Regulatory Authority
Regulatory Authority
Scope of Assessment
Regulatory Fees
Ethics Committee
Ethics Committee
Scope of Review
Ethics Committee Fees
Oversight of Ethics Committees
Clinical Trial Lifecycle
Submission Process
Submission Content
Timeline of Review
Initiation, Agreements & Registration
Safety Reporting
Progress Reporting
Sponsorship
Definition of Sponsor
Site/Investigator Selection
Insurance & Compensation
Risk & Quality Management
Data & Records Management
Personal Data Protection
Informed Consent
Documentation Requirements
Required Elements
Participant Rights
Emergencies
Vulnerable Populations
Children/Minors
Pregnant Women, Fetuses & Neonates
Prisoners
Mentally Impaired
Investigational Products
Definition of Investigational Product
Manufacturing & Import
Quality Requirements
Labeling
Product Management
Specimens
Definition of Specimen
Specimen Import & Export
Consent for Specimen
Quick Facts
Overview
As delineated in ResNo9, ResNo61, and ResNo176, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for reviewing and approving clinical trial applications for drugs to be registered in Brazil. In addition, per ResNo9, the G-DDCMManual, and BRA-8, the clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the DDCM to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. Per ResNo9 and BRA-8, while the DDCM may be submitted at any stage of development, Phase IV post-marketing trials are only subject to Clinical Trial Notification by ANVISA after obtaining ethical approvals. See ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products in Brazil (i.e., medicines for human use that are based on genes, tissues, or cells).
In addition, ResNo205 repealed the ResNo9 requirement that ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel. As indicated in ResNo9 and also noted in BRA-2, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP))’s approval is required for certain studies (e.g., foreign studies), but ANVISA’s decision to approve the DDCM is not dependent on CONEP. Similarly, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory for all studies, but may be requested, according to BRA-1. However, per ResNo9, the EC (CEP) is required to approve substantial protocol amendments prior to implementation. Refer to the Ethics Committee topic for additional information on the CEP/CONEP System; CLNo038 for the criteria CONEP uses to process protocol amendments; and CLNo24 and CLNo24-Note for general guidelines on conducting clinical trials.
Clinical Trial Review Process
As delineated in ResNo61 and ResNo176, ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) is responsible for conducting the review and approval of clinical trial applications (DDCMs). ResNo9 and the G-DDCMManual explain that following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)). The CE lists all the trials included in the DDCM that are permitted to initiate the clinical study. BRA-8 further explains COPEC experts conduct a preliminary review that includes a benefit-risk assessment based on various criteria such as drug registration status and drug status in other agencies (e.g., fast-track or breakthrough therapy). After this evaluation, the reviewer may release the dossier by the expiration deadline date so that the sponsor (applicant) may proceed with conducting the trial, requesting a meeting, or conducting a more detailed and complete dossier evaluation. See the Timeline of Review section for additional ANVISA timeline information. Also, see BRA-79 for additional information on ANVISA’s clinical trial review and approval framework, and BRA-40 for information on ANVISA drug registration requirements.
ANVISA has also released ServBltnNo104 to expedite the evaluation of clinical drug research development in Brazil without compromising the quality of the technical analysis. ServBltnNo104 provides detailed procedures for a simplified technical review of the following:
- DDCM petitions containing at least one (1) clinical trial protocol, at any stage of development, approved by at least one (1) regulatory authority of a member country of the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) or by the United Kingdom’s (UK’s) Medicines and Healthcare Products Regulatory Agency (MHRA). The protocol submitted to ANVISA need not be the same as the one (1) approved by the member country.
- DDCMs for experimental drugs (also referred to as investigational products (IPs)) that are registered in at least one (1) ICH member country or the UK. This DDCM must be identical to the one (1) approved by the ICH member country or the UK, with the exception of the labels and secondary packaging models.
- Substantial quality changes approved by at least one (1) ICH member country or the UK (i.e., changes potentially impacting the quality or safety of the IP, active comparator, or placebo).
According to ServBltnNo104, the IP manufacturing process must also meet the criteria and recommendations described in the ICH guidelines, as applicable, according to the phase of clinical development. In addition, the technical experts in ANVISA’s COPEC require DDCM petitions and substantial quality modifications to meet ServBltnNo104 criteria and be accompanied by the documentation required in ResNo9. COPEC will then analyze: the results of stability studies under accelerated and long-term conditions that support the proposed expiration date for the IP and, where applicable, for the modified placebo and comparator, when the storage recommendation is at room temperature (between 15 and 30 degrees Celsius); and the sample IP label for DDCM petitions.
In the event of non-compliance, COPEC will conduct a non-simplified analysis per ResNo9. ServBltnNo104 further explains that ANVISA may also at any time analyze all the documents required by ResNo9 relating to the IP risk analysis. Refer to the Submission Content section for DDCM petitions and substantial quality modifications documentation requirements.
See BRA-98 for a list of COPEC documents, regulations, and clinical research guidelines available on the ANVISA portal and their corresponding locations, and BRA-60 for COPEC’s 2020-2021 annual report. See also BRA-19 and BRA-90 for guidance on scheduling pre-submission meetings with COPEC to discuss the clinical development of a drug (e.g., DDCM, an amended DDCM (secondary petition), or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted.
Priority Submissions
In addition to the previously stated DDCM requirements, ResNo204 establishes a priority category to register, amend previously registered, or request prior approval for drug submissions. ResNo204 states that the priority submission may be submitted as a DDCM or DEEC. A priority DDCM submission is required to meet one (1) or more of the following criteria: new drug trial in any phase to be carried out in Brazil, the drug is part of the Ministry of Health (MOH)’s National Immunization Program, or the product is determined to be of strategic public health interest and included under the MOH’s Unified Health System (SUS) (BRA-53). A priority DEEC submission is required to comply with the following: the drug is to be used for neglected, emerging or reemerging diseases, health emergencies, or serious debilitating conditions for which there is no alternative; the trial is to be conducted exclusively with the pediatric population; or the drug will be used in a Phase I trial only to be manufactured in Brazil. The sponsor should specify at the time of submission that the new or amended protocol is a priority category request. If not confirmed prior to the technical review phase, the request for approval may be denied. ANVISA is required to issue a first written opinion letter within 45 calendar days from the first working day following protocol submission, a final opinion in 120 days for new drug registration requests, and a final opinion 60 days for post-registration petitions. See the Timeline of Review section detailed timeline information. Refer to ResNo204 and BRA-14 for detailed information on priority submissions. See also BRA-2, BRA-1, and BRA-42 for additional information on priority submission.
New Drugs for Rare Diseases
ResNo205 sets forth specific approval procedures for clinical trials to be conducted to register new drugs to treat, diagnose, or prevent rare diseases. The applications may be submitted as an initial DDCM, a secondary petition linked to the original DDCM, or a DEEC either linked to the original DDCM or for a new process. The sponsor must delineate at the time of submitting a new drug submission (DDCM), an amended DDCM (secondary petition), or DEEC, whether the DDCM is pertaining to a rare disease drug. If not confirmed prior to the technical review phase, the request for approval may be denied.
In addition, per ResNo763, which modifies ResNo205, and BRA-3, 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 for additional submission documentation requirements. BRA-2 also provides a helpful summary of ResNo204 and ResNo205.
Special Reviews During COVID-19 Public Health Emergency
During the COVID-19 public health emergency as described in OrdNo188, ANVISA issued ResNo573 to implement an urgent and temporary amendment to ResNo9. Although OrdNo913 declared an end to the public health emergency as of May 22, 2022, ResNo790 has extended the validity of ResNo573 to May 23, 2024. In addition, ResNo791 has extended the validity of ResNo601 to May 23, 2024.
The ResNo573 amendment specifically affects ANVISA’s technical reviews of DDCMs that fall into at least one (1) of the following categories: national development, biological product clinical development including vaccines, and Phase I or II clinical development studies as delineated in ResNo9 (see Art. 36). Per ResNo573, ANVISA is required to evaluate this category of applications within 120 calendar days, counting from the date of linking the first DEEC to the DDCM. The 120-day review deadline only amends the original 180-day deadline specified in ResNo9 for these types of studies.
Pursuant to ResNo573 and BRA-3, in the event that ANVISA fails to respond within the 120-day deadline, the agency will issue a Document for Importation of Product(s) under Investigation for a DDCM (also known as the Import Document (DI)) that has one (1) or more studies approved by at least one (1) regulatory authority of an ICH founding or standing member country or by the UK’s MHRA. BRA-3 explains that the DI is the list of clinical supplies necessary to carry out the clinical trial, including the experimental drug, as described in the clinical trial submission form (BRA-22). BRA-3 further states that ANVISA will send the initial DDCMs/DEECs and the DI to the sponsor. To prove compliance with the ResNo573 criteria, the sponsor must then submit the subject codes: “12102 – ENSAIOS CLÍNICOS – Análise Simplificada de Anuência em Processo de Pesquisa Clínica Previsto no Plano de Desenvolvimento” (12102 – CLINICAL TRIALS – Simplified Analysis of Consent in the Clinical Research Process Provided for in the Development Plan) for each initial DEEC linked to the DDCM, and “11634 – ENSAIOS CLÍNICOS – Análise Simplificada de Dossiê de Qualidade” (11634 – CLINICAL TRIALS – Simplified Analysis of the Quality Dossier). Once submitted, simplified analysis will be performed only for the corresponding document (i.e., the initial DEEC or the Quality Dossier) for each of the subject codes.
Per ResNo573, the DDCM must also be identical to the one (1) approved by the ICH member country or the UK. An official document issued by the regulatory authority or a declaration of compliance with the criteria described in this document must be presented to prove the authorization or non-objection to carry out the clinical trial by the ICH member country or the UK. In the case of a DDCM that falls within the previously stated provisions, clinical development may begin after the relevant ethical approvals. However, this rule does not apply to DDCMs of vaccines, whose clinical development can only be started after analysis and consent by ANVISA and the relevant ethical approvals. ResNo573 delineates that the provisions of this regulation apply to DDCMs received by ANVISA and whose analysis was not initiated by the technical area. See Submission Process section for details on complying with ResNo573.
ResNo601, in turn, provides for the simplified analysis, on an exceptional and temporary basis of DDCMs, amended DDCMs, and substantial amendments to clinical protocols that are of national importance due to the COVID-19 public health emergency. These submissions may be analyzed in a simplified manner provided that they are identical to the one (1) approved by the ICH member country or the UK. Refer to ResNo601 and BRA-3 for further information on simplified analysis submission requirements.
Overview
In accordance with the FDCAct, 21CFR50, and 21CFR312, the Food & Drug Administration (FDA) has authority over clinical investigations for drug and biological products regulated by the agency. 21CFR312 specifies that the scope of the FDA’s assessment for investigational new drug applications (INDs) includes all clinical trials (Phases 1-4). Based on 21CFR56 and 21CFR312, institutional ethics committee (EC) review of the proposed clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the United States (US)).
As delineated in 21CFR312 and USA-42, sponsors are required to submit an IND to the FDA to obtain an agency exemption to ship investigational drug(s) across state lines to conduct drug or biologic clinical trial(s). An IND specifically exempts an investigational drug or biologic from FDA premarketing approval requirements that would otherwise be applicable. 21CFR312 states that “‘IND’ is synonymous with ‘Notice of Claimed Investigational Exemption for a New Drug.’"
According to USA-42, the FDA categorizes INDs as either commercial or non-commercial (research) and classifies them into the following types:
- Investigator INDs - Submitted by physicians who both initiate and conduct the investigation, and who are directly responsible for administering or dispensing the investigational drug.
- Emergency Use INDs - Enable the FDA to authorize experimental drugs in an emergency situation where normal IND submission timelines cannot be met. Also used for patients who do not meet the criteria of an existing study protocol, or if an approved study protocol does not exist.
- Treatment INDs - Submitted for experimental drugs showing potential to address serious or immediately life-threatening conditions while the final clinical work is conducted and the FDA review takes place.
Per the G-PharmeCTD, non-commercial products refer to products not intended to be distributed commercially and include the above listed IND types.
As indicated in the G-IND-Determination, in general, human research studies must be conducted under an IND if all of the following research conditions apply:
- A drug is involved as defined in the FDCAct
- A clinical investigation is being conducted as defined in 21CFR312
- The clinical investigation is not otherwise exempt from 21CFR312
The G-IND-Determination states that biological products may also be considered drugs within the meaning of the FDCAct.
Further, per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a marketed drug primarily depends on the intent of the investigation and the degree of risk associated with the use of the drug in the investigation. See 21CFR312 and the G-IND-Determination for detailed exemption conditions for marketed drugs.
Clinical Trial Review Process
As delineated in 21CFR312, the FDA's primary objectives in reviewing an IND are to ensure human participant safety and rights in all phases of the investigation. Phase 1 submission reviews focus on assessing investigation safety, and Phase 2 and 3 submission reviews also include an assessment of the investigation’s scientific quality and ability to yield data capable of meeting marketing approval statutory requirements. An IND may be submitted for one (1) or more phases of an investigation.
As per USA-41 and USA-94, the FDA’s Center for Drug Evaluation and Research (CDER) and the Center for Biologics Evaluation and Research (CBER) receive IND submissions for drugs, therapeutic biological products, and other biologicals. Per the FDCAct and 21CFR312, an IND automatically goes into effect 30 calendar days from receipt, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. A clinical hold is an order the FDA issues to delay or suspend a clinical investigation. If the FDA determines there may be grounds for imposing a clinical hold, an attempt will be made to discuss and resolve any issues with the sponsor prior to issuing the clinical hold order. See 21CFR312 for more information on clinical holds.
According to USA-41, with respect to sponsor-investigators, once the FDA receives the IND, an IND number will be assigned and the application will be forwarded to the appropriate reviewing division. A letter will be sent to the sponsor-investigator providing notification of the assigned IND number, date of receipt of the original application, address where future submissions to the IND should be sent, and the name and telephone number of the FDA person to whom questions about the application should be directed.
As indicated in 21CFR312, the FDA may at any time during the course of the investigation communicate with the sponsor orally or in writing about deficiencies in the IND or about the FDA's need for more data or information. Furthermore, on the sponsor's request, the FDA will provide advice on specific matters relating to an IND.
21CFR312 indicates that once an IND is in effect, a sponsor must submit a protocol amendment if intending to conduct a study that is not covered by a protocol already contained in the IND, there is any change to the protocol that significantly affects the safety of subjects, or a new investigator is added to carry out a previously submitted protocol. A sponsor must submit a protocol amendment for a new protocol or a change in protocol before its implementation, while protocol amendments to add a new investigator or to provide additional information about investigators may be grouped and submitted at 30-day intervals. See 21CFR312 for more information on protocol amendments.
As per 21CFR312, if no subjects are entered into a clinical study two (2) years or more under an IND, or if all investigations under an IND remain on clinical hold for one (1) year or more, the IND may be placed by the FDA on inactive status. An IND that remains on inactive status for five (5) years or more may be terminated. See 21CFR312 for more information on inactive status.
21CFR312 indicates that the FDA may propose to terminate an IND based on deficiencies in the IND or in the conduct of an investigation under an IND. If the FDA proposes to terminate an IND, the agency will notify the sponsor in writing, and invite correction or explanation within a period of 30 days. If at any time the FDA concludes that continuation of the investigation presents an immediate and substantial danger to the health of individuals, the FDA will immediately, by written notice to the sponsor, terminate the IND. See 21CFR312 for more information on FDA termination.
For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.
Expedited Processes
USA-84 further indicates that the FDA has several approaches to making drugs available as rapidly as possible:
- Breakthrough Therapy – expedites the development and review of drugs which may demonstrate substantial improvement over available therapy
- Accelerated Approval – allow drugs for serious conditions that fill an unmet medical need to be approved based on a surrogate endpoint
- Priority Review – a process by which the FDA’s goal is to take action on an application within six (6) months
- Fast Track – facilitates the development and expedites the review of drugs to treat serious conditions and fill an unmet medical need
See USA-84 and USA-85 for more information on each process. Additionally, see the FDCAct, as amended by the FDORA, for changes to the accelerated approval process.
Other Considerations
The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.
For information on the appropriate use of adaptive designs for clinical trials and additional information to provide the FDA to support its review, see G-AdaptiveTrials.
For research involving cellular and gene therapy, see the guidance documents at USA-80.
National Health Surveillance Agency (ANVISA)
As set forth in ResNo9, ResNo222, and ResNo76, the sponsor is responsible for paying a Sanitary 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 ResNo222 and ResNo76, once the sponsor has completed the process of submitting a DDCM request (“petition” in Portuguese), ANVISA’s Electronic Petition Request System (BRA-38) generates a Union Collection Guide (Guia de Recolhimento da União (GRU)). According to BRA-43, ANVISA uses the GRU as its primary method to generate TFVS fees. Refer to BRA-51 for detailed information on the GRU and BRA-69 for information on the TFVS fee. See also BRA-10 for additional information on TFVS requirements.
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 BRA-11 that was implemented by OrdNo45 and ResNo198, the fees range from 983.85 Brazilian Reals to 19,677 Brazilian Reals to obtain clinical research approval. BRA-8 further notes that ANVISA charges a fee for substantial amendments to the clinical protocol.
Payment Instructions
As described in ResNo222, the GRU contains a bar code that may be scanned for payment purposes at the Bank of Brazil or any participating financial institution participating in the bank clearing system. BRA-43 states that bank payments may be completed in person, or by using the bank’s website or self-service (ATM) terminals. Payment must be made within 30 days after the GRU has been issued. See BRA-67 for further guidance on how to complete the electronic petition request process for fee payments.
Food & Drug Administration
The Food & Drug Administration (FDA) does not levy a fee to review investigational new drug submissions.
However, per the FDCAct, FDARA, and USA-45, the FDA has the authority to assess and collect user fees from companies that produce certain human drug and biological products as part of the New Drug Application (NDA). Per USA-43, the NDA is the vehicle through which drug sponsors formally propose that the FDA approve a new pharmaceutical for sale and marketing in the United States. The data gathered during the animal studies and human clinical trials of an investigational new drug become part of the NDA.
Overview
As per ResNo466, ResNo446, and OSNo001, Brazil has a centralized registration process for ethics committees (ECs) and requires institutional level EC approval for each trial site. The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs (Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)), and for registering and accrediting the ECs (CEPs). ResNo466, ResNo446, and OSNo001 state that CONEP is a collegiate advisory body directly linked to the National Health Council (Conselho Nacional de Saúde (CNS)), a permanent body within the Ministry of Health (MOH)’s Unified Health System (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, and OSNo001. ResNo466 further notes that institutions conducting research involving human participants may establish one (1) or more ECs (CEPs) according to their particular requirements. For those institutions lacking an EC (CEP), or in the case of an investigator without an institutional affiliation, CONEP is required to suggest an EC (CEP) to conduct the protocol review. Together, the ECs (CEPs) and CONEP represent the ethical review system in Brazil, known as the CEP/CONEP System, as described in ResNo466, OSNo001, and G-ClinProtocols-FAQs. See also BRA-50, BRA-16, and BRA-49 for useful information on CONEP and the CNS.
Ethics Committee Composition
National Research Ethics Commission (CONEP)
As per OSNo001 and ResNo446, CONEP is an independent and multidisciplinary organization consisting of 30 appointed members and five (5) alternate members. The members represent a balanced gender composition; eight (8) members must equally represent various segments of the CNS. In addition, according to BRA-16, five (5) members must have a background in ethical research and health, and eight (8) members must represent the theological, legal, health management, and other related professions. Per ResNo446, CONEP also has an Executive Secretary appointed by the MOH’s Secretariat for Science, Technology and Strategic Inputs and an Assistant Secretary appointed by the CNS to coordinate CONEP’s work and to manage the technical and operational work to be carried out by the Executive Secretary. See ResNo466, OSNo001, ResNo446, and BRA-16 for detailed information on CONEP composition and responsibilities. See also BRA-50 for useful information on CONEP.
Ethics Committees (Committees of Ethics in Research (CEPs))
As per the PANDRH-GCPs, an institutional EC (CEP) must have at least five (5) members who collectively encompass the qualifications and experience required to review and evaluate the scientific, medical, and ethical aspects of a proposed clinical trial. By comparison, the OMREC requires the EC (CEP) to be composed of a minimum of seven (7) members having proven expertise in research. The PANDRH-GCPs, the OSNo001, and OMREC also indicate that the EC (CEP) should be multidisciplinary, represent a balanced gender and age composition, and consist of members embodying community interests and concerns. The OMREC further states that not more than half of its members should belong to the same professional category. In addition, as per the PANDRH-GCPs, in communities where minority ethnic populations predominantly reside, the EC (CEP) should include a member, alternate, or consultant from that group. The EC (CEP) may also designate alternate members whose functions are delineated in the EC’s (CEP’s) standard operating procedures (SOPs). ResNo647 further establishes standards and mandatory requirements for all ECs (CEPs) in Brazil to include Research Participant Representatives (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.
Additional criteria for EC (CEP) membership is available in Section 3.2 of the PANDRH-GCPs and Section 2 of OMREC.
Terms of Reference, Review Procedures, and Meeting Schedule
As set forth in the PANDRH-GCPs and OMREC, each EC (CEP) must have written SOPs, including a process for conducting reviews. The SOPs should include information on EC (CEP) composition, meeting schedules, frequency of reviews, requirements for initial and ongoing evaluation of the research study, and requirements for notifying the investigator and the institution of results related to the study’s initial and ongoing evaluation.
Per the PANDRH-GCPs and OMREC, 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 ResNo370, the registration and appointment terms of EC (CEP) members are valid for three (3) years and may be renewed at the end of that period.
The PANDRH-GCPs also state that the EC (CEP) must retain all relevant records (e.g., SOPs, member lists, member affiliations and occupations, documents presented, meeting minutes, and correspondence) for three (3) years after the study’s conclusion, and make them available to the regulatory authorities upon request.
For detailed EC (CEP) procedures and information on other administrative processes, see Sections 3.3 and 3.4 of the PANDRH-GCPs and the OMREC. Also, see CLNo1-2022 for instructions on submitting administrative documents via email to CONEP to speed up EC (CEP) accreditation and renewal processes and maintain regular functioning of ECs (CEPs), and CLNo25 for guidance on conducting virtual CEP/CONEP system meetings.
Overview
As indicated in 21CFR50, 21CFR56, and 21CFR312, the United States (US) has a decentralized process for the ethics review of clinical investigations. The sponsor must obtain institutional level ethics committee (EC) approval for each study. (Note: Institutional ECs are referred to as institutional review boards (IRBs) in the US.)
As set forth in 21CFR50, 21CFR56, and 21CFR312, all clinical investigations for drug and biological products regulated by the Food & Drug Administration (FDA) require institutional EC approval.
The Pre2018-ComRule and the RevComRule also require that human subjects research receive institutional EC approval. However, note that these regulations’ definition of “human subject” does not include the use of non-identifiable biospecimens. Therefore, the use of non-identifiable biospecimens in research does not, on its own, mandate the application of the Pre2018-ComRule to such research. However, the RevComRule does require federal departments or agencies implementing the policy to work with data experts to reexamine the meaning of “identifiable private information” and “identifiable specimen” within one (1) year of the effective date and at least every four (4) years thereafter. In particular, these agencies will collaboratively assess whether there are analytic technologies or techniques that could be used to generate identifiable private information or identifiable specimens.
(See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)
Per the RevComRule, for non-exempt research (or exempt research that requires limited EC review) reviewed by an EC not operated by the institution doing the research, the institution and the EC must document the institution's reliance on the EC for research oversight and the responsibilities that each entity will undertake to ensure compliance with the RevComRule. Compliance can be achieved in a variety of ways, such as a written agreement between the institution and a specific EC, through the research protocol, or by implementing an institution-wide policy directive that allocates responsibilities between the institution and all ECs not operated by the institution. Such documentation must be part of the EC’s records. The G-HHS-Inst-Engagemt can help an institution to determine if a research study can be classified as non-exempt.
Ethics Committee Composition
As stated in 21CFR56, the Pre2018-ComRule, and the RevComRule, an EC must be composed of at least five (5) members with varying backgrounds to promote complete and adequate research proposal review. The EC must be sufficiently qualified through member experience, expertise, and diversity, in terms of race, gender, cultural backgrounds, and sensitivity to issues such as community attitudes, to promote respect for its advice and counsel in safeguarding human participants’ rights and welfare. EC members must possess the professional competence to review research activities and be able to ascertain the acceptability of proposed research based on institutional commitments and regulations, applicable laws, and standards. In addition, if an EC regularly reviews research involving vulnerable populations, the committee must consider including one (1) or more individuals knowledgeable about and experienced in working with those participants. See the Vulnerable Populations section for details on vulnerable populations.
At a minimum, each EC must also include the following members:
- One (1) primarily focused on scientific issues
- One (1) focused on nonscientific issues
- One (1) unaffiliated with the institution, and not part of the immediate family of a person affiliated with the institution
No EC member may participate in the initial or continuing review of any project in which the member has a conflicting interest, except to provide EC requested information.
Terms of Reference, Review Procedures, and Meeting Schedule
As delineated in 21CFR56, ECs must follow written procedures for the following:
- Conducting initial and continuing reviews, and reporting findings and actions
- Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
- Ensuring that changes in approved research are not initiated without EC review and approval except where necessary to eliminate apparent immediate hazards to participants
- Ensuring prompt reporting to the EC, institution, and FDA of changes in research activity; unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination
Per the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, ECs must establish and follow written procedures for the following:
- Conducting initial and continuing reviews, and reporting findings and actions to the investigator and the institution
- Determining which projects require review more often than annually, and which projects need verification from sources other than the investigator that no material changes have occurred since the previous EC review
- Ensuring prompt reporting to the EC of proposed changes in research and ensuring that investigators conduct the research in accordance with the terms of the EC approval until any proposed changes have received EC review and approval, except where necessary to eliminate apparent immediate hazards to participants
- Ensuring prompt reporting to the EC, the institution, the FDA, and the Department of Health & Human Services (HHS)’ Office for Human Research Protections (OHRP) of any unanticipated problems involving risks to participants or others; any instance of serious or continuing noncompliance with these regulations or EC requirements or determinations; or EC approval suspension/termination.
21CFR56, the Pre2018-ComRule, and the RevComRule further require that an institution, or where appropriate an EC, prepare and maintain adequate documentation of EC activities, including copies of all research proposals reviewed. The applicable records must be retained for at least three (3) years after completion of the research. For more details on the EC records included in this requirement, see the Pre2018-ComRule, the RevComRule, and 21CFR56.
See G-IRBProcs for detailed FDA guidance on EC written procedures to enhance human participant protection and reduce regulatory burden. The guidance includes a Written Procedures Checklist that incorporates regulatory requirements as well as recommendations on operational details to support the requirements.
