant should sign and personally date the informed consent form (ICF). In these studies, the following requirements should be complied with:

• Written informed consent should be obtained from the parent/legal guardian; however, all pediatric participants should be informed to the fullest extent possible about the study in a language and in terms that they are able to understand
• Where appropriate, pediatric participants should additionally provide their assent to enroll in the study, and mature minors and adolescents should personally sign and date a separately designed written assent form
• Although a participant’s wish to withdraw from a study must be respected, there may be circumstances in therapeutic studies for serious or life-threatening diseases in which, in the investigator’s and parent’s/legal guardian’s opinion, a pediatric patient’s welfare would be jeopardized by failing to participate in the study. In this situation, continued parental/legal guardian consent should be sufficient to allow participation in the study

The 2019-CTRules further specifies requirements for pediatric studies involving new drugs. These studies must take into account the following issues:

• The timing of new drug pediatric studies will depend on the medicinal product, the type of disease being treated, safety considerations, and the efficacy and safety of available treatments
• If the new drug is for diseases predominantly or exclusively affecting pediatric patients, clinical trial data should be generated in the pediatric population except for initial safety and tolerability data, which will usually be obtained in adults, unless such initial safety studies in adults would yield little useful information or expose them to inappropriate risk
• If the new drug is intended to treat serious or life-threatening diseases, occurring in both adults and pediatric patients, for which there are currently no or limited therapeutic options, the pediatric population should be included in the clinical trials early, following assessment of initial safety data and reasonable evidence of potential benefit; in circumstances where this is not possible, lack of data should be justified in detail
• If the new drug has a potential for use in pediatric patients, pediatric studies should be conducted
• Pediatric studies should include clinical trials, relative bioequivalence comparisons between pediatric and adult formulations, and pharmacokinetic studies for dose selection across the age ranges of pediatric patients in whom the drug is likely to be used
• If the new drug is a major therapeutic advance for the pediatric population, studies should begin early in the drug development, and this data should be submitted with the new drug application

The reviewing ethics committee (EC) should also include members who are knowledgeable about pediatric, ethical, clinical, and psychosocial issues.

Refer to the 2019-CTRules for detailed pediatric study requirements.

Per the G-ICMR, the EC should also perform a benefit-risk assessment to determine whether there is a need to implement additional safeguards/protections to conduct a study involving children. The EC should consider the circumstances of the children to be enrolled in the study including their age, health status, and other factors and potential benefits to other children with the same disease or condition, or to society as a whole. In addition, the G-Children should be consulted for detailed EC assessment criteria to be used to evaluate research studies involving children.

As per the G-Children, following EC approval of the protocol, the informed consent requirement for children may be waived in the following circumstances:

• When it is impractical to conduct research since confidentiality of personally identifiable information has to be maintained throughout the study (e.g., a study on the disease/burden of HIV/AIDS)
• Research is carried out on publicly available information, documents, records, works, performances, reviews, quality assurance studies, archival materials or third-party interviews, etc.
• Research on anonymized biological samples, leftover samples after clinical investigation/research, cell lines, or cell free derivatives (e.g., viral isolates, DNA or RNA from recognized institutions or qualified investigators, samples or data from repositories or registries, etc.) provided permission for future research on these samples has been taken in the previous ICF
• In emergency situations when no surrogate consent can be taken
• Retrospective studies, where the participants are de-identified or cannot be contacted

Assent Requirements

As delineated in the G-ICMR, the 2019-CTRules, and the G-Children, if the pediatric participant has the capacity for assent, the participant’s affirmative assent is required to participate in a study according to their developmental level and decision-making capacity. Per the 2019-CTRules, mature minors and adolescents should personally sign and date a separately designed written assent form. According to the G-ICMR, mature minors are those from age seven (7) up to age 18.

The G-Children also explains that in addition to the children’s developmental level and capability of understanding, the assent process and form should also take into account their age, maturity, reading level, independence, autonomy as well as cultural and social factors. For children between ages seven (7) and 11, oral assent must be obtained in the presence of their parent/legal guardian. For children between ages 12 and 18, written assent must be obtained.