Per 21CFR56, the Pre2018-ComRule, and the RevComRule, proposed research must be reviewed during convened meetings at which a majority of the EC members are present, including at least one (1) member whose primary concerns are nonscientific, except when an expedited review procedure is used. Research is only considered approved if it receives the majority approval of attending members.
Refer to the Pre2018-ComRule, the RevComRule, 21CFR56, the G-IRBProcs, and the G-IRBFAQs for detailed EC procedural requirements.
In addition, per the Pre2018-ComRule, the RevComRule, and the G-HHS-Inst-Engagemt, any institution engaged in non-exempt human subjects research conducted or supported by a Common Rule department/agency (as identified in USA-65) must also submit a written assurance of compliance to OHRP. According to USA-59, the Federalwide Assurance (FWA) is the only type of assurance of compliance accepted and approved by OHRP for HHS-funded research. See USA-57 for more information on FWAs.
Overview
As set forth in ResNo466, the PANDRH-GCPs, ResNo251, and the G-ClinProtocols-FAQs, the primary scope of information assessed by ethics committees (ECs) (Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) and the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), jointly known as the CEP/CONEP System, relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial.
Per ResNo466, the PANDRH-GCPs, ResNo251, and OSNo001, the CEP/CONEP System members must pay special attention to reviewing informed consent and to protecting the welfare of certain classes of participants deemed to be vulnerable (See the Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these populations). ResNo304 further establishes specific ethical requirements for research studies involving indigenous populations. Detailed information on documentation and consent requirements for studies involving indigenous populations is available in the Documentation Requirements, Vulnerable Populations, and Consent for Specimen sections.
The CEP/CONEP System members are also responsible for ensuring an independent, timely, and competent review of all ethical aspects of the clinical trial protocol as stated in ResNo466, the PANDRH-GCPs, and OSNo001. It must act in the interests of the potential research participants and the communities involved, evaluating the possible risks and expected benefits to participants, confirming the suitability of the investigator(s), facilities, and methods, and verifying the adequacy of confidentiality and privacy safeguards. Refer to ResNo466, the PANDRH-GCPs, and OSNo001 for detailed ethical review guidelines that govern the CEP/CONEP System.
National Research Ethics Commission (CONEP)-Designated Protocol Reviews
Per ResNo580, the Ministry of Health (MOH)’s Secretary of Science, Technology and Strategic Inputs refers protocols to CONEP that are determined to be of strategic public health interest for the Unified Health System (SUS) (BRA-53). ResNo580 recognizes strategic research protocols as those studies that may contribute to public health, justice, reduction of social inequalities and technological dependencies, and those that address public health emergencies. Refer to the Oversight of Ethics Committees section for additional information on CONEP’s review requirements for this type of protocol. A working group was also created to support the MOH’s assessment of research involving human beings when carried out in the SUS sphere, per OrdNo552. The interagency working group includes National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)), CONEP, and the National Health Council (Conselho Nacional de Saúde (CNS)), and is coordinated by an MOH representative.
In addition to conducting public health and international project reviews, per ResNo466, ResNo446, and ResNo340, CONEP is required to review certain studies involving human genetics, human reproduction, invasive therapeutic procedures, indigenous populations, genetically modified organisms, embryonic stem cells, and the establishment and operation of biobanks for research. Refer to ResNo466, ResNo446, and ResNo340 for specific details on CONEP protocol review requirements. See also CLNo172 for additional guidance on classifying protocol thematic areas that require CONEP review (e.g., protocols on the constitution and operation of biobanks for research purposes); CLNo34 for guidance on processing biobank development protocols electronically, and; CLNo041 for CONEP specimens consent instructions. See also ResNo506 for information on the role of CEP/CONEP System members in reviewing protocols submitted for clinical trials with advanced therapy products in Brazil (i.e., medicines for human use based on genes, tissues, or cells).
Review Pathways
ResNo674 provides review criteria and corresponding timelines to classify research and the processing of research protocols involving human beings in the CEP/CONEP System based upon study type and level of intervention in the human body. The regulation divides research into two (2) groups: 1) studies seeking to describe or understand phenomena that has happened or happen in the research participant’s daily life; and 2) studies that aim to verify the effect of an investigational product (IP) or technique used in research, deliberately applied to the participant, prospectively monitored, and which may or may not involve a control group. The studies are further characterized according to procedure and whether it involves intervention in the human body and if it is invasive.
Classification by study design and procedure is as follows: Type A – observational research; Type B – observational research with human body intervention; and Type C – investigational research designed to verify the effect of an IP (including a medicine, drug, biological product, or health device) or an investigational technique used in research, deliberately applied to the participant, prospectively monitored, with or without a control. Type C studies are further divided into two (2) subtypes: C1 studies, in which the object of investigation is not an IP in the health area, and C2 studies, in which the object of investigation is an IP in the health area.
EC analysis varies according to the type of research and modulation factors (i.e., consent process, confidentiality, and/or research methods), and requires the reviewer to verify the documentation the investigator submits in Plataforma Brasil (BRA-34). Per BRA-93, Plataforma Brasil is a national and unified database of human subjects research records that represents the entire CEP/CONEP System. The platform is also used to track research applications from submission to final approval by the EC (CEP), and when necessary, by CONEP. See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.
There are four (4) ways of processing protocols in the CEP/CONEP System: express, simplified, collegiate, and special collegiate; the modulation factors per Annex II of ResNo674 provides additional characteristics to further modify the protocol processing method to be used. See ResNo674, BRA-4, and BRA-5 for additional information on the CEP/CONEP System’s protocol research classification and processing procedures. (Please note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor the Plataforma Brasil webpage for any developments.)
Role in Clinical Trial Approval Process
As delineated in ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, ANVISA and the EC (CEP) (and CONEP, if applicable) must approve a clinical trial application before a trial is permitted to commence. However, ResNo205 repealed the ResNo9 requirement that EC (CEP) approval must be submitted as part of the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel.
In addition, as indicated in ResNo9, and also noted in BRA-2, CONEP’s approval is not a requirement for ANVISA to approve the DDCM. However, the PANDRH-GCPs, ResNo9, and OSNo001 states that the EC (CEP) must review and approve any protocol amendments prior to those changes being implemented. According to BRA-1, when a protocol amendment is submitted to ANVISA, CONEP approval is not mandatory, but may be requested. In these cases, only the EC (CEP) is required to approve the amended protocol prior to implementation and ANVISA should be notified. Per ResNo9, the EC (CEP) is required to approve substantial protocol amendments prior to implementation. See ResNo9 and the G-DDCMManual for additional information on preparing DDCMs, and CLNo038 for the criteria CONEP uses to process protocol amendments.
ResNo466 and OSNo001 specify that the development and submission of research, as well as the implementation and disclosure of EC (CEP) and CONEP opinions, must occur via BRA-34. Also see the Timeline of Review section for additional EC timeline information. There is no stated expiration date for an EC (CEP) approval in ResNo466, the PANDRH-GCPs, ResNo9, or OSNo001. However, in the event that an EC (CEP) revokes its approval of a clinical protocol, it must record its reasons for doing so and immediately communicate this decision to the investigator and ANVISA.
Following the review process, the PANDRH-GCPs also states that the sponsor must receive the following information prior to the trial’s commencement:
- EC (CEP) member profiles (names and addresses)
- Documented approval of EC (CEP)’s favorable opinion
- Copy of EC (CEP) recommendations in case it has based its approval on change(s) in any aspect of the study (e.g., protocol modifications, written informed consent form, (ICF) or any other written information or other procedures)
The sponsor should also obtain documentation and dates relating to any EC (CEP) re-evaluations, re-approvals, withdrawals, or suspensions of approval from the investigator. (See the Submission Content section for additional details on the EC review process).
Additionally, CONEP has published a number of circular letters to clarify protocol review and processing procedures, submission instructions, and investigator responsibilities related to the following:
- Classifying protocol thematic areas requiring CONEP review (CLNo172)
- Processing protocol amendments (CLNo038)
- Providing general clinical trial guidelines (CLNo24 and CLNo24-Note)
- Presenting documentation required for CONEP analysis (CLNo062)
- Conducting virtual CEP/CONEP System meetings (CLNo25)
- Updating the informed consent form (ICF) (CLNo17)
- Additional clarifications on ICF text (CLNo51)
- Obtaining consent for human specimens (CLNo041)
- Using medical records data for research purposes (CLNo039)
- Submitting requests for research center inclusion/exclusion (CLNo046)
- Citing clinical trial registries in protocols (CLNo060)
- Processing biobank development protocols electronically (CLNo34)
- Linking investigator/institutions to the responsible EC in submissions (CLNo183)
- Standardizing consent and electronic assent for research participants and biobanks (CLNo23)
- Submitting research protocols with human bodies and/or anatomical parts (CLNo26)
- Processing adverse events for Brazil and abroad (CLNo13)
- Submitting the Serious Adverse Event (SAE) form and instructions (CLNo008)
The above circulars are described in more detail where appropriate across the Brazil profile.
Foreign Research
As delineated in ResNo292, ResNo446, and ResNo466, applications with coordination and/or sponsorship originating outside of Brazil require additional EC review by CONEP. Per ResNo446, an exception to the required CONEP review applies to studies that have been fully carried out abroad and have been approved by an EC or equivalent body in the country of origin. ResNo580 also amends the ResNo466 requirements related to co-sponsored research projects and those involved with shipping human biological materials. This regulation states that when the MOH’s Secretariat of Science, Technology and Strategic Health Inputs issues an official agreement for a specific research project, the EC (CEP) for the proposing institution may conduct its review without the need for additional review by CONEP.
ResNo292 also explains that the scope of research from abroad or with foreign participation includes: collaboration between public or private foreign individuals or legal entities; sending and/or receiving biological materials from humans; sending and/or receiving data and information collected to aggregate research results; and international multicenter studies. For protocols within this thematic area, per ResNo292, special attention should be given to insuring the EC or equivalent institution within the originating country has issued an approval. If not, the Brazilian EC (CEP) and CONEP must approve the protocol. Refer to ResNo292 and the G-ClinProtocols-FAQs for additional guidance on research studies submitted from abroad.
Multicenter Research
ResNo346 establishes the submission process for multicenter research protocols and indicates that the coordinating center’s EC (CEP) should initially review the protocol and forward it to CONEP for review. Per OSNo001, the principal investigator is also required to submit a list of the participating institutions and associated protocols, the coordinating center, and the EC (CEP) designated to monitor the study’s progress as part of the research protocol package sent to the EC (CEP) for review. ResNo346 further notes that CONEP will only evaluate the first protocol submitted and then send its final opinion to the original EC (CEP) and the other participating institutions. ResNo674 similarly explains that the initial analysis of the research protocol using the research classification procedure will occur at the EC (CEP) of the coordinating center or the accredited EC (CEP), when applicable, and will be subsequently forwarded for analysis by the EC (CEP) of the other co-participating centers and/or institutions, after approval.
See ResNo346 for additional multicenter protocol processing information and OSNo01 for detailed information on the coordinating center’s role in this process.
Overview
21CFR56, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the primary scope of information assessed by the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) relates to maintaining and protecting the dignity and rights of research participants and ensuring their safety throughout their participation in a clinical trial. As delineated in 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC must also 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). The EC is also responsible for ensuring a competent review of the research protocol, evaluating the possible risks and expected benefits to participants, and verifying the adequacy of confidentiality safeguards.
See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.
Role in Clinical Trial Approval Process
In accordance with 21CFR56 and 21CFR312, the Food & Drug Administration (FDA) must review an investigational new drug application (IND) and an EC must review and approve the proposed study prior to a sponsor initiating a clinical trial. The institutional EC review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial. According to 21CFR56, the Pre2018-ComRule, and the RevComRule, the EC may approve, require modifications in (to secure approval), or disapprove the research.
Refer to the G-RevComRule-FDA for information on the impact of the RevComRule on studies conducted or supported by the Department of Health & Human Services (HHS) that must also comply with FDA regulations.
Per 21CFR56, the Pre2018-ComRule, the RevComRule, and the G-IRBContRev, an EC has the authority to suspend or terminate approval of research that is not being conducted in accordance with the EC’s requirements or that has been associated with unexpected serious harm to participants. Any suspension or termination of approval will include a statement of the reasons for the EC’s action and will be reported promptly to the investigator, appropriate institutional officials, and the department or agency head (e.g., the FDA). See the G-IRBContRev for additional information and FDA recommendations on suspension or termination of EC approval.
Expedited Review
21CFR56, the Pre2018-ComRule, and the RevComRule indicate that the FDA and HHS maintain a list of research categories that may be reviewed by an EC through an expedited review procedure (see the G-IRBExpdtdRev for the list). An EC may use the expedited review procedure to review the following:
- Some or all of the research appearing on the list and found by the reviewer(s) to involve no more than minimal risk
- Minor changes in previously approved research during the period (of one (1) year or less) for which approval is authorized
- Under the RevComRule, research for which limited EC review is a condition of exemption
21CFR56, the Pre2018-ComRule, and the RevComRule specify that under an expedited review procedure, the review may be carried out by the EC chairperson or by one (1) or more experienced reviewers designated by the chairperson from among the EC’s members. In reviewing the research, the reviewers may exercise all of the authorities of the EC except that the reviewers may not disapprove the research. A research activity may be disapproved only after review in accordance with the EC’s non-expedited review procedure.
Continuing Review and Re-approval
21CFR56 and the G-IRBContRev state that any clinical investigation must not be initiated unless the reviewed and approved study remains subject to continuing review at intervals appropriate to the degree of risk, but not less than once a year. The G-IRBContRev notes that when continuing review of the research does not occur prior to the end of the approval period specified by the EC, EC approval expires automatically. A lapse in EC approval of research occurs whenever an investigator has failed to provide continuing review information to the EC, or the EC has not conducted continuing review and re-approved the research by the expiration date of the EC approval. In such circumstances, all research activities involving human participants must stop. Enrollment of new participants cannot occur after the expiration of EC approval.
In addition, per the G-IRBContRev, research that qualified for expedited review at the time of initial review will generally continue to qualify for expedited continuing review. For additional information and FDA recommendations regarding continuing review, see the G-IRBContRev.
The Pre2018-ComRule similarly indicates that the EC must conduct reviews at intervals appropriate to the degree of risk, but not less than once per year. However, the RevComRule provides the following exceptions to the continuing review requirement, unless an EC determines otherwise:
- Research eligible for expedited review
- Research reviewed by the EC in accordance with the limited EC review described in Section 46.104 of the RevComRule
- Research that has progressed to the point that it involves data analysis and/or accessing follow-up clinical data from procedures that are part of clinical care
Exemptions under the Revised Common Rule
Per the RevComRule, certain categories of research are exempt from EC review, and some “exempt” activities require limited EC review or broad consent. Users should refer to Section 46.104 of the RevComRule for detailed information on research categories specifically exempt from EC review, or exempt activities requiring limited EC review or broad consent.
Per USA-54, for secondary research that does not qualify for an exemption under the RevComRule, the applicant must either apply for a waiver of the informed consent requirement from the EC, obtain study-specific informed consent, or obtain broad consent.
Further, the RevComRule modifies what constitutes research to specifically exclude the following types of research:
- Scholarly and journalistic activities
- Public health surveillance activities authorized by a public health authority to assess onsets of disease outbreaks or conditions of public health importance
- Collection and analysis of information, biospecimens, or records by or for a criminal justice agency for criminal investigative activities
- Authorized operational activities in support of intelligence, homeland security, defense, or other national security missions
See the G-IRBFAQs, the G-OHRP-IRBApprvl, and USA-54 for frequently asked questions regarding EC procedures, approval with conditions, example research, expedited review, limited review, and continuing review.
Other Considerations
Per the FDA’s G-IRBReview, an EC may review studies that are not performed on-site. When an institution has a local EC, the written procedures of that EC or of the institution should define the scope of studies subject to review by that EC. A non-local EC may not become the EC of record for studies within that defined scope unless the local EC or the administration of the institution agree. Any agreement to allow review by a non-local EC should be in writing. For more information, see G-IRBReview.
Cooperative Research Studies
In the event of multicenter clinical studies, also known as cooperative research studies, taking place at US institutions that are subject to the RevComRule, the institutions must rely on a single EC to review that study for the portion of the study conducted in the US. The reviewing EC will be identified by the Common Rule department/agency (as identified in USA-65) supporting or conducting the research or proposed by the lead institution subject to the acceptance of the department/agency. The exceptions to this requirement include: when multicenter review is required by law (including tribal law) or for research where any federal department or agency supporting or conducting the research determines that the use of a single EC is not appropriate.
Designed to complement the RevComRule, per the NIHNotice16-094 and the NIHNotice17-076, the National Institutes of Health (NIH) issued a final policy requiring all institute-funded multicenter clinical trials conducted in the US to be overseen by a single EC, unless prohibited by any federal, tribal, or state law, regulation, or policy.
For more information on multicenter research, see the FDA’s G-CoopRes. For more information on how new sites added to ongoing cooperative research can follow the same version of the Common Rule, see the HHS Office for Human Research Protections (OHRP)’s G-ComRuleCnsstncy.
National Research Ethics Commission (CONEP)
According to ResNo466 and OMREC, the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) does not permit ethics committees (ECs) (Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)), to charge a fee to review clinical trial protocols. CONEP states that financing to support ethical reviews should come from a specific scientific committee budget designated within each institution.
Many institutional ethics committees (ECs) (referred to as institutional review boards (IRBs) in the United States (US)) charge fees to review research proposals submitted by industry-sponsored research or other for-profit entities. However, this varies widely by institution. Neither the Department of Health & Human Services (HHS) nor the Food & Drug Administration (FDA) regulate institutional EC review fees. Because each EC has its own requirements, individual ECs should be contacted to confirm their specific fees.
Overview
The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central statutory body responsible for the registration, audit, and accreditation of ethics committees (ECs) (Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)). As per ResNo466, OSNo001, and ResNo446, CONEP was created by the Ministry of Health (MOH) to provide ethical oversight of clinical research and to safeguard the rights and welfare of human participants involved in clinical studies. CONEP reports to the National Health Council (Conselho Nacional de Saúde (CNS)), the advisory body to the MOH.
As delineated in ResNo466, OSNo001, and ResNo446, CONEP’s core responsibilities center on:
- Examining the ethical aspects of research involving human participants
- Analyzing and monitoring research protocols and issuing opinions on applications with coordination or sponsorship originating outside Brazil, unless the co-sponsor is the Brazilian Government and applications are related to specialized thematic areas (i.e., human genetics, human reproduction, vaccines, and human biological materials)
- Preparing and updating relevant ethical standards
- Registering, auditing, accrediting, and training ECs (CEPs)
- Monitoring EC (CEP) processes
- Promoting and participating in educational EC (CEP) activities
See also the Scope of Review section for detailed EC (CEP) and CONEP review requirements associated with protocols originating outside of Brazil.
Registration, Auditing, and Accreditation
As per ResNo466, ResNo370, SP006REC, OSNo001, and ResNo446, 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. ResNo370 and CNSResNo506 state that accreditation is valid for three (3) years. To apply for renewal, an EC (CEP) must follow the same procedures as in its initial application. The renewal application must be submitted within the window of 60 days before to 60 days after the accreditation’s expiration date, as noted in ResNo370, SP006REC, and CNSResNo506. See ResNo370, SP006REC, and CNSResNo506 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. (Please note: Per BRA-9, the protocol classification and processing system has not yet been implemented in BRA-34. The ClinRegs team will continue to monitor the Plataforma Brasil webpage for any developments.)
Overview
As delineated in 21CFR56 and 45CFR46-B-E, the Department of Health & Human Services (HHS) and the HHS’ Food & Drug Administration (FDA) have mandatory registration programs for institutional ethics committee (ECs), referred to as institutional review boards (IRBs) in the United States (US). A single electronic registration system (USA-28) for both agencies is maintained by HHS’ Office for Human Research Protections (OHRP).
Registration, Auditing, and Accreditation
In accordance with the G-IRBReg-FAQs and USA-61, EC registration with the HHS OHRP system (USA-28) is not a form of accreditation or certification by either the FDA that the EC is in full compliance with 21CFR56, or by the HHS that the EC is in full compliance with 45CFR46-B-E. Neither EC competence nor expertise is assessed during the registration review process by either agency.
Food & Drug Administration
According to 21CFR56 and the G-IRBReg-FAQs, the FDA requires each EC in the US, that either reviews clinical investigations regulated by the agency under the FDCAct or reviews investigations intended to support research or marketing permits for agency-regulated products, to register electronically in the HHS OHRP system (USA-28). Only individuals authorized to act on the EC’s behalf are permitted to submit registration information. Non-US ECs may register voluntarily. The G-IRBReg-FAQs also indicates that while registration of non-US ECs is voluntary, the information the FDA receives from them is very helpful.
As stated in 21CFR56 and the G-IRBReg-FAQs, any EC not already registered in the HHS OHRP system (USA-28) must submit an initial registration prior to reviewing a clinical investigation in support of an investigational new drug application (IND). The HHS OHRP system (USA-28) provides instructions to assist users, depending on whether the EC is subject to regulation by only the OHRP, only the FDA, or both the OHRP and the FDA.
21CFR56 and the G-IRBReg-FAQs indicate that FDA EC registration must be renewed every three (3) years. EC registration becomes effective after review and acceptance by the HHS.
See 21CFR56 and the G-IRBReg-FAQs for detailed EC registration submission requirements. See the G-IRBInspect for FDA inspection procedures of ECs.
Office for Human Research Protections
Per the Pre2018-ComRule and RevComRule, institutions engaging in research conducted or supported by a Common Rule department/agency (as identified in USA-65) must obtain an approved assurance that it will comply with the Pre2018-ComRule or RevComRule requirements and certify to the department/agency heads that the research has been reviewed and approved by an EC provided for in the assurance.
Per USA-59, a Federalwide Assurance (FWA) of compliance is a document submitted by an institution (not an EC) engaged in non-exempt human subjects research conducted or supported by HHS that commits the institution to complying with Pre2018-ComRule or RevComRule requirements. FWAs also are approved by the OHRP for federalwide use, which means that other federal departments and agencies that have adopted the Federal Policy for the Protection of Human Subjects (Pre2018-ComRule or RevComRule) may rely on the FWA for the research that they conduct or support. Institutions engaging in research conducted or supported by non-HHS federal departments or agencies should consult with the sponsoring department or agency for guidance regarding whether the FWA is appropriate for the research in question.
Per USA-54, institutions do not need to change an existing FWA because of the RevComRule. See USA-57 for more information on FWAs.
Per 45CFR46-B-E and USA-61, all ECs that review human subjects research conducted or supported by HHS and are to be designated under an OHRP FWA must register electronically with the HHS OHRP system (USA-28). An individual authorized to act on behalf of the institution operating the EC must submit the registration information. EC registration becomes effective for three (3) years when reviewed and approved by OHRP.
Per USA-59, an institution must either register its own EC (an “internal” EC) or designate an already registered EC operated by another organization (“external” EC) after establishing a written agreement with that other organization. Additionally, each FWA must designate at least one (1) EC registered with the OHRP. The FWA is the only type of assurance of compliance accepted and approved by the OHRP.
See 45CFR46-B-E, USA-58, and USA-61 for detailed registration requirements and instructions.
Overview
As stated in ResNo9, the G-DDCMManual, and BRA-8, the sponsor, the designated contract research organization (CRO), or the sponsor-investigator must apply to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to obtain approval for a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) for a drug to be registered in Brazil that will have all or part of its development in Brazil. Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside of Brazil require additional EC review by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. ResNo205 repealed the ResNo9 requirement that EC (CEP) approval must be submitted as part of the DDCM submission to ANVISA. Therefore, as explained in BRA-2 and BRA-1, regulatory and ethics reviews may be conducted in parallel.
Regulatory Submission
Per ResNo9, the G-DDCMManual, and BRA-8, the DDCM must contain at least one (1) Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)) in order for the DDCM to be approved. ResNo9 and the G-DDCMManual define a DEEC as a collection of documents submitted as part of the Experimental Drug Development Plan in the DDCM. Per the G-DDCMManual, the DEEC may be linked as a new process to the DDCM being submitted or as a process that modifies a previously submitted DDCM. ResNo9 further notes that DDCM submissions to ANVISA can only be made by a CRO when the sponsor has no headquarters or subsidiary in Brazil. See also BRA-42 for additional information on ANVISA protocol filing requirements.
As indicated in the G-DDCMManual and BRA-8, ANVISA recommends that the DDCM and associated documents (including the protocol, investigator’s brochure, informed consent form, and sponsor and institutional declarations) be translated into Portuguese. If a translated version of the submission is not provided, ANVISA’s technical area reviewer may issue a requirement for the sponsor to provide a free translation of the submitted documentation.
For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA, as stated in ResNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial DDCM submission. If the modification has occurred following ANVISA’s issuance of the authorizing document known as a Special Notice (Comunicado Especial (CE)), per BRA-8, ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version. While sponsors are required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, they are only required to submit substantial protocol amendments via a secondary petition whereas non-substantial DDCM protocol amendments should be submitted as part of the annual clinical trial report. Non-substantial amendments that do not impact the protocol should be presented to ANVISA as part of the drug development safety update report. See BRA-13 for updated ANVISA application forms.
See ResNo742, BRA-8, BRA-6, and BRA-7 for requirements associated with submitting DEECs for comparative bioavailability studies and comparative pharmacokinetic studies for biosimilars.
As described in the G-DDCMManual and BRA-8, all DDCM petitions (both initial and secondary) should be submitted electronically to ANVISA via the Electronic Petition Request System (BRA-38). Per BRA-58, once the DDCM has been submitted, the sponsor is then required to electronically file all the documents corresponding to the initial DDCM petition’s subject code checklist. As explained in BRA-75, the sponsor must electronically attach all the documents required in the related DDCM checklist (accessed online via BRA-38) that corresponds to one (1) of the following related subject codes: 10748, 10749, 10750, 10751, 10752, 10753, 10754, and 10755. BRA-59 provides detailed instructions for submitting the DDCM checklist documents via BRA-38.
As per BRA-59, the sponsor must first submit the DDCM petition request along with payment of the Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) fee. In accordance with ResNo222 and ResNo76, ANVISA will only review the DDCM once the sponsor has paid the TFVS fee and the original electronic bank payment receipt is forwarded together with the original printed copy of the Union Collection Guide (Guia de Recolhimento da União (GRU)), the petition (request), and all of the documentation required for protocol review. (See the Regulatory Fees section for detailed information on the payment process.)
ResNo222 and ResNo76 and further state 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 Electronic Petition Request System (BRA-38)
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-67 for step-by-step instructions on how to submit the initial DDCM petition and TFVS fee, and BRA-21 for the DDCM Petition Request Form.
Per the G-DDCMManual, all of the other documentation associated with the original DDCM including the secondary petitions and the DEEC(s) should be submitted electronically via BRA-38. ResNo204 and BRA-14 further note that DEECs may be submitted as priority requests to ANVISA to register, amend previously registered, or request prior consent for drug submissions. For detailed information on priority petition requirements, see the Scope of Assessment and Timeline of Review sections. The G-DDCMManual also specifies that for the electronic submission of secondary petitions and DEECs, the sponsor should append at least one (1) PDF file for each item contained in the petition checklist to enable text searching. It is possible to attach up to five (5) files of 750 kb each. BRA-8 also provides an example of an electronic submission in Annex 1.
In addition, BRA-92 provides detailed instructions for companies to comply with ANVISA’s requirement to submit an official document issued by an International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) member country regulatory authority or by the United Kingdom’s (UK’s) Medicines and Healthcare Products Regulatory Agency (MHRA), or a declaration of compliance with the criteria described in ResNo573. (Refer to the Scope of Assessment section for detailed information on ResNo573 requirements). Per BRA-92, if the company has already submitted a DDCM, the official document or declaration may be submitted as an attachment via email with the corresponding DDCM file number to: Pesquisaclinica@anvisa.gov.br, using the following subject line: RDC 573/2021 - Amendment - File XXXXXXX/XX-X. This will ensure that the request is reviewed in the shortest time possible. However, this additional submission is unnecessary for those cases in which the official document or declaration has already been attached to the DDCM by subject code of the subject code of “11634 - ENSAIOS CLÍNICOS - Análise Simplificada de Dossiê de Qualidade” (11634 - CLINICAL TRIALS - Simplified Analysis of the Quality Dossier) per ServBltnNo104. Refer to BRA-92 for additional information.
Refer to the Submission Content section for detailed DDCM petitions content requirements and substantial protocol modification documentation requirements.
See also BRA-19 and BRA-90 for guidance on scheduling pre-submission meetings with ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) to discuss the clinical development of a drug (e.g., DDCM, secondary petition, or DEEC), or a meeting to discuss a clinical trial application previously submitted to ANVISA. BRA-90 also provides the items required for scheduling each type of meeting and the corresponding request form to be submitted. Refer to BRA-98 for a list of COPEC documents, regulations, and clinical research guidelines available on the ANVISA portal and their corresponding locations.
Ethics Review Submission
Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the PI must also obtain approval from the EC (CEP). The PI is responsible for submitting the EC (CEP) application online via Plataforma Brasil (BRA-34). If applicable, the PI must also submit the application to CONEP for additional review and approval via BRA-34. Applications with coordination or sponsorship originating outside of Brazil require additional EC review by CONEP, unless the co-sponsor is the Brazilian Government. See BRA-33 for the most current Plataforma Brazil CEP and investigator manuals. Please refer to Scope of Review and Oversight of Ethics Committee sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. See also CLNo183 for instructions on linking investigator/institutions to the responsible EC in submissions; CLNo062 for guidance on submitting documentation required for CONEP analysis; and CLNo046 for instructions on submitting requests for inclusion/exclusion of research center(s).
Per OSNo001, the investigator is required to submit the research protocol in Portuguese to the CEP/CONEP System via BRA-34, and when applicable, accompanied by the originals in the foreign language.
In addition, per OSNo001, in the event of a multicenter clinical trial, the PI is required to submit a list of the participating institutions and the associated protocols as part of the research protocol package sent to the EC (CEP) for review.
Overview
As delineated in 21CFR312, USA-42, and USA-52, the United States (US) requires the sponsor to submit an investigational new drug application (IND) for the Food & Drug Administration (FDA)'s review and authorization to obtain an exemption to ship investigational drug or biological products across state lines and to administer these investigational products in humans. Per 21CFR312 and the G-IND-Determination, whether an IND is required to conduct an investigation of a drug to be marketed (this includes biological products under the FDCAct) primarily depends on the intent of the investigation, and the degree of risk associated with the use of the drug in the investigation. See the Scope of Assessment section for more information.
In addition, per 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the US) review of the clinical investigation may be conducted in parallel with the FDA review of the IND. However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.
Regulatory Submission
According to 21CFR312, meetings between a sponsor and the FDA may be useful in resolving questions and issues raised during the course of a clinical investigation. The FDA encourages such meetings to the extent that they aid in the evaluation of the drug and in the solution of scientific problems concerning the drug, to the degree the FDA's resources permit. See 21CFR312 for more information on meetings with the FDA.
A sponsor who is conducting a clinical trial to support a future marketing application may ask to meet with the FDA for a special protocol assessment (SPA) to help ensure the clinical trial can support the application. For more information, see G-SPA.
Additionally, the G-FDAComm describes the FDA’s philosophy regarding timely interactive communication with IND sponsors, the scope of appropriate interactions between review teams and sponsors, the types of advice appropriate for sponsors to seek from the FDA in pursuing their drug development programs, and general expectations for the timing of FDA response to sponsor inquiries. See the G-FDAComm for more information.
According to the G-PharmeCTD, which implements FDCAct requirements, and as described in USA-34 and USA-53, commercial IND submissions must be submitted in the Electronic Common Technical Document (eCTD) format. Noncommercial INDs are exempt from this eCTD format submission requirement. “Noncommercial products” refer to products not intended to be distributed commercially, including investigator-sponsored INDs and expanded access INDs (e.g., emergency use and treatment INDs). However, the G-AltrntElecSubs indicates that sponsors and applicants who receive an exemption or a waiver from filing in eCTD format should still provide those exempted or waived submissions electronically, in an alternate format.
The G-AltrntElecSubs and USA-35 indicate that for both eCTD and alternate electronic formats, submissions should include only FDA fillable forms and electronic signatures. Scanned images of FDA fillable forms should not be submitted. In addition, before making an electronic submission, a pre-assigned application number should be obtained by contacting the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER). See USA-35 for more information on requesting an application number.
For more information and detailed requirements on eCTD submissions, see the G-PharmeCTD, the G-eCTDTech, USA-35, and USA-36. Additionally, the G-CBER-ElecINDs provides instructions on how to submit an IND using an electronic folder structure on a CD-ROM.
According to the G-eCTDspecs and USA-7, eCTD submissions sized 10 GB and under for most applications must be submitted via the FDA Electronic Submissions Gateway (ESG) (USA-44). However, the G-eCTDspecs adds that the FDA also recommends the use of USA-44 for submissions greater than 10 GB when possible. See USA-8 for information on how to create an account.
As indicated in the G-eCTDspecs, physical media greater than 10 GB should be submitted using a USB drive. For specific instructions on how to submit physical media, email CDER at esub@fda.hhs.gov or CBER at esubprep@fda.hhs.gov. See the G-eCTDspecs for additional physical media information.
The IND must be submitted in English. As indicated in 21CFR312, the sponsor must submit an accurate and complete English translation of each part of the IND that is not in English. The sponsor must also submit a copy of each original literature publication for which an English translation is submitted.
According to USA-41 and USA-94, paper submissions of INDs should be sent to CDER or CBER at the following locations, as appropriate:
Drugs (submitted by Sponsor-Investigators):
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Central Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
Therapeutic Biological Product (submitted by Sponsor-Investigators):
Food and Drug Administration
Center for Drug Evaluation and Research (CDER)
Therapeutic Biological Products Document Room
5901-B Ammendale Rd.
Beltsville, MD 20705-1266
Center for Biologics Evaluation and Research-Regulated Products:
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Document Control Center
10903 New Hampshire Avenue
WO71, G112
Silver Spring, MD 20993-0002
(Note: Per USA-94, CBER also accepts electronic media via mail, but electronic or email submission is preferred.)
Based on information provided in 21CFR312, for paper IND submissions, the sponsor must submit an original and two (2) copies, including the original submission and all amendments and reports.
For more information on CDER and CBER internal policies and procedures for accepting and reviewing applications, see USA-96 and USA-95, respectively.
Ethics Review Submission
Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for clinical trial submission processes.
Regulatory Authority Requirements
As delineated in ResNo9 and the G-DDCMManual, to complete the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), the sponsor, the designated contract research organization (CRO), or the sponsor-investigator is required to submit the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s DDCM Petition Request Form (BRA-21) along with the following documentation (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each one.):
- Sanitary Surveillance Inspection Fee (Taxa de Fiscalização de Vigilância Sanitária (TFVS)) as per ResNo222 and ResNo76 (tax payment imposed on individuals and companies engaged in clinical research)
- Drug development plan (known as experimental drug dossier) (See the G-BioIProdManual for instructions on completing a biological products dossier and the G-SynthDrugProdManual for completing a synthetic/semi-synthetic products dossier)
- Certified copy of the clinical agreement (contract or statement) that has been written, dated, and signed by the sponsor or the CRO
- Clinical research protocol
- Investigator’s Brochure (IB)
- Summary of the investigational product (IP)’s safety aspects based on previous research in humans
- Information on any discontinued development or withdrawal of IP
- IP dossier
- Specific dossier for each clinical trial to be conducted in Brazil
- Proof of clinical trial registration in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE) (Note: the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC) (BRA-45) is a primary registry in the ICTRP network.) Per ResNo449, which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25). Note that per ResNo205, the ResNo9 requirement to include the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval in the initial DDCM or in any protocol amendment submission has been revoked.
Substantial Protocol Modifications
For substantial protocol modifications, the sponsor must submit a secondary petition to ANVISA using the DDCM Petition Request Form (BRA-21), as stated in ResNo9 and the G-DDCMAmdmts. These modifications may be made at any time after initial submission of the DDCM. Per BRA-8, if the modification has occurred following ANVISA’s issuance of the authorizing document known as the Special Notice (Comunicado Especial (CE)), ANVISA will send the sponsor an updated CE to reflect the most current approved protocol version.
While the sponsor is required to submit all amendments to ANVISA, per ResNo9 and the G-DDCMAmdmts, they are only required to submit substantial protocol amendments via a secondary petition whereas non-substantial DDCM protocol amendments should be submitted as part of the annual clinical trial report. Non-substantial amendments that do not impact the protocol should be presented to ANVISA as part of the drug development safety update report. See ResNo9 and the G-DDCMManual for detailed ANVISA application submission requirements, BRA-22 for the clinical trial submission form, and BRA-13 for updated ANVISA application forms. See also BRA-95 for instructions on providing expiration date information for imported IPs to be used during the trial and which the sponsor must include in its submission in BRA-22.
In order to fulfill the DDCM and the substantial quality modification requirements delineated in ServBltnNo104, the sponsor or the legal representative (also known as CRO in some sources) must provide all of the documentation required in ResNo9 and the following:
- An official document issued by at least one (1) of the regulatory authorities from one (1) International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) member country to prove the clinical trial or the substantial quality modification is authorized to be carried out
- A declaration of compliance with the ServBltnNo104 Form Attachment criteria regarding the IP to be administered in the trial to be conducted in Brazil: that it is identical to the one (1) administered in the ICH authorized country; is registered in at least one (1) ICH member country; contains the same substantial quality changes as the IP, active comparator, or placebo, if applicable, as those approved in at least one (1) ICH member country; complies with ICH manufacturing guidelines, where applicable, to the clinical development phase
Per ServBltnNo104, in the absence of the previously described official document, a justification must be presented showing that the conduct of the clinical trial or the substantial quality modification has been authorized.
In addition, ServBltnNo104 states that the previously listed documentation must be presented using the subject code of “11634 - ENSAIOS CLÍNICOS - Análise Simplificada de Dossiê de Qualidade” (11634 – CLINICAL TRIALS – Simplified Analysis of the Quality Dossier) to be linked to the DDCM petition or the substantial quality modification of interest, while the petition is in the queue waiting for ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC))’s technical analysis to begin. The status of the petition code will remain as the subject code of simplified analysis if all of the documentation requirements are met. In the event of non-compliance with the ServBltnNo104 criteria, COPEC will proceed with the non-simplified analysis per ResNo9. These provisions may be applied to DDCM and substantial quality modification petitions submitted prior to the publication of ServBltnNo104, upon request using the subject code of “11634 - ENSAIOS CLÍNICOS - Análise Simplificada de Dossiê de Qualidade” (11634 - CLINICAL TRIALS - Simplified Analysis of the Quality Dossier), as long as the relevant petition is still in the queue waiting for the technical analysis to begin. The ServBltnNo104 provisions do not presuppose prioritizing the analysis of these petitions. Furthermore, ANVISA may at any time analyze all of the documents required in items VII, art. 38 and item III, art. 43 of ResNo9 based on the risk analysis related to the IP. See ServBltnNo104 for detailed information.
Ethics Committee Requirements
As per OMREC and OSNo001, the CONEP requires sponsors to submit the following documentation online via BRA-34 (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each one.):
- Cover Sheet for Research Involving Human Beings (BRA-20)
- Clinical research protocol (in Portuguese)
- Background, justification, and registration in the country of origin for drug and device health products
- Description of materials, methods, rationale, expected results, and bibliography
- Critical risk and benefit analysis
- Duration
- Responsibilities of investigator, institution, and sponsor
- Criteria for project suspension or termination
- Location of implementation of various project steps
- Necessary infrastructure and agreement of the institution
- Statement of Commitment from the principal investigator (PI)
- Informed consent form (ICF) (See Informed Consent topic for additional information)
- Detailed research financial budget and investigator remuneration
- Ownership of information
- Characteristics of the participant population, and justification for the use of vulnerable groups
- Number of participants locally and globally (multicenter)
- Description of methods that affect research participants
- Sources of material and details of the specific collection
- Recruitment plans, inclusion and exclusion criteria
- PI/investigator(s) Curriculum Vitaes (CVs)
- Research project schedule
- Foreign Research or Foreign Cooperation documentation (commitments and advantages for research participants and the country; identification of the national investigator and co-responsible institution; EC approval document in the country of origin or justification; response to the need for personnel training in Brazil; and lists of participating centers abroad and in Brazil)
- Research with new drug, vaccine, and diagnostic test document requirements (current clinical trial phase and demonstration of compliance with previous clinical trial phases; drug substance registration in the country of origin and status of research; IB; clinical information from previous trial phases; justification for using placebo or wash out period; access to the drug, if its superiority is proven; investigator's statement to agree to comply with BRA-20; justification for inclusion of healthy participants; forms of recruitment)
See OMREC and OSNo001 for detailed CEP/National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) System submission requirements. See also BRA-33 for the most current Plataforma Brazil CEP and investigator manuals.
Clinical Protocol
As delineated in the PANDRH-GCPs, OMREC, and OSNo001, the clinical protocol should include the following elements:
- Protocol summary
- Sponsor or authorized representative name and contact information
- PI CV and contact information
- PI statement of responsibility
- IP description (See Investigational Products topic for detailed coverage of this subject)
- Form, dosage, route, method, and frequency of administration; and treatment period
- Summary of potential risks and known benefits to research participants
- Trial objectives and purpose
- Trial design, random selection method, and blinding level
- Participant selection/withdrawal
- Participant treatment
- Safety evaluation
- Adverse event reporting requirements (See Safety Reporting section for additional information)
- Statistics and methods to track trial data
- Sponsor specifications for direct access to source data/documents
- Quality control/quality assurance procedures and practices
- Ethical considerations
- Data management and record maintenance
- Financing and insurance details
- Publication policy
For complete protocol requirements, refer to the PANDRH-GCPs, OMREC, and OSNo001. See also CLNo060 for instructions on citing clinical trial registries in research protocols.
Regulatory Authority Requirements
As specified in 21CFR312, an investigational new drug application (IND) to the Food & Drug Administration (FDA) must include the following documents, in the order provided below:
- Cover sheet (Form FDA 1571 (USA-76)) (including, but not limited to: sponsor contact information, investigational product (IP) name, application date, phase(s) of clinical investigation to be conducted, and commitment that the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) will conduct initial and continuing review and approval of each study proposed in the investigation)
- Table of contents
- Introductory statement and general investigational plan
- Investigator’s brochure (IB)
- Protocols
- Chemistry, manufacturing, and control data
- Pharmacology and toxicology data
- Previous human experience with the IP
- Additional information (e.g., drug dependence and abuse potential, radioactive drugs, pediatric studies)
- Relevant information (e.g., foreign language materials and number of copies - see Submission Process section for details)
For detailed application requirements, see 21CFR312. In addition, see USA-40 for other IND forms and instructions.
Furthermore, for information on the appropriate use of adaptive designs for clinical trials and additional information to provide to the FDA to support its review, see G-AdaptiveTrials.
The G-RWDRWE-Doc states that to facilitate the FDA’s internal tracking of submissions that include real-world data (RWD) and real-world evidence (RWE), sponsors and applicants are encouraged to identify in their submission cover letters certain uses of RWD/RWE. For more information, see the G-RWDRWE-Doc.
The FDCAct, as amended by the FDORA, requires sponsors to submit diversity action plans for certain clinical trials, such as a clinical investigation of a new drug that is a phase 3 study. See the FDORA for more details. (Note: The FDA’s guidance on diversity action plans is currently in draft. The ClinRegs team will continue to monitor this requirement and incorporate any updates as appropriate).
According to the G-PedStudyPlans, a sponsor who is planning to submit to the FDA a marketing application (or supplement to an application) for a new active ingredient, new indication, new dosage form, new dosing regimen, or new route of administration is required to submit an initial pediatric study plan (iPSP), if required by the Pediatric Research Equity Act (PREA). An exception to this is if the drug is for an indication granted an orphan designation. For additional details and recommendations to sponsors regarding the submission of an iPSP, see the G-PedStudyPlans.
Ethics Committee Requirements
Each EC has its own application form and clearance requirements, which can differ significantly regarding application content requirements. However, the requirements listed below comply with 21CFR56 as well as the US-ICH-GCPs and are basically consistent across all US ECs.
As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the EC should obtain the following documents and must ensure the listed requirements are met prior to approving the study (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):
- Clinical protocol
- Informed consent forms (ICFs) and participant information (the RevComRule also requires information regarding whether informed consent was appropriately sought and documented, or waived)
- Participant recruitment procedures
- IB
- Safety information
- Participant payments and compensation
- Investigator(s) current Curriculum Vitaes (CVs)
- Additional required EC documentation
- Risks to participants are minimized and are reasonable in relation to anticipated benefits
- Participant selection is equitable
- Adequate provisions are made to protect participant privacy and maintain confidentiality of data, where appropriate; the Department of Health & Human Services (HHS) will issue guidance to assist ECs in assessing what provisions are adequate to protect participant privacy and maintain the confidentiality of data
Per the RevComRule, where limited EC review applies, the EC does not need to make the determinations outlined above. Rather, limited EC review includes determinations that broad consent will be/was obtained properly, that adequate protections are in place for safeguarding the privacy and confidentiality of participants, and (for secondary studies) that individual research results will not be returned to participants. See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.
See 21CFR56, the Pre2018-ComRule, the RevComRule, and section 3 of the US-ICH-GCPs for additional EC submission requirements.
Clinical Protocol
According to the US-ICH-GCPs, the clinical protocol should contain the following elements:
- General information
- Background information
- Trial objectives and purpose
- Trial design
- Participant selection/withdrawal
- Participant treatment
- Efficacy assessment
- Safety assessment
- Statistics
- Direct access to source data/documents
- Quality control/quality assurance
- Ethics
- Data handling/recordkeeping
- Financing/insurance
- Publication policy
- For complete protocol requirements, see section 6 of the US-ICH-GCPs.
Per the NIHNotice17-064, and provided in USA-29 and USA-27, the National Institutes of Health (NIH) and the FDA developed a clinical trial protocol template with instructional and example text for NIH-funded investigators to use when writing protocols for phase 2 and 3 clinical trials that require IND applications.
Overview
ResNo205 repealed the ResNo9 requirement that ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) approval must be submitted as part of the clinical trial application to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Therefore, as explained in BRA-2 and BRA-1, the regulatory and ethics reviews may be conducted in parallel.
Regulatory Authority Approval
As specified in ResNo9, upon receipt of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))), ANVISA has 90 calendar days to evaluate the application. If the agency fails to issue a response within 90 days of receipt, clinical development can begin as long as all of the ethical approvals have been obtained.
During the COVID-19 public health emergency as described in OrdNo188, ANVISA issued ResNo573 to implement an urgent and temporary amendment to the original ResNo9 180-day review timeline for DDCMs that fall into at least one (1) of the following categories: national development, biological product clinical development including vaccines, and Phase I or II clinical development studies as delineated in ResNo9. Although OrdNo913 declared an end to the public health emergency as of May 22, 2022, ResNo790 has extended the validity of ResNo573 to May 23, 2024.
The ResNo573 amendment requires ANVISA to evaluate these application categories within 120 calendar days, counting from the date of linking the first Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínicos (DEEC)) to the DDCM. In the event that ANVISA fails to respond within the 120-day deadline, the agency will issue a Document for Importation of Product(s) under Investigation for a DDCM (also known as the Import Document (DI)) that has one (1) or more studies approved by at least one (1) regulatory authority of an International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) founding or standing member country or by the United Kingdom’s (UK’s) Medicines and Healthcare Products Regulatory Agency (MHRA).
The DDCM must also be identical to the one (1) approved by the ICH member country or the MHRA. An official document issued by the regulatory authority or a declaration of compliance with the criteria described in this document must be presented to prove the authorization or non-objection to carry out the clinical trial by the ICH member country or the MHRA. In the case of a DDCM that falls within the previously stated provisions, clinical development may begin after the relevant ethical approvals. However, this rule does not apply to DDCMs of vaccines, whose clinical development can only be started after analysis and consent by ANVISA and the relevant ethical approvals. ResNo573 delineates that the provisions of this regulation apply to DDCMs received by ANVISA and whose analysis was not initiated by the technical area. See Submission Process section for details on complying with ResNo573.
According to BRA-60, DDCM petitions that require a longer review period (up to 120 days per ResNo573) are described as “exceptions” requiring technical analysis whereas the 90-day review period for typical petitions are referred to as “no exceptions” and do not require technical analysis. BRA-60 notes that the deadline for analyzing initial DEEC petitions may be relatively longer when dealing with processes considered to be complex, such as with biological products, including the development of vaccines, which are also referred to as “exceptions.”
BRA-60 further states that the median deadline required by ANVISA to complete an analysis of a DDCM petition with technical requirements by the companies was 30 days, with 2 days being the shortest time observed and 197 days being the longest, in cases where there was more than one (1) technical requirement and times for meeting more than one (1) requirement added up. Refer to BRA-60 for detailed petition review timelines. Currently, companies have up to 120 days to respond to any type of agency-issued process and/or petition requirements. Typically, submissions with more complicated DDCM processes require companies to spend more time fulfilling ANVISA’s requirements.
Timeline information for ANVISA’s simplified analysis of DDCMs that meet the criteria for ServBltnNo104 is not available. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.)
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 for detailed information on DEEC submissions. See also BRA-8 and BRA-14 for additional information on priority petitions. See the Scope of Assessment section for further information on priority submissions.
Ethics Committee Approval
As 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 (CAAE) is issued). In addition, per BRA-91, if the project needs to be reviewed by CONEP, the deadline is 15 days for document validation, and 45 days for ethical assessment. If these deadlines have expired, BRA-91 further suggests that the investigator responsible for the research project, contact the CEP to request explanations and, in parallel, send a notification to CONEP (conep.cep@saude.gov.br) requesting a case investigation.
CLNo040 further explains that new investigational brochure (IB) versions to be uploaded to the CEP/CONEP System via Plataforma Brasil (BRA-34) are often limited to updates pertaining to the investigational product’s efficacy and safety data and research team instructions. Updates should not alter research that has already been approved and must be processed as notifications in BRA-34. However, CLNo040 specifies that if the IB changes result in modifications to the detailed protocol and/or the informed consent form (ICF), it is necessary to submit a protocol amendment. In this case, the EC (CEP) will analyze the IB together with the other documents pertaining to the amendment, and, if necessary, the required amendments and/or clarifications will be requested. If the project needs to go through CONEP's appraisal, the deadline for Document Validation is 15 days and for Ethical Review, 45 days.
See the Submission Process section for CEP/CONEP System submission requirements.
Overview
As delineated in 21CFR56 and 21CFR312, institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) review of the clinical investigation may be conducted in parallel with the Food & Drug Administration (FDA)'s review of the investigational new drug application (IND). However, EC approval must be obtained prior to the sponsor being permitted to initiate the clinical trial.
Regulatory Authority Approval
Per the FDCAct and 21CFR312, initial INDs submitted to the FDA’s Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER) automatically go into effect in 30 calendar days, unless the FDA notifies the sponsor that the IND is subject to a clinical hold, or the FDA has notified the sponsor earlier that the trial may begin. As indicated in 21CFR312, the FDA will provide the sponsor with a written explanation of the basis for the hold as soon as possible, and no more than 30 days after the imposition of the clinical hold. See 21CFR312 for more information on clinical hold timelines. For more information on CDER and CBER internal policies and procedures for reviewing applications, see USA-96 and USA-95, respectively.
According to USA-41 and USA-42, clinical studies must not be initiated until 30 days after the FDA receives the IND, unless the FDA provides earlier notification that studies may begin.
Ethics Committee Approval
Each EC maintains its own procedures and processes for review. Consequently, there is no stated regulatory requirement for a standard timeline of review and approval of the clinical trial. However, according to the US-ICH-GCPs, the institutional EC should review a proposed clinical trial within a reasonable time.
Overview
In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, a clinical trial can only commence after the sponsor, the designated contract research organization (CRO), or the sponsor-investigator receives clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) approval from the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Per ResNo9, ResNo466, the PANDRH-GCPs, and OSNo001, the principal investigator (PI) must also obtain approval from the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)). Applications with coordination or sponsorship originating outside Brazil require an additional review and approval by the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)), unless the co-sponsor is the Brazilian Government. Please refer to Scope of Review and Oversight of Ethics Committees sections for detailed information on CONEP responsibilities and other studies requiring CONEP approval. No waiting period is required following the sponsor’s receipt of these approvals.
In addition, per ResNo9, the sponsor or the designated CRO is required to obtain an import license from ANVISA for the shipment of the investigational product (IP) to be used in the trial. (See the Manufacturing & Import section for additional information). The trials should be conducted in compliance with the PANDRH-GCPs, ResNo466, and ResNo9. Clinical trials must also be conducted in a laboratory complying with the Organisation for Economic Co-operation and Development (OECD)’s Good Laboratory Practices (GLP) (BRA-15) as mandated by Brazil’s National Institute of Metrology, Quality and Technology (INMETRO). Refer to BRA-15 and BRA-48 for additional information on GLP requirements.
ResNo9 further states that the sponsor should register the clinical trial start and end dates within 30 calendar days of each date by submitting a secondary petition to the corresponding DDCM (see BRA-21 for the DDCM Petition Request Form).