A child’s dissent or refusal to participate must always be respected, and the child must be informed in an understandable manner that assent may be withdrawn at any time during the study. The EC may also issue a waiver of assent in the following circumstances:

• If the research has the potential to directly benefit the child, and this benefit is only available through this study
• If the research involves children with intellectual and other developmental disabilities, they may not have the developmental level and intellectual capability to give assent

For details and guidance on preparing and using an assent form, see the G-Children.

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

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

As per the 2019-CTRules and the G-ICMR, clinical studies involving pregnant or nursing women and fetuses require additional safeguards to ensure that the research assesses the risks to the women and the fetuses. The following conditions are required for research to be conducted involving pregnant or nursing women or fetuses.

Per the 2019-CTRules:

• Pregnant or nursing women should be included in clinical trials only when the drug is intended for use by pregnant or nursing women, fetuses, or nursing infants, and where the data generated from women who are not pregnant or nursing is unsuitable

Per the G-ICMR:

• For studies related to pregnancy termination, only pregnant women who undergo Medical Termination of Pregnancy as per the Medical Termination of Pregnancy Act, 1971 can be included
• The research should carry no more than minimal risk to the fetus or nursing infant and the research objective is to obtain new knowledge about the fetus, pregnancy, and lactation
• Clinical trials involving pregnant or nursing women would be justified to ensure that these women are not deprived arbitrarily of the opportunity to benefit from investigations, drugs, vaccines, or other agents that promise therapeutic or preventive benefits
• Research related to prenatal diagnostic techniques in pregnant women should be limited to detecting fetal abnormalities or genetic disorders as per the Pre-Conception and Pre-Natal Diagnostic Techniques (Regulation and Prevention of Misuse) Act, 1994, amended in 2003, and not used to determine the sex of the fetus
• Researchers must provide the ethics committee (EC) with proper justification for including pregnant and nursing women in trials designed to address the health needs of such women or their fetuses or nursing infants
• If women of reproductive age are to be recruited, they should be informed of the potential risk to the fetus if they become pregnant, be asked to use an effective contraceptive method, and be told about the options available in case of failure of contraception
• A woman who becomes pregnant must not automatically be removed from the study when there is no evidence showing potential harm to the fetus. The matter should be carefully reviewed, and she must be offered the option to withdraw or continue
• If the female sexual partner of a male participant gets pregnant during the research study, the EC should review the protocol and informed consent form (ICF) to determine if a plan exists to document this event, and both the pregnant partner and fetus must also be followed for the outcome and reported in the study results
• Pregnant women have the right to participate in clinical research relevant to their healthcare needs (e.g., gestational diabetes, pregnancy-induced hypertension, and HIV)
• Benefit-risk assessment must be done at all stages for both the mother and the fetus
• Research involving pregnant women and fetuses must only take place when the objective is to obtain new knowledge directly relevant to the fetus, the pregnancy, or lactation
• Women should not be encouraged to discontinue nursing for the sake of participation in research except in those studies where breastfeeding is harmful to the infant
• Appropriate studies on animals and non-pregnant individuals should have been completed, if applicable
• Researchers should not participate in decision-making regarding any termination of a pregnancy
• No procedural changes, which will cause greater than minimal risk to the woman or fetus, will be introduced into the procedure for terminating the pregnancy solely in the interest of the trial
• When research is planned on sensitive topics (e.g., domestic violence, genetic disorders, and/or rape) confidentiality should be strictly maintained and privacy protected

Fetuses and Neonates

As described in the G-Children, study protocols involving neonates should take into consideration that this group is the most vulnerable within the pediatric population in terms of the risk of long-term effects of interventions, including developmental effects. ECs reviewing such proposed protocols should have an advisory member with expertise in neonatal research/care. ECs should scrutinize all proposed research for potential risks and weigh them against the possible benefits and ensure a competent person(s) conducts a proper scientific review of the protocol. In addition, when possible, older children should be studied before conducting studies in younger children and infants.

The consent of one (1) parent is also required for neonate studies where research exposes them to no or minimal risk, or in studies that offer the prospect of direct benefit to the participant. However, for studies that do not offer the prospect of direct benefit or are high-risk, consent from both parents is required. Exceptions to this requirement include the following:

• Only one (1) parent has legal responsibility for the care and custody of the child
• One (1) parent is deceased, unknown, incompetent, or not available. In such cases, it is the duty of the investigators to provide adequate justification.