Clinical Trial Agreement
As delineated in the PANDRH-GCPs, the sponsor or the CRO must sign an agreement or contract with the participating institution(s) and the investigator. In addition, if a sponsor decides to engage a CRO to conduct the trial, a letter of agreement should also be submitted to ANVISA as specified in the PANDRH-GCPs and ResNo9.
Clinical Trial Registration
As delineated in ResNo9, the sponsor must register the clinical trial in a registry listed on the World Health Organization (WHO)’s International Clinical Trials Registry Platform (ICTRP) (BRA-52) or any other registry recognized by the International Committee of Medical Journal Editors (ICMJE). According to BRA-52, the Brazilian Clinical Trials Registry (Registro Brasileiro de Ensaios Clínicos (ReBEC)) (BRA-45) is a primary registry in the ICTRP network. See also BRA-45 and BRA-46 for further information about ReBEC. Per ResNo449 which amends ResNo9, if a registration receipt is not available to submit with the DDCM, it must be provided with the Start of Clinical Trial Notification Form in Brazil (BRA-25).
Overview
In accordance with 21CFR312, USA-41, and USA-42, a clinical trial can only commence after the investigational new drug application (IND) is reviewed by the Food & Drug Administration (FDA), which will provide a written determination within 30 days of receiving the IND. No waiting period is required following the 30-day FDA review period, unless the agency imposes a clinical hold on the IND or sends an earlier notification that studies may begin. Per 21CFR312 and 21CFR56, ethics approval from an institutional ethics committee (EC) (known as institutional review board (IRB) in the United States (US)) is also required before a clinical trial can commence.
As per 21CFR312, once an IND has been submitted and following the 30-day review period, the sponsor is permitted to import an investigational product (IP). (See the Manufacturing & Import section for additional information).
See the G-CTDiversity for FDA recommendations to sponsors on increasing enrollment of underrepresented populations in their clinical trials.
Clinical Trial Agreement
Prior to the trial’s commencement, as addressed in the 21CFR312 and the G-1572FAQs, the sponsor must obtain from the investigator(s) a signed Statement of Investigator, Form FDA 1572 (USA-77). This form serves as the investigator’s agreement to provide certain information to the sponsor and to ensure compliance with the FDA’s clinical investigation regulations. Refer to the 21CFR312, the G-1572FAQs, and USA-40 for further information.
The US-ICH-GCPs indicates that the sponsor must obtain the investigator’s/institution’s agreement:
- To conduct the trial in compliance with good clinical practice (GCP), with the applicable regulatory requirement(s), and with the protocol agreed to by the sponsor and given approval/favorable opinion by the EC;
- To comply with procedures for data recording/reporting;
- To permit monitoring, auditing, and inspection; and
- 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 must sign the protocol, or an alternative document, to confirm this agreement.
Clinical Trial Registration
The FDAMA, the FDAAA, and 42CFR11 require the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to register electronically with the ClinicalTrials.gov databank (USA-78). Per the FDAAA and 42CFR11, the sponsor/PI must register no later than 21 calendar days after the first human participant is enrolled in a trial.
42CFR11 expands the legal requirements for submitting clinical trial registration information and results for investigational products that are approved, licensed, or cleared by the FDA.
The National Institutes of Health (NIH) issued NIHTrialInfo to complement 42CFR11 requirements. This policy requires all NIH-funded awardees and investigators conducting clinical trials, funded in whole or in part by the NIH, regardless of study phase, type of intervention, or whether they are subject to the regulation, to ensure that they register and submit trial results to ClinicalTrials.gov (USA-78).
See 42CFR11, the NIHTrialInfo, and USA-49 for detailed information on ClinicalTrials.gov (USA-78). See also the FDA’s G-DataBankPnlty for clarification on the types of civil money penalties that may be issued for failing to register a clinical trial.
Safety Reporting Definitions
In accordance with the PANDRH-GCPs, ResNo9, the AESafetyManual, and CLNo13, the following definitions provide a basis for a common understanding of Brazil’s safety reporting requirements (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each one):
- Adverse Event/Experience (AE) – Any adverse medical occurrence in a research participant to whom a drug product was administered, and which does not necessarily bear a causal relationship to the treatment
- Adverse Drug Reaction or Adverse Reaction (ADR) – All harmful unintended responses to a medicinal product related to any dose
- Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) – Any unfavorable occurrence that at any dose results in death, is life-threatening, requires or extends patient hospitalization, results in persistent or significant disability or permanent damage, or is a birth defect or congenital anomaly; significant medical occurrence, which based on appropriate medical judgment, may harm the participant and/or require medical or surgical intervention to prevent any of the other occurrences mentioned
- Unexpected Adverse Drug Reaction – One whose nature or severity is inconsistent with the applicable product information (i.e., the investigator’s brochure for an unapproved investigational product (IP), or package insert/summary of the characteristics of an approved product)
Safety Reporting Requirements
Investigator Responsibilities
As specified in ResNo9 and the AESafetyManual, the investigator must inform the sponsor within 24 hours of all SAEs/SADRs occurring during the study. The PANDRH-GCPs also states that the immediate reports should be followed promptly by detailed, written reports in which the participants are identified by unique code numbers. AEs/ADRs identified in the protocol as critical to safety evaluations should also be reported to the sponsor. Per the AESafetyManual, the investigator(s) should treat all participants who incur AEs/ADRs and assist them until the situation is resolved. In the event of a participant’s death, the investigator must provide the sponsor and the ethics committee (EC) (Comitê de Ética em Pesquisa) (CEP)) with any additional requested information (e.g., autopsy reports and terminal medical reports).
Sponsor Responsibilities
The AESafetyManual states that the sponsor should classify all AEs/ADRs and SAEs/SADRs according to the World Health Organization’s Uppsala Monitoring Centre (WHO-UMC)’s standardized causality assessment system (BRA-31). The recommended criterion to categorize each event is as follows: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and Unassessable/Unclassifiable.
As per ResNo9 and the AESafetyManual, the sponsor should ensure all relevant information pertaining to fatal or life-threatening SAEs/SADRs occurring in Brazil is documented and electronically reported to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) no more than seven (7) days after first knowledge. ResNo9 also indicates that any additional information should be included in the assessment up to eight (8) calendar days from the notification date. Additionally, per ResNo9 and the AESafetyManual, all other unexpected SAEs/SADRs whose causality is possible, probable, or certain for the products under investigation should be reported to ANVISA within 15 calendar days from the date of first knowledge by the sponsor.
Per the AESafetyManual, AEs/ADRs and SAEs/SADRs do not need to be reported to ANVISA under the above timelines when they occur outside of Brazil or are defined in the protocol as a primary or secondary outcome. Additionally, SAEs/SADRs that are categorized as Unlikely, Conditional/Unclassified, or Unassessable/Unclassifiable do not need to be reported under the above timelines. Per ResNo9 and the AESafetyManual, for events occurring within Brazil, this information should be included in the annual drug development safety update report (DDSUR), which must be filed within a maximum of 60 calendar days of the yearly anniversary of the date that ANVISA approves the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). Per ResNo9, in the case of international trials, within 12 months of the study in all countries, the sponsor must submit a final report, which must include information on AEs/ADRs and SAEs/SADRs occurring in other countries.
ResNo9 requires the sponsor to notify investigators of AEs/ADRs and SAEs/SADRs for which the causality has been assessed as possible, probable, or certain. The sponsor must adopt procedures for updating the Investigator’s Brochure (IB) and reassess the risk and benefits to study participants. The PANDRH-GCPs states that the sponsor is also required to notify all concerned investigator(s), institution(s), and ANVISA of findings that could adversely affect participant safety, impact the conduct of the trial, or alter the EC (CEP)’s approval of the trial.
In addition, ResNo9 and the G-DDCMAmdmts state that in cases where the sponsor temporarily suspends a clinical trial or DDCM as an immediate safety measure, they must notify ANVISA within seven (7) consecutive days from the suspension date. Per ResNo9, the reasons for suspension, the scope, the interruption of treatment, and the suspension of participant recruitment must be clearly explained in the notification of temporary suspension. See also BRA-8 for additional information on ANVISA’s AE reporting requirements.
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-70, the CAAE is the number generated by Plataforma Brasil (BRA-34) to identify the research project when it is received by CEP for ethical review.
CLNo13 explains that each SAE must be characterized according to the following:
- Date of SAE occurrence
- Participant number or code
- SAE number or code
- SAE classification (index or subsequent)
- Breakdown of the occurrence (e.g., febrile neutropenia, pneumonia, etc.)
- SAE type (death, life threatening, need for hospitalization, prolonged hospitalization, significant damage, permanent damage, congenital anomaly, at the investigator's discretion, others)
- Participant status on the date of the last update (in progress, recovered without sequelae, recovered with sequelae, and death)
- Description of research participant withdrawal(s)
Additionally, in the case of multicenter studies, the investigator at the coordinating center must prepare the consolidated report (partial and final reports) containing information on SAEs from all of the participating research centers and submit it to the CEP to which it is linked via Plataforma Brasil (BRA-34) using the “notification” functionality. CLNo13 also explains that for SAEs occurring outside the country, it is the responsibility of the coordinating research center investigator to prepare the consolidated SAEs report. If the CEP is linked to the coordinating center, CONEP will also evaluate the SAEs if the protocol is included in item IX.4 of ResNo466.
Refer to CLNo008 for detailed instructions and the CONEP form to report SAEs to the CEP/CONEP System for review, and CLNo13 for information on processing AEs for Brazil and abroad.
Other Safety Reports
For investigational advanced therapy products, SAEs must be reported through the Online Adverse Event Notification Form for Advanced Therapy Products (BRA-101).
Form Completion & Delivery Requirements
As per BRA-37, VigiMed (BRA-83) is ANVISA’s online system for citizens, health professionals, drug registration holders, and study sponsors to report unexpected SAEs related to drugs and vaccines. Upon registration with BRA-83, BRA-37 indicates that companies (sponsors) must submit SAE notifications exclusively via BRA-83. See also BRA-85 for additional information on VigiMed.
Per BRA-78 and BRA-37, sponsors must email notifications of unexpected SAEs to notivisa.pesquisa@anvisa.gov.br. BRA-78 indicates that the title of the email must state “EVENTO ADVERSO GRAVE INESPERADO [NOME DO MEDICAMENTO]” (Unexpected Serious Adverse Event [Name of the medication]). BRA-78 and BRA-37 specify that the email must include the ANVISA Serious Adverse Event Notification Spreadsheet (BRA-84) containing all of the information that was previously registered with ANVISA. BRA-37 states that ANVISA advises sponsors of clinical research with medicines and biological products that have not yet been registered in VigiMed (BRA-83) to also include the following information for the company’s registration in the system:
- Corporate name
- Sender identifier (the official name should be used, if possible, since it will be used to identify the company in VigiMed)
- CNPJ (National Registry of Legal Entities (Cadastro Nacional de Pessoas Jurídicas), which serves as tax identification
- Short name: company name abbreviation [the company name abbreviation will be used in the Notification Identification, following the structure: BR-Company Name-Notification Number (Data element C.1.1 Sender’s (case) Safety Report Unique Identifier, from the ICH E2B (R3) (Electronic Transmission of Individual Case Safety Reports) (BRA-88)
- Data of users to be registered in VigiMed: name and e-mail of two (2) notifiers, who will be registered to enter data from notifications of SAEs occurring in clinical trials
Safety Reporting Definitions
In accordance with 21CFR312, the G-IND-Safety, 42CFR11, and USA-38, the following definitions provide a basis for a common understanding of safety reporting requirements in the United States (US):
- Adverse Event – Any untoward medical occurrence associated with the use of a drug in humans, whether or not considered drug related
- Suspected Adverse Reaction – Any adverse event where there is a reasonable possibility that the drug caused the adverse event
- Adverse Reaction – Any adverse event caused by a drug. Adverse reactions are a subset of all suspected adverse reactions where there is reason to conclude that the drug caused the event
- Serious Adverse Event/Serious Suspected Adverse Reaction – An adverse event/suspected adverse reaction that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, causes persistent or significant disability/incapacity, results in a congenital anomaly/birth defect, or leads to a substantial disruption of the participant’s ability to conduct normal life functions
- Unexpected Adverse Event/Unexpected Suspected Adverse Reaction – An adverse event/suspected adverse reaction that is not listed in the investigator’s brochure (IB), or is not listed at the specificity or severity that has been observed; or if an IB is not required or available, is not consistent with the risk information described in the general investigational plan or elsewhere in the application
- Life-threatening Adverse Event/Life-threatening Suspected Adverse Reaction – An adverse event/suspected adverse reaction is considered “life-threatening” if its occurrence places the participant at immediate risk of death. It does not include an adverse event/suspected adverse reaction that, had it occurred in a more severe form, might have caused death
According to the G-HHS-AEReqs, the Department of Health & Human Services (HHS)’s 45CFR46 regulations (the Pre2018-ComRule, the RevComRule, and 45CFR46-B-E) do not define the terms “adverse event” or “unanticipated problems.” However, the Pre2018-ComRule and the RevComRule do contain requirements relevant to reviewing and reporting these incidents. See the G-HHS-AEReqs, the G-IRBRpting, the Pre2018-ComRule, and the RevComRule for further information.
See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.
Safety Reporting Requirements
Investigator Responsibilities
As delineated in 21CFR312 and the G-IND-Safety, the investigator must comply with the following reporting requirements:
- Serious adverse events, whether or not considered drug related, must be reported immediately to the sponsor
- Study endpoints that are serious adverse events must be reported in accordance with the protocol unless there is evidence suggesting a causal relationship between the drug and the event. In that case, the investigator must immediately report the event to the sponsor
- Non-serious adverse events must be recorded and reported to the sponsor according to the protocol specified timetable
- Report promptly to the ethics committee (EC) all unanticipated problems involving risk to human participants or others where adverse events should be considered unanticipated problems
Sponsor Responsibilities
As delineated in 21CFR312, the G-IND-Safety, and USA-38, the sponsor must report any suspected adverse reaction or adverse reaction that is both serious and unexpected. An adverse event is only required to be reported as a suspected adverse reaction if there is evidence to suggest a causal relationship between the drug and the adverse event.
The sponsor is required to notify the Food & Drug Administration (FDA) and all participating investigators in a written safety report of potential serious risks, from clinical trials or any other source, as soon as possible, but no later than 15 calendar days after the sponsor determines the information qualifies for reporting. Additionally, the sponsor must notify the FDA of any unexpected fatal or life-threatening suspected adverse reaction as soon as possible, but no later than seven (7) calendar days following receipt of the information. The sponsor is required to submit a follow-up safety report to provide additional information obtained pertaining to a previously submitted safety report. This report should be submitted without delay, as soon as the information is available, but no later than 15 calendar days after the sponsor initially receives the information.
Per 21CFR312 and the G-IND-Safety, the sponsor must also report the following:
- Any findings from epidemiological studies, pooled analyses of multiple studies, or clinical studies (other than those reported in the safety report), whether or not conducted under an investigational new drug application (IND), and whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
- Any findings from animal or in vitro testing, whether or not conducted by the sponsor, that suggest a significant risk in humans exposed to the drug
- Any clinically important increase in the rate of a serious suspected adverse reaction over that listed in the protocol or IB
In each safety report, the sponsor must identify all safety reports previously submitted to the FDA concerning a similar suspected adverse reaction and must analyze the significance of the suspected adverse reaction in light of previous, similar reports, or any other relevant information. Refer to 21CFR312 and the G-IND-Safety for more details on these safety reporting requirements.
As part of the clinical trial results information submitted to ClinicalTrials.gov (USA-78), 42CFR11 requires the responsible party, either the sponsor or the principal investigator (PI) designated by the sponsor, to submit three (3) tables of adverse event information. The tables should consist of the following summarized data:
- All serious adverse events
- All adverse events, other than serious adverse events, that exceed a frequency of five (5) percent in any arm of the trial
- All-cause mortalities
Per 42CFR11 and USA-70, this information must be submitted no later than one (1) year after the primary completion date of the clinical trial. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to ClinicalTrials.gov (USA-78) that either: 1) the FDA has not yet approved, licensed, or cleared for marketing the investigational product (IP) being studied; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year.
See 42CFR11 for detailed adverse event reporting requirements.
Form Completion & Delivery Requirements
As per 21CFR312, the G-IND-Safety, and USA-38, the sponsor must submit each safety report in a narrative format on Form FDA 3500A (USA-75), or in an electronic format that the FDA can process, review, and archive, and be accompanied by Form FDA 1571 (USA-76) (cover sheet).
As per the G-IND-Safety and USA-38, the submission must be identified as follows:
- “IND safety report” for 15-day reports
- “7-day IND safety report” for unexpected fatal or life-threatening suspected adverse reaction reports
- “Follow-up IND safety report” for follow-up information
The report must be submitted to the appropriate review division (i.e., Center for Drug Evaluation and Research (CDER) or Center for Biologics Evaluation and Research (CBER)). Per USA-38, the FDA recommends that sponsors submit safety reports electronically. Other means of rapid communication to the respective review division’s Regulatory Project Manager (e.g., telephone, facsimile transmission, email) may also be used. Per USA-90, fatality reports to CBER should be sent to fatalities2@fda.hhs.gov.
Additionally, 21CFR312 and the G-IND-Safety indicate that the FDA will accept foreign suspected adverse reaction reports on CIOMS Form I (See USA-13 and USA-3) instead of Form FDA 3500A (USA-75). See USA-38 and USA-48 for additional information.
Interim and Annual Progress Reports
As per ResNo9 and the G-CTReptsManual, the sponsor must file a progress report, known as an annual clinical trial protocol monitoring report, to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) in the form of a secondary petition electronically attached to the respective protocol to which it is linked. ResNo9 indicates that the annual report should contain the following information for each clinical trial protocol, in tabulated form, exclusively from Brazilian centers:
- Trial title
- Protocol code
- Participant(s) status
- Number of participants recruited by center
- Number/description of deviations and protocol violations by center
- Description of all adverse events/adverse drug reactions occurring by center
The report should be filed within 60 calendar days from the annual anniversary date of the trial’s commencement in Brazil. BRA-8 further explains that currently ANVISA does not require a template to be used to complete the annual clinical trial protocol monitoring report since the information should be based on the ICH Harmonised Tripartite Guideline: Structure and Content of Clinical Study Reports (E3) standardized report format (BRA-27). See BRA-23 for the annual/final report form that may be used.
The PANDRH-GCPs state that the investigator or institution must submit written summaries on the status of the trial to the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP) in Brazil) annually, or more frequently, if requested by the EC (CEP).
Final Report
ResNo9 and the G-CTReptsManual state that the sponsor should submit a final report to ANVISA in the form of a secondary petition electronically attached to the respective protocol to which it is linked. The final report must be filed within 12 months of the clinical trial end date. Per ResNo9 the final report should contain at least the following:
- Trial title
- Protocol code
- Breakdown of the number of participants recruited or removed from the trial
- Description of participants included in each statistical analysis and those who were excluded from the efficacy analysis
- Participant demographics and statistics
- Number/description of protocol deviations and violations
- All adverse events/laboratory abnormalities with causality assessment occurring in participants
- Results obtained in the measurement of outcomes for each participant
- Rationale for early termination in Brazil or elsewhere in the world, where applicable
Per G-CTReptsManual, the annual and final reports for each clinical protocol shall contain the minimum requirements set forth in Articles 68 and 69 of ResNo9, or they may be submitted using the ICH E3 format (BRA-27). See BRA-23 for the annual/final report form.
As specified in the PANDRH-GCPs, upon the trial’s completion, the investigator or the institution should also provide the sponsor with all required reports, present the EC (CEP) with a summary of the trial’s outcome, and supply any additional report(s) required by ANVISA.
Other Reporting Requirements
As stated in ResNo9 and the G-CTReptsManual, in addition to submitting a final report, the sponsor is also responsible for submitting clinical trial start and end date forms for trials conducted in Brazil. The forms with the trial start and end dates must be filed as a secondary petition to the corresponding trial dossier within 30 calendar days after each start and end date. The secondary petition should be submitted to ANVISA using the Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM)) Petition Request Form (BRA-21). See BRA-38 for the petition request system website that allows users to submit these forms electronically, and BRA-25 and BRA-24 for links to the notification forms.
Interim and Annual Progress Reports
As per the US-ICH-GCPs, the investigator should promptly provide written reports to the sponsor and the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) on any changes significantly affecting the conduct of the trial, and/or increasing the risk to participants.
As specified in 21CFR312, the investigator must furnish all reports to the sponsor who is responsible for collecting and evaluating the results obtained. In addition, per 21CFR56 and the US-ICH-GCPs the investigator should submit written summaries of the trial status to the institutional EC annually, or more frequently, if requested by the institutional EC.
21CFR312 states that the sponsor must submit a brief annual progress report on the investigation to the Food & Drug Administration (FDA) within 60 days of the anniversary date that the investigational new drug went into effect. The report must contain the following information for each study:
- Title, purpose, and description of patient population, and current status
- Summary of the participants screened (e.g., failed screenings; participants enrolled, withdrawn, or lost to follow-up; and other challenges)
- Summary information - including information obtained during the previous year’s clinical and nonclinical investigations
- Description of the general investigational plan for the coming year
- Updated investigator’s brochure, if revised
- Description of any significant Phase 1 protocol modifications not previously reported in a protocol amendment
- Brief summary of significant foreign marketing developments with the drug
- A log of any outstanding business for which the sponsor requests a reply, comment, or meeting
As indicated in 42CFR11, trial updates must be submitted to ClinicalTrials.gov (USA-78) according to the following guidelines:
- Not less than once every 12 months for updated general trial registration information
- Not later than 30 calendar days for any changes in overall recruitment status
- Not later than 30 calendar days after the trial reaches its actual primary completion date, the date the final participant was examined or received an intervention for the purposes of final collection data for the primary outcome
Final Report
As indicated in 21CFR312, an investigator must provide the sponsor with an adequate report shortly after completion of the investigator’s participation in the investigation. There is no specific timeframe stipulated for when the report should be completed.
The US-ICH-GCPs also states that upon the trial’s completion, the investigator should inform the institution and the investigator/institution should provide the EC with a summary of the trial’s outcome, and supply the FDA with any additional report(s) required of the investigator/institution.
Additionally, per 42CFR11 and USA-70, the sponsor or the principal investigator (PI) designated by the sponsor must submit results for applicable investigational product (IP) clinical trials to USA-78 no later than one (1) year following the study’s completion date. Submission of trial results may be delayed as long as two (2) years if the sponsor or PI submits a certification to USA-78 that indicates either: 1) the FDA has not yet approved, licensed, or cleared the IP being studied for marketing; or 2) the manufacturer is the sponsor and has sought or will seek approval within one (1) year. The results information must include data on the following:
- Participant flow
- Demographic and baseline characteristics
- Outcomes and statistical analysis
- Adverse events
- The protocol and statistical analysis plan
- Administrative information
See USA-49 for more information and 42CFR11 for more detailed requirements. See NIHTrialInfo for specific information on dissemination of NIH-funded clinical trial data.
As per ResNo466, ResNo9, and the PANDRH-GCPs, a sponsor is defined as an individual, company, institution, or organization that supports research through the initiation, management, or financing of a clinical trial.
ResNo9 states that a sponsor can authorize a contract research organization (CRO) to carry out certain work and obligations regarding the trial. As delineated in ResNo9, any trial-related responsibilities to be transferred and assumed by a CRO should be specified in a written agreement or contract.
As delineated in ResNo9, when a clinical trial is developed by a sponsor-investigator, the institution with which the individual is linked is the primary sponsor. The primary sponsor may delegate responsibilities to the investigator, who will be responsible for conducting the clinical trial at the institution, and the sponsor-investigator will serve as the secondary sponsor. See also BRA-79 for additional information on sponsor and CRO requirements in Brazil.
As per 21CFR312, 21CFR50, and the US-ICH-GCPs, a sponsor is defined as a person who takes responsibility for and initiates a clinical investigation. The sponsor may be an individual or pharmaceutical company, governmental agency, academic institution, private organization, or other organization. The sponsor does not actually conduct the investigation unless the sponsor is a sponsor-investigator. 21CFR312, 21CFR50, and the US-ICH-GCPs define a sponsor-investigator as an individual who both initiates and conducts an investigation, and under whose immediate direction the investigational product is administered or dispensed.
In addition, 21CFR312 and the US-ICH-GCPs state that a sponsor may transfer responsibility for any or all obligations to a contract research organization (CRO).
Any trial-related responsibilities transferred to and assumed by a CRO should be specified in writing, and those obligations not covered by the written description will be deemed not to have been transferred. Further, a CRO that assumes any sponsor obligations must comply with the specific regulations delineated in 21CFR312 and will be subject to the same regulatory action as the sponsor for failure to comply with any obligation assumed under these regulations. However, per the US-ICH-GCPs, although a sponsor may transfer all trial-related duties and functions to a CRO, the sponsor is ultimately responsible for the study data’s quality and integrity.
As indicated in 21CFR312, a sponsor may be either domestic or foreign.
Overview
As set forth in the PANDRH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial while taking into account the appropriateness and availability of the study site and facilities. The sponsor must also ensure that the investigator(s) are qualified by education, training, and experience to assume responsibility for the proper conduct of the trial. Investigator(s) should also provide evidence of all the qualifications specified by the applicable regulatory requirements through up-to-date curriculum vitae(s) (CVs) and/or other relevant documentation requested by the sponsor, the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)), and/or the regulatory authority(ies).
Prior to entering into an agreement with the investigator(s) and the institution(s) to conduct a study, the sponsor should provide the investigator(s) with the protocol and an investigator’s brochure. Additionally, the sponsor must define and allocate all study related duties and responsibilities to the relevant parties participating in the study. See the Submission Content section for additional information on clinical trial application requirements. See also CLNo046 for the National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidance on submitting requests for inclusion/exclusion of research center(s).
Foreign Sponsor Responsibilities
As specified in the PANDRH-GCPs and ResNo9, the sponsor may transfer any or all of the sponsor’s study related duties and functions to a contract research organization (CRO). However, the sponsor is ultimately responsible for the study data’s quality and integrity. Any study related duties, functions, or responsibilities transferred to and assumed by a local representative or CRO must be specified in writing. Other duties, functions, or responsibilities not specifically transferred shall be deemed as retained by the sponsor. However, as per ResNo9, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil.
Data Safety and Monitoring Board
According to ResNo9, an Independent Safety Monitoring Committee (ISMC) should be established to systematically evaluate aggregate adverse event/adverse drug reaction data.