A parent who is a minor should not provide consent. If both parents are minors, then enrollment of such a baby should be avoided as much as possible. Investigator(s) should provide adequate justification to the EC to enroll such neonates for research. A legally acceptable representative should provide an informed consent in such situations.

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.

As noted in the G-ICMR, prisoners are included in the description of vulnerable populations due to their diminished autonomy caused by dependency or being under a hierarchical system.

The G-ICMR specifies that during the review process, the ethics committee (EC) must ensure compliance with the following:

• Enrolling participants is specifically pertinent to the research questions and is not merely a matter of convenience
• Extra efforts are made to respect the autonomy of these individuals because they are in a hierarchical position and may not be in a position to disagree to participate for fear of authority
• It is possible for the participant to deny consent and/or later withdraw from the study without any negative repercussions on their care
• Mechanisms to avoid coercion due to being part of an institution or hierarchy should be described in the protocol

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.

The G-ICMR states that, in the case of differently abled participants, such as those with physical, neurological, or mental disabilities, appropriate methods should be used to enhance the participants’ understanding. The G-ICMR also states that the presence of a mental disorder is not synonymous with incapacity of understanding or inability to provide informed consent. However, ethics committees (ECs) have special responsibilities when research is conducted on participants who are suffering from mental illness and/or cognitive impairment. ECs should exercise caution and require researchers to justify exceptions and their need to depart from the guidelines governing research. ECs should ensure that these exceptions are as minimal as possible and are clearly spelled out in the informed consent form. The G-ICMR also upholds the Declaration of Helsinki (IND-63).

As set forth in the MHA2017, every person, including a person with mental illness, must be deemed to have the capacity to make decisions regarding mental healthcare or treatment providing the person has the ability to engage in the following:

• Understand the information that is relevant to make a decision on treatment, admission, or personal assistance
• Appreciate any reasonably foreseeable consequence of a decision or lack of decision on the treatment, admission, or personal assistance, or
• Communicate the decision by means of speech, expression, gesture, or any other means

Per MHA2017, information must be provided to a person with mental illness using simple and understandable language, sign language, visual aids, or any other means to enable the person to understand the information. In the case in which a person makes a decision regarding one’s mental healthcare or treatment that is perceived by others as inappropriate or wrong, that by itself, must not be interpreted as the person not having the capacity to make such a decision, as long as the person has the capacity to meet the above stated requirements.

MHA2017 further delineates that every person with mental illness who is not a minor must have the right to appoint a nominated representative. The nomination must be made in writing on plain paper with the person’s signature or thumb impression. The person appointed as nominated representative must not be a minor, be competent to discharge the duties or perform the assigned functions under the MHA2017, and give consent in writing to the mental health professional to discharge the person’s duties and perform the assigned functions. A person who has appointed an individual as the nominated representative may revoke or alter the appointment at any time. The appointment of a nominated representative, or the inability of a person with mental illness to appoint a nominated representative, must not be construed as the lack of capacity of the person to make decisions about mental healthcare or treatment. All persons with mental illness must have the capacity to make mental healthcare or treatment decisions but may require varying levels of support from their nominated representative to make decisions. When fulfilling responsibilities, the nominated representative must have the right to give or withhold consent for research under circumstances.

Pursuant to MHA2017, professionals conducting research must obtain free and informed consent from all persons with mental illness for participation in any research that involves interviewing the person, or any research that involves psychological, physical, chemical, or medicinal interventions. In the case of research involving psychological, physical, chemical, or medicinal interventions to be conducted on a person who is unable to give free and informed consent, but does not resist participation in such research, permission to conduct such research must be obtained from the appropriate State Authority. The State Authority may allow the research to proceed based on informed consent being obtained from the person’s nominated representative if the State Authority is satisfied that the following criteria are met:

• The proposed research cannot be performed on persons who are capable of giving free and informed consent
• The proposed research is necessary to promote the mental health of the population represented by the person
• The purpose of the proposed research is to obtain knowledge relevant to the particular mental health needs of persons with mental illness
• A full disclosure of the interests of the persons and organizations conducting the proposed research is made and there is no conflict of interest involved, and,
• The proposed research follows all the national and international guidelines and regulations concerning the conduct of such research, and ethical approval has been obtained from the institutional EC where such research is to be conducted

A research-based study of the case notes of a person who is unable to give informed consent will be permitted so long as the anonymity of the person is secured. In addition, the person with mental illness or the nominated representative who gives informed consent for participation in any research under MHA2017 may withdraw consent at any time during the research period.