Multicenter Studies
Per the PANDRH-GCPs, in the event of a multicenter clinical trial, the sponsor or the CRO should ensure that all investigators conduct the trial in strict compliance with the protocol as well as with the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s and the EC(CEP)’s requirements. The sponsor must also organize a coordinating committee or select coordinating investigators.
Overview
As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for selecting the investigator(s) and the institution(s) for the clinical trial and for ensuring that the investigator(s) are qualified by training and experience. Prior to permitting an investigator(s) to conduct a study, the sponsor must obtain the following:
- Signed investigator’s statement (Form FDA 1572 (USA-77))
- Curriculum vitae
- Clinical protocol
- Financial disclosure information
As addressed in the G-1572FAQs, Form FDA 1572 (USA-77) serves as the investigator’s agreement to provide certain information to the sponsor and to assure compliance with the Food & Drug Administration (FDA)'s clinical investigation regulations. Refer to the G-1572FAQs and USA-40 for further information.
In addition, prior to the start of the study, the sponsor must provide the investigator(s) with the protocol and the investigator’s brochure.
See G-InvstgtrResp for more information on investigator responsibilities.
As per the G-InvstgtrAdmin, the FDA may disqualify a clinical investigator from receiving investigational drugs (including biologics) if the FDA determines that the investigator has repeatedly or deliberately violated the agency’s regulations, or submitted false information to the sponsor or FDA in any required report. See the G-InvstgtrAdmin for more details.
Foreign Sponsor Responsibilities
No information is currently available.
Data and Safety Monitoring Board
As per 21CFR50 and the G-DMCs, Data and Safety Monitoring Boards (DSMBs), (also known as a Data Monitoring Committees (DMCs)), are not required by FDA regulations, except in the case of research conducted in emergency settings in which fulfilling the informed consent requirement is unfeasible. In this case, as stated in 21CFR50, the FDA requires the establishment of an independent data monitoring committee to exercise oversight of the clinical investigation. See the G-DMCs for FDA recommendations on DSMB/DMC establishment.
Additionally, the Pre2018-ComRule and the RevComRule indicate that for all human subjects research funded and/or sponsored by a Common Rule department/agency (as identified in USA-65), the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must ensure that, when appropriate, the research plan makes adequate provisions for monitoring the data collected during the study to ensure participant safety. Moreover, per the NIHDataSftyMntrng and USA-72, all National Institutes of Health (NIH)-funded clinical trials require a Data and Safety Monitoring Plan and monitoring should be commensurate with risk. DSMBs are also required for multi-site clinical trials with interventions that involve potential participant risk. See the NIHDataSftyMntrng and USA-72 for detailed Department of Health & Human Services (HHS)/NIH requirements.
Although not specified as a sponsor requirement, the US-ICH-GCPs states that a DSMB may be established to assess the progress of a clinical trial, including the safety data and the critical efficacy endpoints at intervals, and to recommend to the sponsor whether to continue, modify, or stop a trial.
Multicenter Studies
For all human subjects research funded and/or sponsored by a Common Rule department/agency, institutions that are located in the US and engaged in multicenter research/cooperative research studies must use a single EC to review the research. See the Scope of Review section, the RevComRule, and G-CoopRes for additional information.
The US-ICH-GCPs indicates that in the event of a multicenter clinical trial, the sponsor must ensure that:
- All investigators conduct the trial in strict compliance with the protocol agreed to by the sponsor, and given EC approval
- The case report forms (CRFs) are designed to capture the required data at all multicenter trial sites
- Investigator responsibilities are documented prior to the start of the trial
- All investigators are given instructions on following the protocol, complying with a uniform set of standards to assess clinical and laboratory findings, and completing the CRFs
- Communication among investigators is facilitated
See US-ICH-E17 for additional FDA guidance related to multi-regional clinical trials.
Insurance
As set forth in the PANDRH-GCPs, the sponsor is responsible for providing insurance coverage for any unforeseen injury to research participants. Before the clinical trial begins, the sponsor should also provide insurance or indemnify the investigator and the institution against claims arising from malpractice or negligence.
In addition, according to BRA-1, in the event that ANVISA asks for additional information to assess insurance and indemnity coverage for injures related to the study, the sponsor must provide a Medical Assistance Letter. See BRA-79 for additional information on sponsor/contract research organization (CRO) insurance coverage requirements in Brazil.
Compensation
Injury or Death
As specified in the PANDRH-GCPs and ResNo466, the sponsor is responsible for providing compensation to research participants and/or their legal heirs in the event of trial-related injuries or death. The sponsor must also ensure that participants who suffer any trial-related injuries are provided with free medical treatment for such injuries.
Trial Participation
As specified in ResNo466 and the G-ClinResSubjectRts, compensation to participants is only provided for transportation costs and meals for the participants and/or their legal representative(s) or guardian(s) during the trial.
Post-Trial Access
According to ResNo563, for protocols involving research participants diagnosed with ultra-rare diseases, the sponsor must ensure free access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective at the end of the study, for a period of five (5) years after obtaining National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) registration. In addition, per ResNo466, at the end of the study, the sponsor much ensure free and indefinite access to the best prophylactic, diagnostic, and therapeutic methods that have proven to be effective. Access must also be guaranteed to participants between the time they stop their participation in the trial and the end of the study.
Furthermore, ResNo311, which amends ResNo38, states that the sponsor/CRO should guarantee access to the post-study drug supply program for research participants enrolled in a clinical study in accordance with the Resolutions of the National Health Council (Conselho Nacional de Saúde (CNS)). The free supply of medicines should also be made available to participants when the study is terminated early. The sponsor is required to complete the Sponsor’s Responsibility and Commitment Statement Form for Expanded Access, Compassionate Use, or Post-Study Medicine Supply Programs (see Annex VI of ResNo38). See also BRA-79 for additional information on sponsor/CRO insurance coverage.
Insurance
The United States (US) regulations do not require insurance.
Compensation
The G-IRBFAQs state that institutional policy, not Food & Drug Administration (FDA) regulation, determines whether compensation and medical treatment(s) will be offered and the conditions that might be placed on participant eligibility for compensation or treatment(s).
Injury or Death
According to the US-ICH-GCPs, the sponsor's policies and procedures should address the costs of treatment of trial subjects in the event of trial-related injuries in accordance with the applicable regulatory requirement(s).
As specified in 21CFR50, the Pre2018-ComRule, the RevComRule, and US-ICH-GCPs, for research involving more than minimal risk, participants must be informed as to whether any compensation or medical treatments are available in the event of trial-related injuries. See the Required Elements section for additional information.
Trial Participation
As per the FDA’s G-SbjctPayment, compensation for participation is considered a recruitment incentive and not a benefit, and is often offered when the participant’s health benefits are remote or non-existent. Payment amounts and schedules should be presented to the institutional ethics committee (EC) (institutional review board (IRB) in the US) at the time of the initial review. The EC should ensure the payment amount and the proposed method and timing of disbursement are not coercive or present undue influence and are also included in the informed consent document. Payment to participants who withdraw may be made at the time that they would have completed the study. While the entire payment should not be contingent upon completion of the entire study, a small payment provided as an incentive for completion is acceptable to the FDA. Further, the FDA does not consider reimbursement for travel expenses to and from the clinical trial site and associated costs such as airfare, parking, and lodging to raise issues regarding undue influence.
Quality Assurance/Quality Control
As stated in ResNo9 and the PANDRH-GCPs, the sponsor or the contract research organization (CRO) is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data are generated, recorded, and reported in compliance with the protocol, the PANDRH-GCPs, the International Conference on Harmonisation (ICH)’s Guideline for Good Clinical Practice E6(R2) (BRA-28), and other applicable requirements.
The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed.
The sponsor must also obtain the investigator(s) and the institution(s) agreement to:
- Conduct the trial in compliance with the PANDRH-GCPs, applicable regulatory requirement(s), and the protocol agreed to by the sponsor and approved by the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP))
- Comply with data recording and reporting procedures
- Permit monitoring, auditing, and inspection
- Retain essential documents until the sponsor indicates they are no longer needed
Monitoring Requirements
As part of its QA system, ResNo9 and the PANDRH-GCPs note that the sponsor or the CRO should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also verify that the audit is conducted in accordance with their own SOPs, the auditor observations are documented, and data is available as needed for the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s review. No specific timeframe is provided for the audit process.
In addition, per ResNo449, which amends ResNo9, ANVISA is allowed to use remote Good Clinical Practice (GCP) inspection mechanisms for temporary and emergency use in lieu of in-person inspections. Remote inspections are carried out by means of videoconferencing and data transmission technologies for GCP verification. Remote inspections replace the need for in-person inspectors in the establishment. Establishments under inspection may be inspected remotely at any time by ANVISA.
NormNo122 provides further guidance on ANVISA inspection procedures to ensure drug clinical trials are conducted in compliance with GCPs delineated in ResNo9, the PANDRH-GCPs, and the BRA-28. Per BRA-30, ANVISA’s administrative unit, the Coordination of Clinical Research on Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)), requires all clinical trial inspections to be conducted in accordance with BRA-28.
In the event of a routine inspection, NormNo122 states that ANVISA will notify the institution at least 15 calendar days in advance of the visit. Both the sponsor and/or the CRO are responsible for preparing for the inspection. ANVISA shall also notify the principal investigator (PI) of the scheduled visit to the center to be inspected, when applicable, by means of a GCP Inspection Notification Letter. For more detailed information on ANVISA’s inspection process, refer to NormNo122.
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 NormNo122 with the goal of guiding those involved in the inspection procedures to ensure a unified standard and the safety of all involved parties.
GuideNo35-2020 and GuideNo36-2020 explain that GCP inspections of sponsors and clinical research organization 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 NormNo122. In addition, per GuideNo35-2020 and GuideNo36-2020, the inspections will involve at least two (2) ANVISA inspectors, one (1) of whom will be the lead inspector and the focal point for communication with either the clinical trial center or the sponsor/CRO(s). The inspections for both entities will take place over a maximum period of five (5) working days unless the period is altered with due justification. See GuideNo35-2020 and GuideNo36-2020 for additional details.
See ResNo620 for information on the Certification of Good Practices for conducting bioavailability/bioequivalence drug studies and requirements for which bioavailability/bioequivalence drug studies must be carried out in certified research centers.
Premature Study Termination/Suspension
As set forth in ResNo9, the sponsor may cancel or suspend a clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) or a clinical trial, at any time, provided that the appropriate technical-scientific justifications are submitted to ANVISA along with a plan to monitor the research participants in clinical trial(s) that have already begun. Per ResNo9 and the G-DDCMManual, DDCM or clinical trial suspensions and cancellations must be submitted to ANVISA in the form of a secondary petition attached to the previously submitted DDCM or Specific Clinical Trial Dossier (Dossiê Específico de Ensaio Clínico (DEEC)). Refer to the Submission Content section for instructions on submitting a secondary petition to suspend or cancel a DDCM or clinical trial.
ResNo9 and the G-DDCMAmdmts state that the sponsor must notify ANVISA within a maximum period of 15 consecutive days following a decision to suspend or cancel a clinical trial or DDCM. In cases of the temporary suspension of a clinical trial or DDCM as an immediate safety measure, the sponsor must notify ANVISA within seven (7) consecutive days from the suspension date. Per ResNo9, the reasons for suspension, the scope, the interruption of treatment, and the suspension of participant recruitment must be clearly explained in the notification of temporary suspension. As per the G-DDCMAmdmts, in the case of a temporary suspension of a DDCM or a clinical trial protocol, the suspension can be reversed with the submission of a secondary petition to ANVISA. ResNo9 specifies that these requests must be accompanied by due justification so that the trial(s) can be restarted. The clinical trial(s) or DDCM may be reactivated only after approval is obtained by ANVISA. The timeline for ANVISA’s review of these cases is not delineated in ResNo9 or in the G-DDCMAmdmts.
Regarding DDCM cancellations, the G-DDCMAmdmts emphasizes that cancellations, under the terms of ResNo9, are definitive, with no possibility of further reactivation, and that once a DDCM is cancelled, no clinical trial related to it can be continued in the country. In the specific case of a voluntary request to cancel a DDCM, the sponsor must follow the requirements detailed in the AESafetyManual when submitting the follow-up plan and the risk minimization/mitigation measures to protect the participants of clinical trials already underway. A DDCM cancellation can occur even if it has not yet been evaluated. Similarly, clinical trial cancellations are also definitive under ResNo9, with no possibility of further reactivation. The cancellation only applies to clinical trial protocols that have already been initiated by the sponsor. If the protocol is provided for in the DDCM, but has not yet been started, the protocol must be deleted.
In addition, ResNo9 states that ANVISA may, at any time, cancel or suspend a DDCM or any related clinical trial if it believes that the approval conditions have not been met or if there are safety or efficacy reports that significantly affect either the trial participants or scientific validity. In this case, ANVISA will inform the sponsor of the reasons for this cancellation or suspension. Per ResNo9, the sponsor must immediately inform those involved in a clinical trial when it is prematurely cancelled or suspended for any reason. The PANDRH-GCPs also explains that if the sponsor or the CRO chooses, or is required to terminate a study, the investigator(s) should promptly inform the institution. The investigator or institution should also immediately inform the EC (CEP) and provide a detailed explanation of the cancellation or suspension.
Quality Assurance/Quality Control
Per the US-ICH-GCPs, the sponsor should implement a system to manage quality throughout all stages of the trial process, focusing on trial activities essential to ensuring participant protection and the reliability of trial results. The quality management system should use a risk-based approach that includes:
- During protocol development, identify processes and data that are critical to ensure participant protection and the reliability of trial results
- Identify risks to critical trial processes and data
- Evaluate the identified risks, against existing risk controls
- Decide which risks to reduce and/or which risks to accept
- Document quality management activities and communicate to those involved in or affected by these activities
- Periodically review risk control measures to ascertain whether the implemented quality management activities are effective and relevant
- In the clinical study report, describe the quality management approach implemented in the trial and summarize important deviations from the predefined quality tolerance limits and remedial actions taken
As stated in the US-ICH-GCPs, the sponsor is responsible for implementing and maintaining quality assurance (QA) and quality control (QC) systems with written standard operating procedures (SOPs) to ensure that trials are conducted and data generated, recorded, and reported in compliance with the protocol, the US-ICH-GCPs, and the applicable regulatory requirements. The sponsor is responsible for obtaining agreement from all involved parties to ensure direct access to all trial related sites, source data/documents, reports for monitoring and auditing purposes, and inspection by domestic and foreign regulatory authorities. QC should be applied to each stage of data handling to ensure that all data are reliable and have been correctly processed. A written agreement must be signed by both the sponsor and the investigator or any other parties involved with the clinical trial, verifying that all parties agree to the trial protocol, the monitoring and auditing practices, the SOPs, and their respective duties.
Per the G-ICH-E19, the Food & Drug Administration (FDA) has adopted the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s E19 guidance, A Selective Approach to Safety Data Collection in Specific Late-Stage Pre-Approval or Post-Approval Clinical Trials. The document describes circumstances in which it may be appropriate to reduce the collection of safety data in late-stage pre-approval and post-approval clinical trials, e.g., long-term outcome trials, when appropriate and with agreement from regulatory authorities. See the G-ICH-E19 for more information.
Furthermore, the FDA’s G-CTEmrgncy provides general considerations to assist sponsors, institutional ethics committees (ECs) (institutional review boards (IRBs) in the United States (US)), and clinical investigators in assuring the safety of trial participants, maintaining compliance with good clinical practice (GCP), and minimizing risks to trial integrity during disasters and public health emergencies that may lead to a major disruption of clinical trial conduct and operations. See the G-CTEmrgncy for more information.
See the G-eHealthRecords for the FDA’s guidance related to the use of electronic health records in clinical research.
Additionally, the G-CovariatesCT provides the FDA’s recommendations for the use of covariates in the analysis of randomized, parallel group clinical trials that are applicable to both superiority trials and noninferiority trials. See the G-CovariatesCT for more information.
The G-RWDRWE-Reg, issued as part of the FDA’s Real-World Evidence (RWE) Program (see USA-17), discusses the applicability of the 21CFR312 IND regulations to various clinical study designs that utilize real-world data (RWD). See the G-RWDRWE-Reg for more information.
Additionally, see USA-47 for a list of FDA clinical trials related guidance documents.
See USA-6 for information on the National Institutes of Health (NIH)’s data management and sharing policy, the NIHDataMngmnt, which applies to all research that is funded or conducted in whole or in part by the NIH, and results in the generation of scientific data.
Monitoring Requirements
As part of its QA system, the US-ICH-GCPs notes that the sponsor should ensure the trial is monitored and audited. The purpose of the audit should be to evaluate trial conduct and compliance with the protocol, SOPs, the US-ICH-GCPs, and other applicable regulatory requirements. The sponsor should appoint auditors to review the clinical trial. The sponsor should ensure that the auditors are qualified by training and experience, and the auditor’s qualifications should be documented. The sponsor must also ensure that the audit is conducted in accordance with the sponsor’s own SOPs and the auditor observations are documented. The sponsor should develop a systematic, prioritized, risk-based approach to monitoring clinical trials. The extent and nature of monitoring is flexible and permits varied approaches that improve effectiveness and efficiency. The sponsor may choose on-site monitoring, a combination of on-site and centralized monitoring, or where justified, centralized monitoring. The sponsor should document the rationale for the chosen monitoring strategy (e.g., in the monitoring plan).
The FDA’s G-RiskMntrng states that for each clinical trial, the sponsor should develop a monitoring plan that describes the monitoring methods, responsibilities, and requirements for the trial. The monitoring plan should include a brief description of the study, its objectives, and the critical data and study procedures, with particular attention to data and procedures that are unusual in relation to clinical routine. The monitoring plan should also require training of study site staff. Additionally, the plan should communicate the specific risks to be addressed by monitoring and should provide those involved in monitoring with adequate information to effectively carry out their duties. The FDA also encourages greater use of centralized monitoring practices, where appropriate, with correspondingly less emphasis on on-site monitoring. Centralized monitoring techniques should be used to the extent appropriate and feasible to:
- Supplement or reduce the frequency and extent of on-site monitoring with monitoring activities that can be done as well or better remotely or with monitoring activities that can be accomplished using centralized processes only. Examples include monitoring data quality through routine review of submitted data, as well as completing administrative and regulatory tasks.
- Target on-site monitoring by identifying higher risk clinical sites (e.g., sites with data anomalies or a higher frequency of errors, protocol violations, or dropouts relative to other sites).
For more FDA guidance on a risk-based approach to monitoring and monitoring plans, see the G-RiskMntrng and the G-RiskMntrngQA.
Premature Study Termination/Suspension
As delineated in 21CFR312 and the US-ICH-GCPs, if the sponsor determines the study presents an unreasonable and significant risk to the participants, the sponsor must discontinue the study as soon as possible, and no later than five (5) working days after making the determination. The sponsor must also notify the FDA, all ECs, and all investigators who have participated in the study about the termination. Additionally, the sponsor must ensure the disposition of all remaining drugs and provide the FDA with a full report on the sponsor’s actions.
According to the US-ICH-GCPs, if it is discovered that noncompliance significantly affects or has the potential to significantly affect participant protection or reliability of trial results, the sponsor should perform a root cause analysis and implement appropriate corrective and preventive actions. Further, the EC should also be informed promptly and provided the reason(s) for the termination or suspension by the sponsor.
The G-InfrmdCnsnt, which is the FDA’s discussion of the regulations in 21CFR50, further states that if a study is terminated, participants should be provided with as much information as possible regarding the reason for the termination. Such a discussion provides an opportunity to address questions that participants may have about an investigational product (IP) that was administered to them (e.g., immediate safety concerns, ability to participate in another clinical trial, and appropriate waiting period to do so) and what long-term follow-up may be available or necessary.
21CFR312 indicates that if the FDA terminates an investigational new drug application (IND) based on deficiencies in the IND or in the conduct of an investigation under an IND, the sponsor must end all clinical investigations conducted under the IND and recall or otherwise provide for the disposition of all unused supplies of the drug. See 21CFR312 for more information on FDA termination.
Electronic Data Processing System
Per the PANDRH-GCPs, when using electronic trial data processing systems, the sponsor or the contract research organization (CRO) must ensure that the system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance, and that standard operating procedures (SOPs) are maintained when using these systems. Refer to the PANDRH-GCPs for detailed information on electronic trial data systems.
Records Management
As set forth in ResNo9, the sponsor or the CRO should maintain the clinical trial data on file in physical or digital format for a period of five (5) years after the last approval of a request for registration in Brazil. ResNo9 and the PANDRH-GCPs also state that the sponsor should retain clinical trial data in physical or digital format for at least two (2) years in case of the following instances: the investigational product’s clinical development is discontinued, completion of the registration application is not achieved, a marketing application receives the last approval, or there are no pending or contemplated marketing applications. Per the PANDRH-GCPs, the sponsor should inform the investigator(s) and the institution(s) in writing when trial-related records are no longer needed.
Electronic Data Processing System
Per the US-ICH-GCPs, when using electronic trial data handling processing systems, the sponsor must ensure and document that the electronic data processing system conforms to the sponsor’s established requirements for completeness, accuracy, reliability, and consistency of intended performance. To validate such systems, the sponsor should use a risk assessment approach that takes into consideration the system’s intended use and potential to affect human subject protection and reliability of trial results. In addition, the sponsor must maintain standard operating procedures (SOPs) that cover system setup, installation, and use. The SOPs should describe system validation and functionality testing, data collection and handling, system maintenance, system security measures, change control, data backup, recovery, contingency planning, and decommissioning. With respect to the use of these computerized systems, the responsibilities of the sponsor, investigator, and other parties should be clear, and the users should receive relevant training. Refer to the US-ICH-GCPs for additional information.
Records Management
As set forth in 21CFR312 and the US-ICH-GCPs, the sponsor must retain all sponsor-specific essential documents pertaining to the trial for at least two (2) years after a marketing application (known as a new drug application (NDA)) is approved for the drug; or if a NDA is not approved, until two (2) years after shipment and delivery of the drug for investigational use is discontinued and the Food & Drug Administration (FDA) has been notified. The sponsor should also inform the investigator(s)/institution(s) in writing of the need for record retention and when the trial-related records are no longer needed. Additionally, per 21CFR312, the sponsor must upon request from the FDA, permit an officer or employee to access, copy, and verify any records and reports relating to the clinical investigation. Upon written request by the FDA, the sponsor must also submit the records or reports (or copies of them) to the agency.
In addition, the US-ICH-GCPs states that the sponsor and investigator/institution should maintain a record of the location(s) of their respective essential documents including source documents. The storage system used during the trial and for archiving (irrespective of the type of media used) should allow for document identification, version history, search, and retrieval. The sponsor should ensure that the investigator has control of and continuous access to the data reported to the sponsor. The investigator/institution should have control of all essential documents and records generated by the investigator/institution before, during, and after the trial.
Responsible Parties
For the purposes of data protection requirements, LawNo13.709 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 sponsor may carry out studies as a research body, guaranteeing, whenever possible, the anonymization of personal data.
Data Protection
As set forth in C-AmndtNo115, the protection of personal data is a guaranteed fundamental right in Brazil. LawNo13.709 further delineates data protection principles (e.g., purpose, adequacy, necessity, free access, data quality, transparency, security, prevention, non-discrimination, and accountability) with which the sponsor must comply.
Per LawNo13.709, the data quality principle is fulfilled when the sponsor 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 sponsor must keep a record of the personal data processing operations carried out, especially when the processing operation is for an official purpose. The sponsor must also provide instructions to the operator, the person responsible for processing the personal data on the sponsor’s behalf, to check compliance with the specified instructions and rules. Additionally, the sponsor 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.
LawNo13.709 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 LawNo13.709, the sponsor may implement a privacy governance program that, at a minimum:
- Demonstrates the sponsor’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 LawNo13.709 and BRA-76 for detailed information on data protection requirements in Brazil.
Consent for Processing Personal Data
As set forth in LawNo13.709, 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.
In addition, data holders 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 LawNo13.709 for additional information on the rights of data holders.
See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ethics committees (Comitês de Ética em Pesquisas (CEPs)) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. See also CLNo039 for CONEP guidance on accessing and using a participant’s medical records for research purposes while ensuring compliance with privacy and confidentiality standards. The guideline also states that all participants should be treated with dignity, respect for their autonomy, and ensure protection for vulnerable populations.
Consent for Processing Personal Data of Children/Adolescents
Per LawNo13.709, 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.
Responsible Parties
As stated in USA-86, the HIPAA Privacy Rule establishes the conditions under which protected health information (PHI) may be used or disclosed by covered entities for research purposes (Per USA-87, the Privacy Rule is located at 45CFR160 and Subparts A and E of 45CFR164; see USA-87 for more information). The Privacy Rule builds upon protections, described in Department of Health & Human Services (HHS) (the Pre2018-ComRule and the RevComRule) and Food & Drug Administration (FDA) (21CFR50 and 21CFR56) regulations, that help ensure the privacy of participants and the confidentiality of information. (Please note: ClinRegs does not provide information on state level personal data protection requirements.)
Per the Privacy Rule, a covered entity means: a health plan; a health care clearinghouse; or a health care provider who transmits any health information in electronic form in connection with a transaction covered by the Privacy Rule.
Data Protection
According to the FDA’s G-CertCnfdntlty, a Certificate of Confidentiality (CoC) is intended to help protect the privacy of human subject research participants from whom identifiable, sensitive information is being collected or used in furtherance of the research. CoCs must be issued for federally funded human subject research that collects or uses identifiable, sensitive information (mandatory CoCs). For non-federally funded research, issuance of CoCs is not required but may be issued at the discretion of the FDA (discretionary CoCs). If an institutional ethics committee (EC) (institutional review board (IRB) in the United States) determines that data collected in a clinical trial are sufficiently sensitive to warrant requesting a CoC, then the EC may request that a CoC be obtained in order to secure EC approval. Any disagreement between an EC, sponsor, and/or investigators regarding the need to request a CoC for a study should be resolved by communications among the parties. See the G-CertCnfdntlty for more information on CoCs.
NIH Privacy Requirements
The NIHPrvcy indicates that the HHS’ National Institutes of Health (NIH) follows the PrvcyAct, which includes procedures for: 1) protecting records that can be retrieved by personal identifiers such as a name, social security number, or other identifying number or symbol, and 2) persons to access their identifiable records and to request correction(s) of these records. See the NIHPrvcy and the PrvcyAct for more information.
Consent for Processing Personal Data
Per USA-86, the Privacy Rule defines the means by which individuals will be informed of uses and disclosures of their medical information for research purposes, and their rights to access information about themselves held by covered entities. Researchers may obtain, create, use, and/or disclose individually identifiable health information in the course of conducting research. Under the Privacy Rule, covered entities are permitted to use and disclose PHI for research with individual authorization, or without individual authorization under limited circumstances. To use or disclose PHI without authorization by the research participant, a covered entity must obtain one (1) of the following:
- Documented EC or privacy board approval
- Representations from the researcher that the use or disclosure of the PHI is solely to prepare a research protocol (or for similar purposes preparatory to research), the researcher will not remove any PHI from the covered entity, and PHI for which access is sought is necessary for the research purpose
- Research on protected health information of decedents
- Limited data sets with a data use agreement
- Research use/disclosure with individual authorization
- Accounting for research disclosures
See USA-86 for more information on these circumstances.
Obtaining Consent
In all Brazilian clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in the PANDRH-GCPs, ResNo466, and the G-ClinResSubjectRts. Per OMREC and G-ClinResSubjectRts, the informed consent form (ICF) is also known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.
As per the PANDRH-GCPs, ResNo466, the G-ClinResSubjectRts, and OMREC, the ICF is viewed as an essential document that must be reviewed and approved by an ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and provided to the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) with the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))). CLNo51 further clarifies that the ICF should be written as an invitation rather than as a statement as this may reduce the participant’s autonomy. Refer to CLNo51 for detailed information. See the Required Elements section for details on contents to be included in the form.
The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the investigator, or their designated representative, must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). As delineated in ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, OMREC, and the G-ClinProtocols-FAQs, the ICF content should be presented in a clearly organized format using practical and non-technical language commensurate with the participant’s level of understanding. Per the PANDRH-GCPs and the G-ClinResSubjectRts, neither the investigator nor the research staff should coerce or improperly influence a potential participant to enroll in the clinical trial. The PANDRH-GCPs further explains that none of the oral and written information concerning the research study, including the written ICF, should contain any language that causes the participant or the legal representative(s) and/or guardian(s) to waive or to appear to waive their legal rights, or that releases or appears to release the investigator(s), the institution, the sponsor, or their representatives from their liabilities for any negligence. ResNo466 and the G-ClinResSubjectRts further note that the investigator must bear in mind that the prospective participant's ability to understand the information required to give consent depends on their maturity, ethics, intelligence, education, and cultural beliefs. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and the G-ClinProtocols-FAQs, the information should be in both written and oral form, and the participant and the legal representative(s) or guardian(s) should also be given adequate time to consider whether to participate.
Re-Consent
According to the PANDRH-GCPs and CLNo17, any change in the ICF due to a protocol modification or an alteration in treatment modality, procedures, or site visits, should be approved by the EC (CEP) and submitted to ANVISA before such changes are implemented. Per the PANDRH-GCPs, the G-ClinResSubjectRts, and CLNo51, the investigator must ensure that the participant and/or the legal representative(s) or guardian(s) sign the revised ICF and any other updated information. CLNo17 further notes that changes made to the ICF through separate documents are not considered acceptable. The update requires the investigator to generate a single and complete version of the new document, free of addenda and/or other documents associated with it. The investigator or their delegated representative should also emphasize the changes contained in the updated ICF. The clarifications delineated in CLNo17 also apply to assent forms.
Language Requirements
As earlier stated, the PANDRH-GCPs and the G-ClinResSubjectRts require the ICF to be presented orally and in writing at a level that the participant is able to understand. Per the PANDRH-GCPs, the investigator should provide the ICF in the participant’s own language when they do not speak the language currently spoken in the country. The G-ClinProtocols-FAQs further notes that the ICF must be adequately adapted and be fully revised in Portuguese to ensure that the document is properly translated.
Documenting Consent
The PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC state that the participant and/or the legal representative(s) or guardian(s), and the investigator(s) must sign and date the ICF. In addition, the PANDRH-GCPs explains that if the participant and/or the legal representative(s) or guardian(s) is illiterate, an impartial witness should be present throughout the consent process. At this time, the participant and/or the legal representative(s) or guardian(s) will give verbal, and, if possible, written consent, and the witness should sign and date the form, certifying that the written information was explained accurately and understood.
Before participating in the study, per the PANDRH-GCPs, OMREC, and the G-ClinResSubjectRts, the participant should receive a copy of the signed and dated ICF, and any other written information provided during the informed consent process. ResNo466 and the G-ClinProtocols-FAQs specify that two (2) original copies of the ICF should be prepared with all pages initialed and signed by the participant and/or the legal representative(s) or guardian(s), and the investigator(s) or person(s) overseeing the consent process.
Waiver of Consent
No information is available on consent waivers for research participants. See the Consent for Specimen section information on waivers pertaining a participant’s stored genetic materials.
Obtaining Consent
In all United States (US) clinical trials, a freely given informed consent is required to be obtained from each participant in accordance with the requirements set forth in 21CFR50 for Food & Drug Administration (FDA) regulated clinical trials, and the Pre2018-ComRule or the RevComRule for federally funded or sponsored clinical trials. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on agency-specific compliance.) Department of Health & Human Services (HHS)-funded or sponsored clinical trials must also comply with 45CFR46-B-E. The FDA has also adopted the US-ICH-GCPs as guidance.
As per 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) is viewed as an essential document that must be reviewed and approved by an institutional ethics committee (EC) (institutional review board (IRB) in the US) and provided to the FDA with the investigational new drug application (IND).
Per the G-RevComRule-FDA, the informed consent requirements of the RevComRule are not inconsistent with FDA regulations. Therefore, there may not be a need for sponsors or investigators to develop, and have ECs review, two (2) separate ICFs for research that must comply with both the RevComRule and FDA regulations. (See the Required Elements section for ICF content details.) Per the RevComRule, which took effect January 21, 2019, for each clinical trial conducted or supported by a federal department or agency, one (1) EC-approved ICF used to enroll subjects must be posted by the awardee or the federal department or agency component conducting the trial on a publicly available federal website that will be established as a repository for such ICFs. According to USA-12, two (2) federal websites have been identified to meet this requirement: ClinicalTrials.gov (USA-78) and a docket folder on Regulations.gov (USA-79). According to the RevComRule, if the federal department or agency supporting or conducting the clinical trial determines that certain information should not be made publicly available on a federal website (e.g., confidential, commercial information), such federal department or agency may permit or require redactions to the information posted. The ICF must be posted on the federal website after the clinical trial is closed to recruitment and no later than 60 days after the last study visit by any subject, as required by the protocol.
According to 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the investigator must provide detailed research study information to the participant and/or the legal representative(s) or guardian(s). ICF content should be briefly and clearly presented orally and in writing, in a manner that is easy to understand and commensurate with the comprehension level of the research participants, and without coercion or unduly influencing a potential participant to enroll in the clinical trial. The participant and/or the legal representative(s) or guardian(s), should also be given adequate time to consider whether to participate.
As indicated in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, none of the oral and written information concerning the research study should contain any language that causes the participant and/or the legal representative(s) or guardian(s) to waive or appear to waive legal rights, or that releases or appears to release the investigator, sponsor, institution or its agents from liability for negligence.
Additionally, per the RevComRule, participants must be provided with the information that a “reasonable person” would want to have in order to make an informed decision and an opportunity to discuss that information. Furthermore, the RevComRule requires that the informed consent, except for broad consent, must begin with a concise and focused presentation of the key information and organized to facilitate comprehension. Broad consent may be obtained in lieu of a full informed consent only with respect to the storage, maintenance, and secondary research uses of private identifiable information and identifiable biospecimens. See USA-54 and USA-60 for additional information regarding informed consent and broad consent requirements.
In addition, per 21CFR50, the Pre2018-ComRule, and the RevComRule, the ICF may be presented as either a full length written ICF or as a short form stating the consent requirements have been presented orally. The full length written ICF may be presented orally but must then be provided to the participant and/or a legal representative(s) or guardian(s) to read before it is signed.
See the FDA’s G-ElectronicIC for recommendations on the use of electronic systems and processes that may employ multiple electronic media to obtain informed consent for both HHS-regulated human subject research and FDA-regulated clinical investigations of medical products.
See the G-InfrmdCnsnt for the FDA’s discussion of the regulations in 21CFR50. Also, see USA-54 and USA-60 for additional information regarding informed consent.
Re-Consent
According to 21CFR50, the US-ICH-GCPs, and the G-IRBFAQs, the EC should determine the need to re-consent enrolled participants in the event of an ICF modification due to protocol changes or new information which may, in turn, affect the willingness of already enrolled participants to continue in the study. The communication of this information should be documented.
The G-IRBFAQs indicates that the FDA does not require re-consenting of participants who have completed their active participation in the study, or of participants who are still actively participating when the change will not affect their participation. One such case is when the change will be implemented only for subsequently enrolled participants.
Language Requirements
21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that any information provided must be in a language understandable to the participant and/or the legal representative(s) or guardian(s).
As delineated in the FDA’s G-InfrmdCnsnt, when non-English speaking participants are enrolled in a study, ECs and investigators must ensure that the information provided to prospective participants and/or their legal representative(s) or guardian(s) is in a language that is understandable to them. The EC must review and approve all consent documents that are to be used by investigators to document the informed consent. When translation and interpretation are needed for written and oral information to be presented to participants, the FDA recommends that the EC review and approve reasonable procedures for ensuring that the translations will be prepared by a qualified individual or entity, and that interpretation assistance is available. The FDA also recommends that whenever non-English speaking participants are enrolled in a study, appropriate interpreter services be made available throughout the course of the study.
USA-63 also states that when an oral presentation of the ICF is provided, the witness present should be fluent in both English and the participant’s language, and the translator may serve as the witness. See the G-InfrmdCnsnt and USA-63 for detailed information.
Documenting Consent
As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the participant and/or a legal representative(s) or guardian(s) must sign and date an EC-approved written ICF. A written copy of the form must be given to the participant and/or a legal representative(s) or guardian(s). In addition, the RevComRule explicitly allows electronic signatures for consent documentation.
Per 21CFR50, the Pre2018-ComRule, and the RevComRule, if the consent information is only presented orally using the short form, the participant and/or the legal representative(s) or guardian(s) must sign the form, the witness must sign both the short form and a copy of the summary once consent has been provided, and the person obtaining the consent must sign a copy of the summary. A copy of both the summary and the short form must be given to the participant and/or the legal representative(s) or guardian(s). The FDA’s G-InfrmdCnsnt further states that participants who cannot write can instead indicate their consent by "making their mark" on the consent document. In these situations, a note should be included in participant case histories indicating the reason for the lack of a signature and date as required in 21CFR50. The date consent was obtained should be recorded in this note.
According to the US-ICH-GCPs, where the participant is illiterate and/or the legal representative(s) and/or guardian(s) is illiterate, an impartial witness should be present during the entire informed consent discussion. The witness should sign and date the ICF after the following steps have occurred:
- The written ICF and any other written information to be provided to the participant is read and explained to the participant or the legal representative(s)/guardian(s)
- The participant or the legal representative(s)/guardian(s), has orally consented to the participant’s involvement in the trial, and has signed and dated the ICF, if capable of doing so
Per the US-ICH-GCPs, before participating in the study, the participant or the legal representative(s)/guardian(s) should receive a copy of the signed and dated ICF.
Waiver of Consent
Per the Pre2018-ComRule and the RevComRule, the EC may waive the requirement to obtain a signed ICF if it finds any of the following:
- The ICF would risk a breach of confidentiality by linking the participant to the study
- The research presents minimal risk and involves no procedures for which written consent is required outside of the study
The RevComRule also adds that the EC may waive the requirements to obtain a signed ICF if the participants are part of a distinct cultural group or community in which signing the form is not the norm, the research presents minimal risk, and there is an alternative approach to document informed consent.
The Pre2018-ComRule and the RevComRule further indicate that in cases where the documentation requirement is waived, the EC may require the investigator to provide the participant or the legal representative(s)/guardian(s) with a written statement regarding the research.
In addition, the Pre2018-ComRule states that for an EC to approve a general waiver or alteration of consent, the EC must find that:
- The research involves no more than minimal risk
- The research could not practicably be carried out without the requested waiver or alteration
- If the research involves using identifiable private information or identifiable biospecimens, the research could not practicably be carried out without using such information or biospecimens in an identifiable format
- The waiver or alteration will not adversely affect the rights and welfare of the participants
- Whenever appropriate, the participant will be provided with additional pertinent information after participation
In the G-MinRiskWaiver, the FDA informs sponsors, investigators, and ECs that it does not intend to object to an EC waiving or altering informed consent requirements for certain minimal-risk, clinical investigations.
Furthermore, the Pre2018-ComRule, the RevComRule, and the G-MinRiskWaiver specify that although voluntary informed consent is always a requirement for every trial, the EC may approve a waiver or alteration of consent if the study involves a public benefit and service program conducted by or subject to the approval of state or local officials and could not be carried out without the waiver or alteration.
Based on the PANDRH-GCPs, ResNo466, and OMREC, the informed consent form (ICF) should include the following statements or descriptions, as applicable (Note: The sources provide overlapping and unique elements so each of the items listed below will not necessarily be in each one):
- The study purpose, the procedures, and duration of the trial
- The participant’s responsibilities
- Experimental aspects of the study
- The approximate number of participants in the study
- Any expected risks or discomforts to the participant, and when applicable, to an embryo, fetus, or nursing infant
- Any expected benefits to the participant; if no benefit is expected, the participant should be informed of this point
- Treatments available to participants, how they are administered, and the probability of receiving every treatment
- Compensation and/or treatment available for the participant in the case of trial-related injury
- The disclosure of specific appropriate alternative procedures or therapies available to the participant
- The probability for random assignment to each treatment
- Any expenses the participant needs to pay to participate in the trial
- Confidentiality of records identifying the participant will be maintained, and permission given to monitors, auditors, the ethics committee(s), and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to access the participant’s medical records to verify the procedures or trial data without violating the participant’s confidentiality, insofar as the applicable laws and regulations permit
- That participation is voluntary, and that the participant can withdraw from the study at any time without penalty or loss of benefits, including medical treatment, to which the participant is otherwise entitled
- Contact information for the sponsor and investigator in the event of participant problems or trial-related injuries
- Foreseeable circumstances under which the investigator(s) may remove the participant without consent
- The consequences of a participant’s decision to withdraw from the research, and procedures for orderly withdrawal by the participant
- That the participant and/or the legal representative(s) or guardian(s) will be notified in a timely manner if significant new findings develop during the course of the study which may affect the participant's willingness to continue
See the Vulnerable Populations and Consent for Specimen sections for further information.
Based on 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the informed consent form (ICF) must include the following statements or descriptions, as applicable (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):
- The study purpose, procedures, and expected duration of the trial
- Identification of any experimental procedures
- Any expected risks or discomforts to the participant, and when applicable, to an embryo or fetus
- Any expected benefits to the participant
- Disclosure of appropriate alternative procedures that might be advantageous to the participant
- Confidentiality of records identifying the participant will be maintained and the possibility that the Food & Drug Administration (FDA) may inspect the records
- Compensation and/or treatment available for the participant in the case of trial-related injury
- Contact information for relevant individuals to contact in the event of a trial-related injury
- That participation is voluntary, that refusal to participate will involve no penalty or loss of benefits to which the participant is otherwise entitled, and that the participant can withdraw from the trial at any time without penalty or loss of otherwise entitled benefits
- Foreseeable circumstances under which the investigator may remove the participant without consent
- Any expenses the participant needs to pay to participate in the trial
- The consequences of a participant’s decision to withdraw from the study, and procedures for orderly withdrawal by the participant
- Any significant new findings developed during the study that may affect a participant’s willingness to continue participation
- Approximate number of participants in the study
As per 21CFR50, for FDA-regulated research, the following statement must be included on the informed consent documents: “A description of this clinical trial will be available on https://www.ClinicalTrials.gov, as required by U.S. Law. This Web site will not include information that can identify you. At most, the Web site will include a summary of the results. You can search this Web site at any time.”
In the G-InfrmdCnsnt, the FDA also recommends the consent document advise participants that data collected on them up until the point of their withdrawal from a study will remain part of the study database and may not be removed. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.
The RevComRule also requires the following statements to be included in the ICF:
- Whether research results will be disclosed to participants
- Whether or not the participant’s information or biospecimens will be used or distributed for future research
- That participant’s biospecimens (even if identifiers are removed) may be used for commercial profit and if the participant will share in this profit
- Whether biospecimens research may include whole genome sequencing
See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.
Compensation Disclosure
The FDA’s G-InfrmdCnsnt further states that if no compensation in the event of injury is available, the consent process should include a statement informing the participant. See the G-InfrmdCnsnt for an example statement.
Overview
In accordance with ResNo466, the PANDRH-GCPs, and OMREC, Brazil’s ethical standards promote respect for all human beings and safeguard the rights of research participants, including rights to their autonomy, culture, beliefs, and values. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process. (See the Required Elements; Vulnerable Populations; Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information regarding requirements for participant rights.)
See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. See also CLNo039 for CONEP guidance on accessing and using a participant’s medical records for research purposes while ensuring compliance with privacy and confidentiality standards. The guideline also states that all participants should be treated with dignity, respect for their autonomy, and ensure protection for vulnerable populations.
The Right to Participate, Abstain, or Withdraw
As set forth in the ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, the participant or the legal representative(s) or guardian(s), should be informed that participation is voluntary, that they may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.
The Right to Information
As delineated in the ResNo466, the PANDRH-GCPs, the G-ClinResSubjectRts, and OMREC, a potential research participant, and/or the legal representative(s) or guardian(s), has the right to be informed about the nature and purpose of the research study, its anticipated duration, study procedures, any potential benefits or risks, any compensation for participation or injury/treatment, and any significant new information regarding the research study.
The Right to Privacy and Confidentiality
As per the ResNo466, the PANDRH-GCPs, and OMREC, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. The PANDRH-GCPs also states that it is the responsibility of the investigator(s) to safeguard the confidentiality of research data to protect the identities and records of research participants.
The Right of Inquiry/Appeal
The PANDRH-GCPs, OMREC, and the G-ClinResSubjectRts explain that the research participant, and/or the legal representative(s) or guardian(s), should be provided with contact information for the sponsor and the investigator(s) to address trial-related inquiries and/or to appeal against a violation of their rights.
The Right to Safety and Welfare
ResNo466 and PANDRH-GCPs clearly state that a research participant’s right to safety and the protection of the participant’s health and welfare must take precedence over the interests of science and society.
Overview
In accordance with 21CFR50, 21CFR312, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, the United States’ (US) ethical standards promote respect for all human beings and safeguard the rights of research participants. A participant’s rights must also be clearly addressed in the informed consent form (ICF) and during the informed consent process.
The Right to Participate, Abstain, or Withdraw
As set forth in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential participant and/or a legal representative(s) or guardian(s) must be informed that participation is voluntary, that the participant may withdraw from the research study at any time, and that refusal to participate will not involve any penalty or loss of benefits to which the participant is otherwise entitled.
The Right to Information
As delineated in 21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, a potential research participant and/or a legal representative(s) or guardian(s), 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 21CFR50, the Pre2018-ComRule, and the RevComRule, participants should be given a statement describing the extent, if any, to which confidentiality of records identifying them will be maintained. Per the US-ICH-GCPs, all participants must be afforded the right to privacy and confidentiality, and the ICF must provide a statement that recognizes this right. 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 RevComRule does allow the use of identifiable private information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the US) determines the research could not practicably be carried out without the information. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for additional information on identifiable private information or biospecimens, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.
The G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, delineates how data should be handled when an enrolled participant decides to withdraw from a trial. Data collected on participants up to the time of withdrawal from clinical investigations of drugs conducted under an investigational new drug application (IND) must remain in the study database to maintain the scientific validity of the research. The FDA recommends that participants be advised in the consent document that the data collected on them up until the point of their withdrawal will remain part of the study database and may not be removed. If a participant withdraws from the interventional portion of the clinical investigation but agrees to continued follow-up not addressed in the original consent document, the investigator must obtain the participant’s informed consent for this limited participation using an EC-approved consent document. If a participant withdraws from the interventional portion of a clinical investigation and does not consent to continued follow-up of associated clinical outcome information, the investigator must not access the participant’s medical record or other confidential records that would require additional consent from the participant. However, such records may be accessed consistent with the original consent process, without additional consent, to obtain information collected prior to the participant’s withdrawal from the study. See the G-InfrmdCnsnt for additional information.
The Right of Inquiry/Appeal
21CFR50, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs state that the research participant and/or a legal representative(s) or guardian(s), 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 the participant’s rights.
The Right to Safety and Welfare
The US-ICH-GCPs clearly states 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.
As per the PANDRH-GCPs, in an emergency, if the signed informed consent form (ICF) cannot be obtained from the research participant, the consent of the legal representative(s) or guardian(s) should be obtained. If the prior consent of the participant or the legal representative(s) or guardian(s) cannot be obtained, the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) must provide documented approval in order to protect the participant’s rights, safety, and well-being, pursuant to the applicable regulations. The participant or the legal representative(s) or guardian(s) should provide consent as soon as possible. OMREC and ResNo251 similarly state that the EC (CEP) is responsible for approving the conditions or limits in which the informed consent should be approved in an emergency situation, and the investigator should inform the research participant in a timely manner about participation in the study.
21CFR50, 21CFR56, the US-ICH-GCPs, and the G-ICEmrgncyReqs make provisions to protect the rights of a research participant during the informed consent process when the procedure is complicated by life-threatening medical emergencies, public health emergencies, or military operations.
Medical Emergencies
As per the US-ICH-GCPs, in an emergency, if the signed informed consent form (ICF) has not been obtained from the research participant and/or a legal representative(s) or guardian(s), or if an effective treatment is lacking but the investigational product (IP) could address the participant’s emergency needs, the clinical trial may be conducted. However, the method used on the participant must be explained clearly in the trial protocol, and the institutional ethics committee (EC) (referred to as an institutional review board (IRB) in the United States (US)) must approve the protocol in advance. The participant and/or the legal representative(s) or guardian(s) should be informed about the trial as soon as possible, and consent to continue and other consent should be requested, as appropriate.
Emergency Use Situation
21CFR56 describes emergency use as the use of a test article, such as an IP, on a human participant in a life-threatening situation in which no standard acceptable treatment is available, and in which there is not sufficient time to obtain EC approval.
21CFR50 and the G-EmrgncyUse indicate that even in an emergency use situation, obtaining participant consent is required unless the investigator and a physician not participating in the trial certify in writing the following:
- The participant is confronted by a life-threatening situation
- Informed consent cannot be obtained due to an inability to communicate with the participant
- Time is insufficient to obtain consent from the participant’s legal representative(s) and/or guardian(s)
- No alternative methods of approved or generally recognized therapy are available
Per 21CFR50 and the G-EmrgncyUse, if immediate use of the IP is, in the investigator's opinion, required to preserve the participant’s life and time is not sufficient to obtain an independent physician’s determination prior to using the IP, the investigator’s determinations should be carried out. However, within five (5) working days following the use of the IP, the investigator’s decision must be reviewed and evaluated in writing by a physician not participating in the investigation. According to 21CFR50, 21CFR56, and the G-EmrgncyUse, the investigator must also notify the EC within five (5) working days.
21CFR56, the G-EmrgncyUse, and the G-IRBFAQs further state that following emergency use of the IP, EC review and approval is required for any subsequent use of the IP.
Emergency Research
The G-ICEmrgncyReqs defines emergency research as a planned clinical investigation that requires prior written Food & Drug Administration (FDA) authorization to proceed, and involves participant(s) who are in a life-threatening situation for which available treatments or in vitro diagnostic tests are unproven or unsatisfactory.
21CFR50 and the G-ICEmrgncyReqs delineate that for emergency research, the EC may approve the investigation without requiring the consent of all the participants if the EC (with the concurrence of a licensed physician who is an EC member or EC consultant, and not otherwise participating in the investigation) finds and documents the following:
- The participants are in a life-threatening situation, available treatments are unproven or unsatisfactory, and the collection of valid scientific evidence is necessary to determine the safety and effectiveness of particular interventions
- Obtaining informed consent is not feasible because: (i) the participants will not be able to give their informed consent as a result of their medical condition; (ii) the intervention under investigation must be administered before consent from the participants’ legal representative(s) and/or guardian(s) is feasible; and (iii) there is no reasonable way to identify prospectively the individuals likely to become eligible for participation in the clinical investigation
- Participation in the research holds out the prospect of direct benefit to the participants
- The clinical investigation could not practicably be carried out without the waiver
- The proposed investigational plan defines the length of the potential therapeutic window based on scientific evidence, and the investigator has committed to attempting to contact a legal representative and/or guardian for each participant within that window of time and, if feasible, to asking them for consent within that window rather than proceeding without consent
- The EC has reviewed and approved informed consent procedures and an informed consent document consistent with 21CFR50
- Additional protections of the rights and welfare of the participants will be provided
See 21CFR50 and the G-ICEmrgncyReqs for more details.
USA-60 notes that in certain emergency circumstances, the Department of Health & Human Services (HHS) Secretarial waiver of informed consent under 46.101(i) of the RevComRule may be applicable. The HHS waiver applies to research that may be carried out in human participants who need emergency therapy and for whom, because of the participants’ medical condition and the unavailability of the participants’ legal representative(s) and/or guardian(s), no legally effective informed consent can be obtained. Furthermore, if the research is regulated by the FDA, the HHS waiver permits the research to be conducted under a comparable provision. See the G-HHS-Emrgncy for additional guidance, USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.
Military Operations
21CFR50 and 10USC55 indicate that in the case of IP administration to a member of the armed forces in connection with participation in a particular military operation, the requirement for the member’s prior consent may be waived only by the US President. The US President may grant the waiver only after determining, in writing, that obtaining consent is not feasible; is contrary to the best interests of the military personnel; or is not in the interests of national security. See 21CFR50 and 10USC55 for detailed requirements.
Overview
As per the PANDRH-GCPs and the G-ClinResSubjectRts, in all Brazilian clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. The PANDRH-GCPs, ResNo466, and the G-ClinResSubjectRts characterize vulnerable populations as those who are relatively (or absolutely) incapable of protecting their own interests due to a lack of autonomy, intelligence, education, resources, strength, or other necessary attributes. These participants may include those with incurable diseases, people in convalescent homes, the unemployed or indigent, patients in emergency situations, ethnic minorities, homeless people, seasonal workers, refugees, minors, and those who cannot give their consent.
The G-ClinResSubjectRts further notes that in general, all individuals including healthy research participants should be seen as intrinsically vulnerable. These participants may currently be exposed to or are at risk of being exposed to an investigational product of unknown safety and efficacy, or one that is not fully understood, which could affect their overall health. In addition, other social, cultural, economic, psychological, or medical factors may adversely affect a participant’s ability to make rational and objective decisions that protect their own interests; however, this factor(s) may not be easily perceptible to the investigator.