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.

As delineated in the 2019-CTRules, an investigational product (IP) is defined as the pharmaceutical formulation of an active ingredient or a placebo (including the comparator product) being tested or used as a reference in a clinical trial.

The 2019-CTRules further defines an investigational new drug as a new chemical or biological entity or a product having a therapeutic indication, but which has never been tested before on human participants.

Manufacturing

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

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

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

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

Import

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

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

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

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

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

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

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

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

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

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

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

Advanced Therapy Products

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

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

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

Manufacturing

As specified in the 2019-CTRules and IND-31, the Drugs Controller General of India (DCGI) is responsible for authorizing the manufacture of investigational products (IPs) in India. The DCGI approves the manufacture of IPs as part of the clinical trial application review and approval process. The DCGI is head of the Central Drugs Standard Control Organization (CDSCO) and is commonly referred to as the Central Licensing Authority in the Indian regulations.

To obtain permission to manufacture an IP for clinical trial purposes, the 2019-CTRules explains that applicants must apply to the DCGI using the Application for Grant of Permission to Manufacture New Drug or Investigational New Drug for Clinical Trial or Bioavailability or Bioequivalence Study or for Examination, Test and Analysis (CT-10). Per Notice16Jan24, applicants may access this form via the National Single Window System (NSWS) portal (IND-3).

Per IND-73, once users have completed the NSWS portal (IND-3) registration process, they can search for their required approval applications/registrations using the NSWS Central Approvals webpage (IND-23), or by selecting the Know Your Approvals (KYA) module (IND-12) via the NSWS portal (IND-3).

IND-73 explains that the NSWS Central Approvals webpage (IND-23) allows users to filter their search by ministry/department to obtain a complete list of approval applications (e.g., the Ministry of Health and Family Welfare (MOHFW) filter would pull up a complete list of MOHFW/CDSCO approval applications.) When an approval application link is selected, users can review additional details about the approval including who can apply, applicability, related acts and rules, period of validity, and learn whether the application can be submitted via the NSWS portal (IND-3). Users may also choose to add the application to their “Dashboard” of approvals in order to complete the application process. See the IND-11 for guidance additional instructions on submitting CDSCO approvals via IND-3. Also, please note that, at this time, per Notice1Jan24 and Notice16Jan24, only a few CDSCO steps and processes (e.g., medical device related registration, manufacturing/import applications, and drug manufacturing/import applications) have been moved to the NSWS portal (IND-3).

Per the 2019-CTRules, after reviewing CT-10 and any supplemental information, the DCGI will either grant permission to manufacture the IP via Form CT-11 or reject the application, for reasons to be recorded in writing, within 90 working days from the date of application receipt. If applicable, the DCGI must inform the applicant of deficiencies in the application within 90 working days. If the applicant chooses to rectify the deficiencies within the specified period and provide the required information and documents, the DCGI must review the application again. Based on the review, the DCGI will either grant manufacturing permission to the applicant or reject the application within a period of 90 working days from the date the required information and documents were provided. In the case of rejection, the applicant may request the DCGI reconsider the application within a period of 60 working days from the rejection date along with payment of the specified fees in the 2019-CTRules and submission of the required information and documents. Refer to the 2019-CTRules for additional timeline information and the applicable forms. See also IND-23 for additional approval details on CT-10.

In addition, while applications are now required to be submitted via IND-3, Notice18Feb20 still provides clarifying information in IND-31 concerning where to mail CT-10 applications. For biological drugs, applications should be sent to CDSCO Headquarters (HQ) at FDA Bhavan, New Delhi; for drugs other than biologicals, applications should be sent to the appropriate zonal office/sub-zonal office for pure chemical testing, and the zonal office/sub-zonal office or CDSCO HQ for clinical trials or BA/BE studies. Furthermore, if the applicant obtains permission to manufacture new drugs/IPs for a clinical trial or BA/BE study, the applicant should automatically consider the approval as permission to conduct other chemical/physical testing and analysis on these new drugs/IPs. Refer to IND-58 for detailed CDSCO HQ, zonal office/sub-zonal office contact information. Notice18Feb20 also states that applicants must clearly mention the site where the product will be manufactured in their applications using the following statement: M/s. [name and address of the firm] having manufacturing premises for test and analysis at [name and address of the manufacturing site for test and analysis]. Refer to Notice18Feb20 for additional information.