The ResNo466 and PANDRH-GCPs specify that ethics committees (ECs) (Comitês de Ética em Pesquisas (CEPs)) must pay special attention to protecting participants who are from vulnerable populations. If the EC (CEP) regularly evaluates studies involving vulnerable populations, it should consider including members or consultants who know or have had experience working with the group in question. ResNo466 and the G-ClinResSubjectRts also state that vulnerable groups should not be included unless the research is necessary to promote the health of the population represented, and this research cannot instead be performed on legally competent participants.
See CLNo1-2021 for National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) guidelines for investigators and ECs (CEPs) related to contact with research participants (e.g., obtaining informed consent and ensuring confidentiality) and/or data collection at any phase of a research study in a virtual environment. See also CLNo039 for CONEP guidance on accessing and using a participant’s medical records for research purposes while ensuring compliance with privacy and confidentiality standards. The guideline also states that all participants should be treated with dignity, respect for their autonomy, and ensure protection for vulnerable populations.
Indigenous Peoples
As delineated in ResNo304, special attention should be paid when conducting a study involving indigenous peoples in Brazil. Studies involving this population should comply with ethical requirements while also considering the unique qualities of each community. The benefits and advantages resulting from conducting a study with indigenous peoples must also meet the needs of individuals or groups targeted by the study or of related societies, and/or the country as a whole. Investigators should take into account the need to promote and maintain the well-being of participants while protecting and preserving their biological, cultural, individual, and collective health while also contributing to the development of the participants’ knowledge and abilities. Refer to ResNo304 for detailed information on research and protection requirements when conducting a study with this population.
See the Children/Minors; Pregnant Women, Fetuses & Neonates; Prisoners; and Mentally Impaired sections for additional information about these vulnerable populations.
Overview
As per 21CFR56, the Pre2018-ComRule, the RevComRule, and the US-ICH-GCPs, in all United States (US) clinical trials, research participants selected from vulnerable populations must be provided additional protections to safeguard their health and welfare during the informed consent process. Institutional ethics committees (ECs) (institutional review boards (IRBs) in the US) must pay special attention to protecting such participants. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)
21CFR56 and the US-ICH-GCPs require special considerations for vulnerable populations and characterize them as those whose willingness to volunteer in a trial may be unduly influenced by the expectation, whether justified or not, of benefits associated with participation, or of a retaliatory response for refusing to participate. Examples of these participants include members of a group with a hierarchical structure, such as medical, pharmacy, dental, and nursing students; subordinate hospital and laboratory personnel; pharmaceutical industry employees; members of the armed forces; and persons kept in detention. Per 21CFR56 and US-ICH-GCPs, other vulnerable subjects include children, pregnant women, physically or mentally disabled persons, patients with incurable diseases, persons in nursing homes, economically or educationally disadvantaged persons, patients in emergency situations, ethnic minority groups, homeless persons, nomads, refugees, minors, and those incapable of giving consent.
The Pre2018-ComRule describes children, prisoners, pregnant women, handicapped persons, mentally disabled persons, or economically or educationally disadvantaged persons as vulnerable populations. The RevComRule describes children, prisoners, individuals with impaired decision-making capacity, or economically or educationally disadvantaged persons as vulnerable populations.
For more guidance documents related to vulnerable populations, see USA-64.
See the Children/Minors; Pregnant Women, Fetuses, & Neonates; Prisoners; and Mentally Impaired sections for additional information about these vulnerable populations.
The applicable regulatory requirements do not specify the age of minors.
As per PANDRH-GCPs, ResNo466, and OMREC, when the research participant is a child, the child’s legal representative(s) and/or guardian(s) must sign the informed consent form. However, all pediatric participants should be informed to the fullest extent possible about the study in language and terms that they are easily able to understand.
As stated in the G-ClinResSubjectRts, children should only participate in clinical studies when their participation is necessary to promote the health of the population represented.
Assent Requirements
ResNo466 also indicates that an assent form should be used to obtain informed consent from children. 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 legal representative(s) or guardian(s).
See the Personal Data Protection section for requirements on processing personal data of children and adolescents.
As set forth in 21CFR50 and 45CFR46-B-E, children are defined as persons who have not attained the legal age for consent to treatments or procedures involved in the research, under the applicable law of the jurisdiction in which the study will be conducted. USA-25 further states that the age of majority in most states is 18 and therefore for legal purposes, children are those individuals who have not reached the age of 18. See USA-25 for a table delineating the legal age of majority by state in the United States (US).
Per the Pre2018-ComRule and the RevComRule, children require additional safeguards to be included in any research study in order to protect their rights and welfare. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)
As delineated in the US-ICH-GCPs, when the research participant is a minor, informed consent should be obtained from a legal representative(s) or guardian(s). All pediatric participants should be fully informed about the trial and its risks and benefits in a language and in terms that they are easily able to understand. If capable, the participant should sign and date the written informed consent.
For all clinical trials that do not involve greater than minimal risk, 21CFR50 and 45CFR46-B-E state that a study may only be conducted if adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s).
For all clinical trials that involve greater than minimal risk but present the prospect of direct benefit to the child, 21CFR50 and 45CFR46-B-E indicate that a study may only be conducted if the following applies:
- The risk is justified by the anticipated benefit to the child
- The anticipated benefit is greater than or equal to the available alternative approaches
- Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardians
For all clinical trials involving children/minors that involve greater than minimal risk and do not present the prospect of direct benefit to the child, but will likely result in increased knowledge about the child’s disorder or condition, 21CFR50 and the 45CFR46-B-E state that a study may only be conducted if the following applies:
- The risk is slightly greater than minimal
- The trial presents experiences that are similar to those associated with the child’s actual or expected medical, dental, psychological, social, or educational situation
- Adequate provisions are made to obtain the child’s assent and the permission of their legal representative(s) or guardian(s)
For all clinical trials that present a reasonable opportunity to further understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors but is not otherwise approvable per 21CFR50 and 45CFR46-B-E, a study may only be conducted if the following applies:
- The institutional ethics committee (EC) (institutional review board (IRB) in the US) finds that the investigation presents a reasonable opportunity to further the understanding, prevention, or alleviation of a serious problem affecting the health or welfare of children, and,
- The Commissioner of Food and Drugs consults with an expert panel and has an opportunity for public review and comment to determine that the investigation satisfies the conditions of one (1) of the other earlier described research types, or the following conditions are met: the investigation will be conducted in accordance with sound ethical principles and adequate provisions are made for soliciting the assent of children and the permission of their legal representative(s) or guardian(s)
Per the RevComRule, certain exemptions may apply to observational research involving children. See the RevComRule for details.
For additional Food & Drug Administration (FDA) guidance on clinical research in children, see US-ICH-E11 and USA-60. Additionally, see the G-InfrmdCnsnt for FDA discussion of the regulations in 21CFR50.
Assent Requirements
Per 21CFR50 and 45CFR46-B-E, when determining whether children/minors are capable of providing assent, the EC must consider their age, maturity, and psychological state. Assent from a child/minor is not necessary for proceeding with the clinical trial if the following applies:
- The capability of some or all of the children/minors is so limited that they cannot reasonably be consulted
- The trial presents a potential direct benefit that is important to the health or well-being of the children/minors and is only available through the investigation
Further, the EC may waive assent, even if the children/minors are capable of providing assent, if it finds and documents the following:
- Trial involves no more than minimal risk
- The waiver will not negatively affect the rights and welfare of the children/minors
- The trial could not be implemented without the waiver
- The children/minors will be given additional information after participation, whenever appropriate
When legal representative or guardian permission is necessary, the EC must determine whether the permission of one (1) legal representative or guardian is sufficient, or if permission from both is required. If the EC determines assent is required, it must also determine whether and how assent must be documented. 21CFR50 and 45CFR46-B-E do specify, however, that the consent of both legal representative(s) or guardian(s) is required in the following cases:
- When there is greater than minimal risk to the child with no direct benefit to the child, but the study will likely result in increased knowledge about the child’s disorder or condition
- Research that presents an opportunity to understand, prevent, or alleviate a serious problem affecting the health or welfare of children/minors, but is not otherwise approvable
Exceptions to the two (2) legal representatives’ and/or guardians’ consent requirement are when one (1) legal representative or guardian is deceased, unknown, incompetent, or not reasonably available, or, when only one (1) legal representative or guardian has legal responsibility for the care and custody of the child.
The G-InfrmdCnsnt indicates that when obtaining legal representative or guardian permission, in the event that the legal representative(s) or guardian(s) of a child does not understand English, the permission must be obtained and documented in a language that is understandable to the legal representative(s) or guardian(s). The child who will be participating in the research should not be used as an interpreter for the legal representative(s) or guardian(s), even if the child is fluent in English and may be able to assent. Further, legal representative or guardian permission and child assent should be viewed as an ongoing process throughout the duration of a clinical investigation. If and when a child who was enrolled in a clinical investigation with legal representative or guardian permission reaches the legal age of consent, that participant no longer meets the definition of a child under 21CFR50, and the investigator should obtain the participant’s informed consent prior to performing any further research interventions and/or procedures involving that participant. See the G-InfrmdCnsnt for additional FDA discussion of the regulations in 21CFR50.
As per ResNo466, the PANDRH-GCPs, and the G-ClinResSubjectRts, any Brazilian clinical studies involving women of childbearing age or who are pregnant, require additional safeguards to ensure that the participants are fully aware of the risks and that the research assesses the risks and benefits as well as any potential impact on fertility, pregnancy, the embryo or fetus, labor, lactation, and the newborn. ResNo466 further states that research on pregnant women should be preceded by research on women outside the gestational period, except when pregnancy is the fundamental purpose of the study. The investigator(s) should also ensure that female participants have the right to participate in the research without the use of compulsory contraceptives—if they have expressly indicated that they are free from the risk of pregnancy and sexual practices, or they are sexually active in a non-reproductive way.
As per 21CFR50 and 45CFR46-B-E, for studies involving women of childbearing age or who are pregnant, a statement should be provided in the informed consent form (ICF) indicating that the treatment or procedure may involve risks to the participant, embryo, or fetus, which are currently unforeseeable. According to the US-ICH-GCPs, the ICF should include a statement on the reasonably foreseeable risks or inconveniences to the participant, and when applicable, to an embryo, fetus, or nursing infant.
Per the Pre2018-ComRule, pregnant women require additional safeguards to be included in any research study in order to protect their rights and welfare. Furthermore, according to the RevComRule, all of the available exemptions of the RevComRule for observational research may be applied to research involving pregnant women, fetuses, and neonates. See the RevComRule for details. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)
All Department of Health & Human Services (HHS)-sponsored or -funded research involving pregnant women, human fetuses, neonates of uncertain viability, or nonviable neonates must comply with Subpart B of 45CFR46-B-E.
Pregnant Women and Fetuses
As per 45CFR46-B-E, pregnant women and fetuses may participate in research if all of the following criteria are met:
- Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
- Risk to the fetus is caused solely by procedures that provide potential direct benefit to the woman or fetus. If there is no potential direct benefit, then the risk to the fetus cannot be greater than minimal, and the intent of the study is to develop important biomedical knowledge that cannot be obtained otherwise
- Least possible risk involved for achieving the research objectives
- Consent is obtained from the woman for studies that provide potential direct benefit to the pregnant woman and/or fetus, and studies with minimal risk to the fetus conducted to develop important biomedical knowledge that cannot be obtained otherwise
- Consent is obtained from the pregnant woman and the father if the study provides potential direct benefit solely to the fetus. Paternal consent is not required if the father is unavailable, incompetent, temporarily incapacitated, or the pregnancy was a result of incest or rape
- All individuals providing consent are fully informed about the foreseeable impact on the fetus or neonate
- No inducements will be offered to terminate a pregnancy
- Participants will not be involved in determining the timing, method, or procedures for terminating a pregnancy
- Participants will not be involved in determining the viability of a neonate
Neonates
45CFR46-B-E states that neonates may not be involved in research unless all of the following criteria are met:
- Preclinical and clinical studies have been conducted and provide data for assessing potential risks, where scientifically appropriate
- All individuals providing consent are fully informed about the foreseeable impact on the neonate
Neonates of uncertain viability may not be involved in research unless the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the following additional conditions are met:
- Research provides the potential for increasing the probability of survival to the point of viability, and involves the least possible risk
- The purpose is to develop important biomedical knowledge that cannot be obtained otherwise and there is no added risk resulting from the research
- Informed consent is obtained from either parent, or if neither parent is able to provide consent, then consent is obtained from the neonate’s legal representative and/or guardian. Paternal consent is not required if pregnancy was a result of incest or rape.
Nonviable neonates may not be involved in research unless the following additional conditions are met:
- Vital functions will not be maintained artificially
- Research will not terminate the heartbeat or respiration
- The purpose is to develop important biomedical knowledge that cannot be obtained otherwise, and there is no added risk resulting from the research
- Consent is obtained from both parents. If neither parent is able to provide consent, informed consent of one (1) parent will suffice. Paternal consent is not required if pregnancy was a result of incest or rape. Consent of a legal representative or guardian of either or both parents will not suffice.
Viable neonates may only be included in research to the extent permitted by and in accordance with the RevComRule and subparts B and D of 45CFR46-B-E.
According to the PANDRH-GCPs, prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research. ResNo466 also states that freedom of consent must be guaranteed to those research participants who are fully competent but are exposed to specific constraints or have restricted autonomy. These participants must have the freedom to decide whether to participate without any fear of reprisal.
21CFR56, 45CFR46-B-E, and the US-ICH-GCPs include prisoners in their description of vulnerable populations. As set forth in 45CFR46-B-E, a prisoner is defined as any individual involuntarily confined or detained in a penal institution. Prisoners are considered vulnerable because incarceration could affect their ability to make a voluntary decision regarding participation in research.
Per the Pre2018-ComRule and the RevComRule, prisoners require additional safeguards to be included in any research study in order to protect their rights and welfare. As delineated in the RevComRule, none of its observational research exemptions may be applied to research involving prisoners, except for research aimed at involving a broader subject population that only incidentally includes prisoners. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)
45CFR46-B-E states that prisoners may participate in biomedical or behavioral research conducted or supported by the Department of Health & Human Services (HHS) only if the following criteria are met:
- The institution conducting the research has certified to the HHS Secretary that the research has been approved by the institutional ethics committees (EC) (institutional review board (IRB) in the United States (US)); research involves minimal risk; and studies focus on the possible causes, effects, and processes of incarceration and criminal behavior, prisons as institutional structures, or prisoners as incarcerated persons
- Research should focus on conditions specifically affecting prisoners as a class, or practices that have the intent and likelihood of improving the health or well-being of participants only after the HHS Secretary has consulted the appropriate experts, and a Federal Register notice is published indicating intent to approve such research
See USA-62 for more HHS information on prisoner research.
As per 45CFR46-B-E, ECs have additional approval responsibilities when reviewing research studies involving prisoners. An EC must only approve these studies if it determines that:
- The research under review represents one (1) of the permissible categories of research delineated in Subpart C
- The prisoner’s judgement will not be impaired by any possible advantages accruing to the prisoner through participation in the research, when compared to the general living conditions, medical care, quality of food, amenities, and opportunity for earnings in the prison
- Research risks are commensurate with those that would be accepted by non-prisoner volunteers
- Procedures for participant selection within the prison are fair to all prisoners and immune from arbitrary intervention by prison authorities or prisoners
- Information is presented in a language understandable to the prisoner population
- Adequate assurance exists that parole boards will not take into account a prisoner's participation in the research in making decisions regarding parole, and each prisoner is clearly informed in advance that participation in the research will have no effect on parole
- As needed, adequate provisions have been made for follow-up examination or care of participants, taking into account the varying lengths of individual prisoners' sentences, and for informing participants of this fact
See Subpart C of 45CFR46-B-E for additional EC requirements related to prisoner research.
According to ResNo466 and the G-ClinResSubjectRts, the ethics committee (Comitê de Ética em Pesquisa (CEP)) must approve the participation of research participants who are mentally or physically incapable of giving consent, and sufficient justification must be provided for involving this population in a study. As delineated in the PANDRH-GCPs, consent should only be provided once the participant is informed about the study, to the extent that the participant is able to understand it, and if able, the participant should sign and date the written informed consent in person. The participant’s legal representative(s) or guardian(s) must also be present during the informed consent process and sign and date the informed consent form.
In accordance with 21CFR56, the Pre2018-ComRule, and the US-ICH-GCPs, an institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) must approve the participation of research participants who are mentally incapable of giving consent. According to the G-InfrmdCnsnt, which is the Food & Drug Administration (FDA)’s discussion of the regulations in 21CFR50, impaired consent capacity may involve partial impairment, impairment that fluctuates over time, or complete impairment. Consent capacity can be affected by a wide range of disorders and conditions, such as dementia, stroke, traumatic brain injury, intellectual and developmental disabilities, serious mental illness, intoxication, and delirium.
Per the Pre2018-ComRule and the RevComRule, this population requires additional safeguards to be included in any research study to protect the rights and welfare of participants likely to be vulnerable to coercion or undue influence. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.)
USA-60 further indicates that while Department of Health & Human Services (HHS) regulations do not provide specific procedures, it is expected that for research involving adult participants with mental illnesses or cognitive impairments, the EC and investigator(s) must be knowledgeable about the condition and any level of impairment that is likely to be present in the participant population.
As stated in the FDA’s G-InfrmdCnsnt, ECs and investigators should carefully consider whether the inclusion in research of individuals who lack consent capacity is ethically appropriate and scientifically necessary. Considerations that may help address these challenges and provide additional safeguards include:
• Assessing consent capacity of prospective participants, for example, through use of an independent, qualified professional
• Establishing a waiting period in the decision-making process to allow additional time for decision-making
• Using methods to enhance consent capacity, for example through (1) simplification and/or repetition of information, (2) involvement of a participant advocate or trusted family member/friend to assist when sharing information about the clinical investigation, and (3) refraining from discussions during periods of heightened impairment, when possible
• Assessing a participant’s understanding after information about the clinical investigation has been imparted, for example, through use of a questionnaire
• Re-assessing consent capacity after initiation of the clinical investigation for participants with progressive disorders whose cognition may decline
• Involving a legally authorized representative and/or guardian either initially or later in the clinical investigation if consent capacity diminishes
• Assessing whether prospective participants who cannot provide legally effective consent on their own behalf may nonetheless be able to provide some form of oral agreement at the outset of the study and, as appropriate, throughout the course of the research (e.g., for participants with progressive disorders), and how such oral agreement would be documented
• Emphasizing the voluntary nature of the decision to participate and the right to withdraw at any time
• Determining whether the EC or a third party should observe the consent process
See the G-InfrmdCnsnt for additional information and FDA discussion of the regulations in 21CFR50.
As delineated in the PANDRH-GCPs, an investigational product (IP) is defined as a dosage form of an active ingredient or placebo that is being tested or used as a reference in a clinical trial. ResNo9, the G-BioIProdManual, and the G-SynthDrugProdManual add that the IP may also be referred to as an experimental drug, comparator, or any other product to be used in a trial. According to BRA-8, the definition of an IP in ResNo9 differs from that of the PANDRH-GCPs because when ResNo9 was adopted, an IP was mainly thought of in relation to the imports required to carry out each clinical trial. For this reason, the definition of “product under investigation” encompasses all products to be used in a trial, including medicine comparators, equipment, and laboratory kits. In addition, the PANDRH-GCPs definition further states that an IP may include a product with a marketing authorization when it is used or assembled (formulated or packaged) in a different way from the approved form, or when it is used to gain further information about an approved use. Note: The terms experimental drug and IP are used interchangeably throughout the profile.
As delineated in 21CFR312, an investigational new drug is defined as a new drug or biological drug that is used in a clinical investigation. This includes a biological product that is used in vitro for diagnostic purposes. The terms ‘investigational drug’ and ‘investigational new drug’ are deemed to be synonymous for the purposes of this part.
Additionally, the US-ICH-GCPs defines an investigational product as a pharmaceutical form of an active ingredient or placebo being tested or used as a reference in a clinical trial, including a product with a marketing authorization when used or assembled (formulated or packaged) in a way different from the approved form, or when used for an unapproved indication, or when used to gain further information about an approved use.
Manufacturing
As stated in ResNo9, the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) is responsible for authorizing the manufacture of investigational products (IPs) in Brazil. ANVISA approves the manufacture of an IP as part of its review and approval of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))).
ANVISA has also released ServBltnNo104 to expedite the evaluation of clinical drug research development in Brazil without compromising the quality of the technical analysis. (See Scope of Assessment section for details on the criteria for the DDCM to undergo a simplified analysis.) According to ServBltnNo104, the IP manufacturing process must meet the criteria and recommendations described in the current International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH)’s guidelines, as applicable, according to the phase of clinical development. In addition, the technical experts in ANVISA’s Coordination of Clinical Research in Medicines and Biological Products (Coordenação de Pesquisa Clínica em Medicamentos e Produtos Biológicos (COPEC)) require DDCM petitions and substantial quality modifications to meet ServBltnNo104 criteria and be accompanied by the documentation required in ResNo9. COPEC will then analyze the following:
- The results of stability studies under accelerated and long-term conditions that support the proposed expiration date for the IP and, where applicable, for the modified placebo and comparator, when the storage recommendation is at room temperature (between 15 and 30 degrees Celsius)
- The sample IP label for DDCM petitions
In the event of non-compliance, COPEC will conduct a non-simplified analysis per ResNo9. ServBltnNo104 further explains that ANVISA may also at any time analyze all the documents required by ResNo9, related to the IP risk analysis. Refer to the Submission Content section for DDCM petitions and substantial quality modifications documentation requirements.
Import
Per ResNo9 and the G-DDCMManual, ANVISA is also responsible for authorizing the import of IPs. The sponsor may request approval to import/export IPs for study purposes at the same time that a DDCM is submitted to ANVISA, as indicated in ResNo9. Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while their DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation in the case of non-manifestation of the DDCM. The sponsor is required to present one (1) of these ANVISA documents at the location where IPs for import/export are unloaded. (See Submission Process and Submission Content sections for additional application requirements). See also BRA-103 for detailed instructions on obtaining a drug import license authorization and BRA-102 to check on the status of a petition submission.
BRA-95 provides instructions to sponsors and/or their legal representatives in Brazil on completing the expiration date information for imported IPs in the clinical trial submission form (BRA-22). The expiration date is frequently updated, and is, therefore, often linked to inconsistencies and requests for clarification of requirements by those responsible for importing drugs and products for clinical trials. See BRA-95 for detailed information on stability requirements and instructions on completing the form.
ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing IPs for clinical research purposes following ANVISA’s approval of a DDCM. Pursuant to ResNo74, the process involves electronically submitting ANVISA’s Industry Petition Form (BRA-71) to the Integrated Foreign Trade System (SISCOMEX)’s Single Portal (BRA-80). ResNo81 explains that the following documentation must be included with the petition:
- Copy of the CE (Note: per ResNo9, other ANVISA authorizations may need to be included as well—i.e., CEE and Document for Importation of Product(s) under Investigation)
- Shipment document (Includes shipment date, proof of IP deposit to the importer, and carrier/transportation type: Airborne Cargo - Air Waybill (AWB), Aquatic Cargo - Bill Landing (BL), and Land Cargo – Knowledge of International Transport by Highway (CTR))
- Access inspection authorization
- Commercial invoice
- Finished product analysis certificate or copy of IP purchase invoice, specifying all lots; and statement signed by technical manager containing number of lots, IP active ingredient name and trade name if IP is produced by a manufacturer other than the importer/clinical study sponsor
See ResNo81 for detailed import documentation requirements. See also BRA-8 for frequently asked questions on importation requirements and BRA-87 for additional information on BRA-80.
Per ResNo172, investigators accredited by the National Council for Scientific and Technological Development ((Conselho Nacional de Desenvolvimento Científico e Tecnológico) (CNPq)) and whose tax regime is exempt, will be automatically granted an import license via BRA-80.
However, ResNo172 specifies that imports intended for clinical trials whose objective is registration or alteration of product registration will be analyzed within five (5) days after protocol approval and compliance with legal requirements.
Other requirements delineated in ResNo81 and ResNo172 include, but are not limited to, a prohibition on imports with accompanied and unaccompanied baggage; compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; and a mandate that once research is completed, the investigator or institution authorize final destination of the materials in accordance with the legal provisions of environmental control.
LawNo10.742 (amending LawNo6.360) also notes that new drugs, intended exclusively for experimental use and under medical supervision, may be imported with the express authorization of the Ministry of Health (MOH) and are exempted from registration. This exemption will only be valid for up to three (3) years. Following this period, the product must be registered or be subject to a penalty of seizure to be determined by the MOH.
In addition, per ResNo102, in the case of a company requesting a global transfer of ownership for product registration or the updating of company operation and certification data as a result of corporate transactions or business operations, the CE, CEE, or Document for Importation of Product(s) under Investigation will be issued in the name of the new company. Company registration updates should include any changes to the company operating authorization, Good Manufacturing Practices Certificate (CBPF), or Good Distribution and Storage Practices Certificate (CBPDA). Please refer to ResNo102 for detailed instructions on submitting appropriate documentation for these updates. See also the Submission Process section for detailed information on documentation to be submitted.
Per BRA-96, ANVISA has also modified the global transfer of responsibility request process for a clinical trial or assistance program for medicines and biological products. The requests must be carried out electronically by the company that has requested the transfer via BRA-38 using the DDCM petition’s subject code 12130 for medicines and 11795 for advanced therapy products. See BRA-96 for additional information.
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 practices (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.
Advanced Therapy Products
Per BRA-86 and BRA-94, ANVISA has also initiated a project for applicants to request an import license for advanced therapy products to be used for clinical research or commercial/industrial purposes. The process involves registering an import license through the Licenses, Permissions, Certificates and Other Documents (LPCO) module of BRA-80, and attaching the ANVISA import license petition to this application—which is obtained using ANVISA’s Electronic Petition Request System (BRA-38). See G-LPCOImprtPetition for additional information on filing an import license petition for an advanced therapy product with ANVISA. Per ResNo506, advanced therapy products refer to medicines for human use that are based on genes, tissues, or cells. Refer to ResNo506 for information on ANVISA’s role in reviewing and approving clinical trial applications submitted for studies using advanced therapy products. See also BRA-104 for detailed instructions on submitting an import license petition to ANVISA through LPCO.
Per ResNo172, ANVISA will analyze and release imported goods and products intended for use in human subjects research within 48 hours after arrival in Brazil, provided that the legal requirements are met and that the purpose of the research is not to register or change the registration of a product. Also specified in ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172), is the requirement that the investigator and institution submit the imported products through one (1) of the following methods: BRA-80 or Express Shipping. While each import option has different documentation requirements, they all require the submission of an Industry Petition Form (BRA-71), a commercial invoice, a signed statement of responsibility (see ResNo81 (Chapter XXVII) and ResNo172 (Annex I)), 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. Refer to ResNo81 for additional required items based on the import method used.