Per Notice16Jan24, applicants who intend to manufacture an unapproved active pharmaceutical ingredient (API) to develop a pharmaceutical formulation for clinical trial purposes should submit the following to the DCGI via the NSWS portal (IND-3) along with any supplemental information:

• If applying as a pharmaceutical formulation manufacturer, use the Application for Grant of Permission to Manufacture Formulation of Unapproved Active Pharmaceutical Ingredient for Test or Analysis or Clinical Trial or Bioavailability or Bioequivalence study (CT-12)
• If applying as an API manufacturer, use the Application for Grant of Permission to Manufacture Unapproved Active Pharmaceutical Ingredient for Development of Formulation for Test or Analysis or Clinical Trial or Bioavailability or Bioequivalence Study (CT-13)

As stated in the 2019-CTRules, after reviewing the submission and conducting further inquiry, if needed, the DCGI will grant permission to the applicant to manufacture the unapproved API in Form CT-15 and permission to the manufacturer of the pharmaceutical formulation in Form CT-14 within 90 working days. If dissatisfied, the DCGI will reject the application, for reasons to be recorded in writing, within a period of 90 working days from the application submission date. Refer to the 2019-CTRules for additional timeline information and the applicable forms. See also IND-23 for additional approval details on CT-12 and CT-13. Refer to the instructions provided in the preceding paragraphs to submit CT-12 and CT-13 via the NSWS portal (IND-3).

Per Notice13Mar20, when the application is solely to conduct a clinical trial, the DCGI also requires the sponsor (also known as applicant) to submit the international non-proprietary name (INN) or generic name, drug category, dosage form, and data supporting IP stability in the intended container-closure system for the duration of the clinical trial. See the 2019-CTRules (Second Schedule, Table 1) for detailed data requirements. Additionally, for Phase III clinical trial batches, process validation data requirements may not be required; however, this requirement will vary depending on the IP’s complexity (biological, high tech, etc.). If approved, the DCGI will grant permission for a period of three (3) years to both manufacturers of new drugs or investigational new drugs and manufacturers of unapproved APIs. In exceptional circumstances, the DCGI may extend the period of permission for an additional year. See the 2019-CTRules and IND-31 for more detailed information on manufacturing application submission requirements.

Import

As delineated in the 2019-CTRules and IND-31, the DCGI is responsible for authorizing the import of IPs in India. The DCGI approves the import of IPs as part of the clinical trial application review and approval process.

Per the 2019-CTRules and IND-31, the sponsor is required to obtain a license from the DCGI using the Application for Grant of License to Import New Drug or Investigational New Drug for Clinical Trial or Bioavailability or Bioequivalence Study or for Examination, Test and Analysis (CT-16) to import an IP (new drug or investigational new drug) for clinical trial purposes. Additionally, as explained in IND-31, the Application to Import Drugs for the Purposes of Examination, Test or Analysis (Form 12) should be used to obtain permission to import a drug that is not a new drug as required by the DCA-DCR. See also IND-23 for additional approval details on CT-16 and Form 12. Refer to the instructions provided above to submit CT-16 and Form 12 via the NSWS portal (IND-3).

Per the 2019-CTRules, the sponsor must also ensure that the imported IPs are manufactured in accordance with Good Manufacturing Practices (GMPs) as laid down in the DCA-DCR. Refer to Schedule M of the DCA-DCR to review the GMP requirements. See also the Second Schedule in the 2019-CTRules for the data requirements to be included in the DCGI’s import application.

The 2019-CTRules and IND-31 further state that the DCGI will grant an import license within 90 working days of receipt of the application. Once approved, the import license must remain valid for three (3) years from the date of issue, unless suspended or cancelled. In exceptional circumstances, the DCGI may extend the license for an additional year. (See the Submission Process and Submission Content sections for detailed clinical trial application requirements). See also IND-35 for a checklist of manufacturing and import related forms to be included in a global clinical trial application submission. See Regulatory Fees section for information on manufacturing and import fees. Refer to IND-43 and IND-42 for detailed fee requirements and online payment instructions via the SUGAM portal (IND-59).