Please note: Brazil is party to the Nagoya Protocol on Access and Benefit-sharing (BRA-63), which may have implications for studies of IPs developed using certain non-human genetic resources (e.g., plants, animals, and microbes). For more information, see BRA-81.
Manufacturing
According to 21CFR312 and USA-42, the Food & Drug Administration (FDA) is responsible for authorizing the manufacture of investigational products (IPs) (also known as investigational new drugs in the United States (US)).
Per 21CFR312, sponsors that use an IP not already subject to a manufacturer’s investigational new drug application (IND) or marketing application are required to provide all of the technical chemistry, manufacturing, and control (CMC) information outlined in the application content and format requirements section of 21CFR312, unless such information may be referenced from applicable scientific literature. Sponsors using an IP already subject to a manufacturer’s application should follow the same general application format but may, if authorized by the manufacturer, refer to the manufacturer’s application to provide the technical (CMC) information supporting the proposed clinical investigation.
Moreover, as stated in 21CFR312, a sponsor may ship an IP to the investigators named in the IND under the following conditions:
- Thirty (30) days after the FDA receives the IND, or
- FDA provides earlier authorization to ship the IP
The sponsor is responsible for complying with the principles of good manufacturing practice (GMP) as specified in 21CFR210, the G-CGMP-Phase1, and the G-INDPrep. The US-ICH-GCPs also states that the sponsor must ensure that the products are manufactured in accordance with GMPs.
Import
As set forth in 21CFR312, the FDA is also responsible for authorizing the import and export of IPs. An IP may be imported into the US if it is subject to an IND that is in effect for it and complies with one (1) of the following requirements:
- The IP consignee is the IND sponsor, or
- The consignee is a qualified investigator named in the IND, or
- The consignee is the domestic agent of a foreign sponsor, is responsible for the control and distribution of the IP, and the IND identifies the consignee and describes what, if any, actions the consignee will take with respect to the IP
Investigator's Brochure
In accordance with ResNo9, the PANDRH-GCPs, and the G-DDCMManual, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). ResNo9 and the G-DDCMManual state that the IB must provide coverage for the following areas:
- Experimental drug
- Formulation
- Pharmacological and toxicological effects of the experimental drug in animals and in humans, where applicable
- Information on safety and efficacy in humans obtained from clinical trials that have already been carried out
- Possible risks and adverse events related to experimental medications, based on past experience, as well as precautions or special procedures to be followed during development
The sponsor should also update the IB as significant new information becomes available.
Quality Management
The G-DDCMManual, the G-BiolProdManual, and BRA-8 further explain that the sponsor must include manufacturing process information in the Experimental Drug Dossier as part of the clinical trial application (Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) submission as described in ResNo9. Please refer to ResNo9, the G-DDCMManual, and the G-BiolProdManual for additional experimental drug dossier requirements.
As specified in ResNo9 and the PANDRH-GCPs, the sponsor must also ensure that the products are manufactured in accordance with the Good Manufacturing Practices (GMPs) as laid down in ResNo301. In addition, per ResNo205, the DDCM submitted to National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)) to conduct a clinical trial using investigational products for rare diseases should also be accompanied by a request for GMPs certification. See ResNo205 for detailed submission information.
Investigator's Brochure
In accordance with 21CFR312 and the US-ICH-GCPs, the sponsor is responsible for providing investigators with an Investigator’s Brochure (IB). The IB must contain all of the relevant information on the investigational new drug(s)/investigational product(s) (IPs) obtained through the earlier research phases. The sponsor must also update the IB as significant new information becomes available.
As specified in 21CFR312 and the US-ICH-GCPs, the IB must provide coverage of the following areas (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):
- A brief description of the drug substance and the formulation, including the structural formula, if known
- A summary of the pharmacological and toxicological effects of the drug in animals and, to the extent known, in humans
- A summary of the pharmacokinetics and biological disposition of the drug in animals and, if known, in humans
- A summary of information relating to safety and effectiveness in humans obtained from prior clinical studies
- A description of possible risks and side effects to be anticipated on the basis of prior experience with the drug under investigation or with related drugs, and of precautions or special monitoring to be done as part of the investigational use of the drug
- Summary of data and guidance for the investigator
See 21CFR312 and the US-ICH-GCPs for detailed IB content guidelines.
For investigational new drug applications (INDs) that include clinical data provided from studies conducted outside of the United States (US), 21CFR312 states that the sponsor or applicant must submit a description of the actions taken to ensure that the research conformed to good clinical practices (GCPs). See Section 312.120 of 21CFR312 for detailed requirements.
Quality Management
According to USA-39, submitting a copy of the Certificate of Analysis (CoA) of the clinical batch is suggested, but not required by the Food & Drug Administration (FDA).
The US-ICH-GCPs state that the sponsor must maintain a CoA to document the identity, purity, and strength of the IP(s) to be used in the clinical trial.
Investigational product (IP) labeling in Brazil must comply with the requirements set forth in ResNo9, the PANDRH-GCPs, and the G-BiolProdManual. As described in the G-BiolProdManual, the following labeling information must be included on the primary package label (or any intermediate packaging), and the outer packaging:
- Sponsor name
- Pharmaceutical form, route of administration, quantity of dosage units, and the drug name and concentration in the case of open studies
- Batch or product identification code
- Clinical trial reference code
- Clinical trial participant identification code
- Instructions for use (reference may be made to an explanatory pamphlet or other document that guides the trial participants or person administering the IP
- Storage conditions
- Expiration date
- Warning phrases in capital letters such as: “EXCLUSIVE USE IN CLINICAL TRIALS” and “KEEP OUT OF REACH OF CHILDREN”
In addition, per the G-BiolProdManual, all of the text labeling must be written in Portuguese. Symbols, pictograms, and warnings may also be included on both the primary and outer packaging. The G-BiolProdManual further notes it is not necessary to include the primary contact’s address and telephone number on the label to obtain IP or clinical trial information, or to break the blinding code. The trial participant receives a leaflet or card containing contact information in the case of trial-related concerns or adverse events. If the expiration date changes, additional labeling may be superimposed on the previous label to update the shelf life so that the new information does not conflict with the original batch number. The G-BiolProdManual mentions that the labeling of the other study IPs should also follow the same model as the experimental product, and when any field(s) is not applicable, justification should be provided.
The PANDRH-GCPs further indicates that the IP should be coded and labeled in a manner that protects the blinding, if applicable, and be suitably packaged to prevent contamination and unacceptable deterioration during transport and storage. BRA-8 adds that while a label template is requested for each clinical trial application (Clinical Drug Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) submission, if the label template differs between studies in a multicenter clinical trial, a note should be included in the DDCM to explain that separate templates will be provided for the specific dossiers.
As described in ResNo9, the following external packaging information must also be provided with the IP to be imported into Brazil:
- Special Notice (CE), Specific Special Notice (CEE), or Document for Importation of Product(s) under Investigation
- IP quantity
- Special storage precautions (e.g., temperature, humidity, and brightness)
- IP physical/pharmaceutical form
- Period of validity of the IP
- Batch number or serial number
The following IP packaging requirements are also delineated in the G-BiolProdManual:
- Provide technical specifications for primary, and where applicable, outer packaging
- Include an assessment of possible interaction between the active substance and primary packaging, if applicable
- Describe how the tamper resistance of the packaging will be guaranteed until the time of IP use
Investigational new drug/investigational product (IP) labeling in the United States (US) must comply with the requirements set forth in Section 312.6 of 21CFR312, which include the following:
- The immediate package of an IP intended for human use must bear a label with the following statement: “Caution: New Drug-Limited by Federal (or US) law to investigational use”
- The label or labeling of an IP must not bear any false or misleading statements and must not represent that the IP is safe or effective for the purposes for which it is being investigated
The appropriate Food & Drug Administration (FDA) Center Director may grant an exception or alternative to the requirements above for specific lots, batches, or other units of a human drug or biological product that is or will be included in the Strategic National Stockpile.
In addition, the US-ICH-GCPs states that the IP must be coded and labeled in a manner that protects the blinding, if applicable.
Supply, Storage, and Handling Requirements
As delineated in ResNo9 and the PANDRH-GCPs, the sponsor must also supply the investigator(s)/institution(s) with the investigational product(s) (IP), including the comparator(s) and placebo, if applicable. The sponsor is responsible for importing the necessary IP amount to conduct the study, but should only distribute the IP to institutions that are listed in the approved clinical trial application (known as the Drug Clinical Development Dossier (Dossier de Desenvolvimento Clínico de Medicamento (DDCM))) as authorized by the ethics committee (EC) (Comitê de Ética em Pesquisa (CEP)) and the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA)). Following DDCM analysis and approval, ANVISA issues an authorizing document known as a Special Notice (Comunicado Especial (CE)) that may also be used for IP import/export requests for the trial. ANVISA may also issue either a Specific Special Notice (Comunicado Especial Específico (CEE)) to permit the sponsor to import/export an IP while their DDCM is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation in the case of non-manifestation of the DDCM. The sponsor is required to present one (1) of these ANVISA documents at the location where IPs for import or export are unloaded. (See the Submission Process and Submission Content sections for detailed application requirements).
Per ResNo9 and the PANDRH-GCPs, the sponsor must ensure that the qualitative information and specifications include the following:
- IP product quality and stability over the period of use
- IP manufactured according to good manufacturing practices (GMPs) as per ResNo9 and ResNo301
- Proper coding, packaging, and labeling of the IP(s)
- IP use record including information on the quantity, loading, shipment, receipt, dispensing, handling, reclamation, and destruction of the unused IP
- Acceptable storage temperatures, conditions, and times for the IP
- Written procedures including instructions for handling and storage of the IP, adequate and safe receipt, dispensing, retrieval of unused IP(s), and return of unused IP(s) to the sponsor
- Timely delivery of the IP(s)
- Establishment of management and filing systems for the IPs
See ResNo9 and PANDRH-GCPs for detailed sponsor-related IP 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 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.
Record Requirements
Per the PANDRH-GCPs, the sponsor is required to maintain records that document shipment, receipt, disposition, return, and destruction of the IPs. The sponsor must also maintain a system for retrieving IPs and documenting this retrieval and maintain a system for the disposition of unused IPs. Additionally, the sponsor should maintain sufficient samples from each batch and keep a record of their analyses and characteristics for reference so that, if necessary, an independent laboratory could reconfirm the same data.
The sponsor should inform the investigator(s) and institution(s) in writing of the need for record retention and should notify the investigator(s) and institution(s) in writing when the trial-related records are no longer needed. Sponsor-specific essential documents should also be retained until at least two (2) years after the last approval of a marketing application, until there are no pending or contemplated marketing applications, or at least two (2) years have elapsed since the formal discontinuation of the IP’s clinical development.
Supply, Storage, and Handling Requirements
As defined in the US-ICH-GCPs, the sponsor must supply the investigator(s)/institution(s) with the investigational new drug(s)/investigational product(s) (IP(s)), including the comparator(s) and placebo, if applicable. The IPs must also be suitably packaged in a manner that will prevent contamination and unacceptable deterioration during transport and storage.
Per 21CFR312, the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep, the sponsor must ensure the following (Note: The regulations provide overlapping and unique elements so each of the items listed below will not necessarily be in each source):
- IP product quality and stability over the period of use
- IP manufactured according to any applicable good manufacturing practices (GMPs)
- Proper coding, packaging, and labeling of the IP(s)
- Acceptable storage temperatures, conditions, and times for the IP
- Timely delivery of the IP(s)
Refer to the US-ICH-GCPs, the G-CGMP-Phase1, and the G-INDPrep for detailed sponsor-related IP requirements.
Record Requirements
According to 21CFR312, the sponsor must maintain adequate records showing the receipt, shipment, or other disposition of the IP. These records are required to include, as appropriate, the name of the investigator to whom the drug is shipped, and the date, quantity, and batch or code mark of each such shipment. The sponsor is also required to maintain records showing financial interest paid to investigators. See 21CFR312 for more details.
As per 21CFR312 and the US-ICH-GCPs, the sponsor and the investigator(s) must retain the clinical investigation records and reports for two (2) years after a marketing application (known as a New Drug Application (NDA)) is approved for the IP; or, if an NDA is not approved, until two (2) years after shipment and delivery of the IP is discontinued for investigational use and the Food & Drug Administration (FDA) has been so notified.
As per OrdNo2201, ResNo504, ResNo441, and the G-BiolMatTransprt, a specimen is defined as any human biological material such as organs, tissues, cells, body fluids, excreta, and other fluids of human origin obtained from a single participant at a particular time. ResNo508 adds that these biological samples are intended to be used for laboratory or quality control tests.
In addition, the G-BiolMatTransprt states that these materials are not considered hazardous if they are unlikely to cause disease in humans or animals. However, they are considered infectious substances, therefore dangerous materials, if through exposure to them, these substances can spread diseases.
A specimen, referred to as patient specimen in 49CFR173, is defined as human or animal material collected directly from humans or animals and transported for research, diagnosis, investigational activities, or disease treatment or prevention. Patient specimen includes excreta, secreta, blood and its components, tissue and tissue swabs, body parts, and specimens in transport media (e.g., transwabs, culture media, and blood culture bottles).
In addition, 42CFR73 defines specimen as samples of material from humans, animals, plants, or the environment or isolates or cultures from such samples for diagnosis, verification, or proficiency testing.
The RevComRule defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator or associated with the biospecimen. (See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the RevComRule applies to research.)
ResNo208 (amending ResNo81) and ResNo613 (amending ResNo172) delineate the procedures associated with importing human biological materials for clinical research purposes. Pursuant to ResNo74, the process involves electronically submitting National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA))’s Industry Petition Form (BRA-71) to the Integrated Foreign Trade System (SISCOMEX)’s Single Portal (BRA-80). To obtain an import license through BRA-80, ResNo208 (amending ResNo81), and ResNo613 (amending ResNo172) specify that the investigator and institution should submit the imported human biological materials through one (1) of the following methods: BRA-80 or Express Shipping. ResNo81 and ResNo172 explain that the following documentation must be included with the petition form:
- Shipment document (Includes shipment date, proof of investigational product (IP) deposit to the importer, and carrier/transportation type: Airborne Cargo - Air Waybill (AWB), Aquatic Cargo - Bill Landing (BL), or Land Cargo - Knowledge of International Transport by Highway (CTR))
- Inspection authorization
- Commercial invoice
- Bill of lading
- Signed statement of responsibility (see ResNo81 (Chapter XXVII) and ResNo172 (Annex I))
- 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 ResNo81 for detailed import documentation requirements. See also BRA-8 for frequently asked questions on importation requirements and BRA-87 for additional information on BRA-80.
ResNo172 further notes that an import license may be automatically granted via BRA-80 to investigators accredited by the National Council for Scientific and Technological Development ((Conselho Nacional de Desenvolvimento Científico e Tecnológico) (CNPq)) and whose tax regime is exempt.
ResNo172 also states that ANVISA will analyze and release human biological samples intended for use in clinical research within 48 hours after arrival in Brazil, provided that the legal requirements are met. Refer to ResNo81 and ResNo172 for additional required items depending on the import method used.
Other requirements described in ResNo81 and ResNo172 include, but are not limited to, compliance with packaging, transportation, and storage standards provided by manufacturer or supplier; a mandate that the investigator or institution provide a final destination for the materials in accordance with the legal provisions of environmental control; and in ResNo172, a prohibition on imports with accompanied and unaccompanied baggage.
As explained in ResNo504 and the G-BiolMatTransprt, the procedures for the import and export of human biological material should be determined by the biological material type and the mode of transport. Regardless of the mode of transport or material type, transport operations are required to be recorded and standardized through regularly updated written instructions. All documents and records of activities relating to human biological material transport equipment should be readily available to the health authorities, upon request. The biological material must be packed in a form that will preserve its integrity and stability and must be validated and approved by the supervisory technician.
According to ResNo504, human biological material is classified as Category A or B infectious biological material, or Category Risk Minimum. Category A includes materials where exposure can cause permanent disability or fatal disease to humans and animals. Category B includes those materials not listed in Category A such as samples suspected or known to contain infectious agents causing diseases in humans. Category Risk Minimum or “exempt human specimens” include biological materials from healthy individuals. Human biological materials must also be classified according to the World Health Organization (WHO)’s risk classification diagram available in the WHO’s Guidance on Regulations for the Transport of Infectious Substances (BRA-54). Labeling should conform to the material type, risk classification, and specific requirements of the biological materials to be transported. The label for imported materials must be legible, understandable, and in English and Portuguese.
In addition to complying with ResNo504 and the G-BiolMatTransprt, human biological material transport should be conducted in accordance with legislation from applicable regulatory bodies including the Ministry of Infrastructure, the National Land Transportation Agency, the National Civil Aviation Agency, and the National Agency for Waterway Transport. Refer to the G-BiolMatTransprt for detailed import and export transport requirements.
Refer to ResNo504 and the G-BiolMatTransprt for detailed instructions on shipping biological materials within these categories. See also ResNo508 for detailed transport requirements relating to human cells and advanced therapy products, and BRA-97 for preparing reports on biobanking for research purposes.
Import/Export
The import and export of human specimens, also known as patient/diagnostic specimens/substances or human biological materials in the United States (US), is governed by several federal agencies working cooperatively to ensure the safe transport of these materials. These agencies include, but are not limited to, the Department of Transportation (DOT)’s Pipeline and Hazardous Materials Safety Administration (PHMSA), the Centers for Disease Control and Prevention (CDC)’s Import Permit Program (IPP), the Department of Health & Human Services (HHS), the United States Postal Service (USPS), and the International Air Transport Association (IATA). The IATA has also adopted all of the hazardous materials requirements set forth in the Technical Instructions for the Safe Transport of Dangerous Goods by Air (USA-10) published biannually by the United Nations (UN)’ International Civil Aviation Organization (ICAO).
Infectious Specimens
Per 49CFR173, 42CFR73, 42CFR71, USA-21, USA-4, USA-11, and USA-31, DOT’s PHMSA, IATA, USPS, and CDC’s IPP refer to an infectious specimen/substance as a Division 6.2 material (Category A or Category B), or a select agent, etiologic agent, toxin, or a vector of human disease. The CDC’s IPP is specifically responsible for the importation of infectious specimens/substances/biological agents/vectors of human disease per 42CFR71 and for regulating the possession, use, and transfer of select agents and toxins per 42CFR73. See 42CFR71, 42CFR73, USA-31, and USA-73 for further information and permit applications for these import/transfer programs.
Additionally, the Department of Commerce (DOC)’s Bureau of Industry and Security is responsible for regulating the export of a wide range of infectious specimens that may require a DOC license. Refer to the Commerce Control List (CCL) in 15CFR774 and USA-30 to determine if a DOC export permit is required for specific specimens.
According to 49CFR173, USA-21, and USA-4, certain materials and specimens are exempt from the DOT’s PHMSA, IATA, and USPS requirements for import/export of infectious specimens. These include materials that do not contain infectious substances; non-infectious biological materials from humans, animals, or plants; and specimens for which there is a low probability that the sample is infectious. Exempt human or animal specimens are not subject to regulation as hazardous materials but are subject to specific packaging procedures that must be followed when shipped. Please refer to 49CFR173, USA-21, USA-4, and USA-11 for detailed DOT, IATA, and USPS shipping instructions.
NIH Specimen Requirements
The HHS’ National Institutes of Health (NIH) researchers must also comply with all applicable federal and international air and ground transport laws and regulations. Researchers must also receive prior authorization from the NIH’s Quarantine Permit Service Office to obtain permits for the import, transfer, or export of all specimens to the NIH. Detailed instructions about how to proceed are outlined in USA-71.
Per USA-2, the NIH also requires researchers to use an agreement (e.g., Material Transfer Agreement (MTA) or contract) to transfer materials among academic, nonprofit, and/or industrial organizations. See USA-2 for detailed MTA requirements and Appendix 4 for a sample MTA.
In accordance with OrdNo2201, ResNo441, ResNo466, and ResNo340, prior to collecting, storing, or using a research participant’s human biological material, consent must be obtained from the participant or the legal representative in writing. Per OrdNo2201, ResNo340, OMREC, and CLNo041, the informed consent form (ICF) is also known as the Free and Informed Consent Form (Termo de Consentimento Livre e Esclarecido (TCLE)) in Brazil.
As delineated in OrdNo2201, ResNo441, and ResNo340, investigator(s) must also obtain 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 of a new research project involving human biological materials. Per ResNo340, if it is not possible to obtain the participant’s consent, a formal justification shall be presented to the EC (CEP) for evaluation.
In addition, per ResNo441 and ResNo340, investigators should explain the possibility of using the participant’s stored genetic materials in a new research project in the ICF. In this case, the participant will be contacted for further authorization or their waiver. If it is impossible to obtain either one (1) of these documents, this fact shall be justified to the EC (CEP). The investigator(s) is also required to explain to the participant that the material will only be used upon approval of a new project by the EC (CEP) and when necessary, CONEP. OrdNo2201 further states that when it is not possible to contact the research participant, the EC (CEP) must authorize use of the biological material stored in a biobank.
As described in ResNo340, the G-ClinProtocols-FAQs, and CLNo041, the ICF for genetic research projects must communicate the following information to the participant:
- A clear explanation of the exams and tests that will be performed to identify genes and clarification of the genetic materials to be studied and their possible correlation with the participant’s health
- A guarantee of secrecy, privacy, and when necessary, anonymity
- The provision of free genetic advice, planning, and clinical surveillance by responsible people
- The type and degree of access to results by the participant, with the option to acknowledge this information or not
- In the case of genetic material storage, the ICF should explain the possibility of the materials being used in a new research project and that the participant will be contacted for further authorization
- Measures to be taken to protect participant data, exam, and test results, including limiting clinical report access to the involved investigators
- Measures to be taken to protect the participant from any collective discrimination and/or stigmatization
- The need for a separate ICF to be completed by each family member in the case of a family investigation. An explicit statement of the need for new consent for each study, or an explicit waiver of consent for each new study
CLNo041 further notes that for human genetics research, CONEP requires investigator(s) to be able to describe the genes studied in a grouped manner according to functionality or effect (e.g., genes related to the onset of cancer, inflammation, cell death, or response to treatment). In the case of studies involving large-scale genetic studies (e.g., complete genome or exoma sequencing), the ICF shall contain an explanation of the procedure to be performed in a language the participant can understand.
Biobanks
ResNo441 and the G-ClinProtocols-FAQs, in turn, state that the ICF for the collection, deposit, storage, and use of human biological materials in biobanks must include the following:
- A reference to the data types that may be obtained from the participant’s stored biological material for future research
- An express guarantee of the participant’s right to access the biological material information including who to contact, knowledge of the results obtained and implications of findings when the biological material is used, and the provision of genetic counseling, when applicable
- An explicit statement of the participant’s wishes regarding the cession of rights to the stored material to successors, or others appointed by him, in case of death or disabling condition
- A statement informing the participant that the biological information provided, collected, and obtained from the current research may be used in future research
- A reference to the participant’s authorization to dispose of the remainder of the material and the situations in which it is possible
As delineated in OrdNo2201 and ResNo441, the participant or the legal representative may withdraw consent at any time for care and use of biological material stored in a biorepository or biobank without any negative consequences. The G-ClinProtocols-FAQs further indicates that the participant or the legal representative may also withdraw consent specifically for genetic data stored in a storage bank without any negative impact. The withdrawal is valid from the date that the decision is communicated. The withdrawal must also be formalized in a document signed by the participant or the legal representative. In addition, the transfer of human biological material to be stored at a biorepository or a biobank, or another institution, must be communicated to the participant. If it is not possible to communicate with the participant or the legal representatives, a justification must be submitted to the CEP/CONEP System, per ResNo441. 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, and; CLNo23 for instructions on standardizing consent and electronic assent for research participants and biobanks.
Please refer to OrdNo2201, ResNo441, and the G-ClinProtocols-FAQs, for detailed requirements and issues associated with storing human biological materials in a biorepository or a biobank. See also ResNo508 for informed consent requirements pertaining to human cell collection and other procedures conducted by cell processing centers.
(See the Required Elements and Participant Rights sections for additional information on informed consent).
As delineated in the G-IC-IVDs, the Food & Drug Administration (FDA) only provides informed consent guidance with respect to its regulations governing the informed consent requirement when human specimens are used for FDA-regulated in vitro diagnostic device investigations.
Informed consent requirements guiding Department of Health & Human Services (HHS)-conducted or -supported research on human research participants is regulated by the Pre2018-ComRule and 45CFR46-B-E.
Per the Pre2018-ComRule and the G-SpecimensResrch, the HHS views research involving human subject specimens as research involving human participants and subject to informed consent requirements, if the specimens obtained may be classified as identifiable private information. Identifiable private information or identifiable specimens are those that can be linked to specific individuals by the investigator(s) either directly or indirectly through coding systems. The RevComRule further defines an identifiable biospecimen as one for which the identity of the participant is or may readily be ascertained by the investigator. See the Pre2018-ComRule, RevComRule, the G-SpecimensResrch, USA-2, USA-9, and USA-1 for additional information. See also the G-SpecimensResrch for exemptions to this definition.
Additionally, as defined by the HHS’ National Institutes of Health (NIH) in USA-72, research with specimens, cells, cell lines, or data involves human subjects when:
- The specimens, cells, or data must be or must have been obtained from individuals who are alive, and must be or must have been obtained by an investigator conducting research; and
- The investigator either must be obtaining or must have obtained specimens, cells, or data through interaction or intervention with living individuals, or must be obtaining or have obtained individually identifiable private information.
See USA-72 for detailed frequently asked questions (FAQs) on this topic.
Per the Pre2018-ComRule, the RevComRule, and USA-2, prior to collecting, storing, or using a research participant’s biological specimen(s), consent must be obtained from the participant and/or a legal representative(s). See USA-65 for a list of Common Rule departments/agencies, and the Regulatory Authority section for more information on when the Pre2018-ComRule and the RevComRule apply to research.
The RevComRule requires the informed consent form to provide one (1) of the following statements about any research that involves the collection of identifiable private information or identifiable biospecimens:
- A statement that identifiers might be removed from the identifiable private information or identifiable biospecimens and that, after such removal, the information or biospecimens could be used for future research studies or distributed to another investigator for future research studies without additional informed consent from the subject or the legally authorized representative, if this might be a possibility
- A statement that the subject's information or biospecimens collected as part of the research, even if identifiers are removed, will not be used or distributed for future research studies
- A statement that the subject's biospecimens (even if identifiers are removed) may be used for commercial profit and whether the subject will or will not share in this commercial profit
- Whether the research will (if known) or might include whole genome sequencing (i.e., sequencing of a human germline or somatic specimen with the intent to generate the genome or exome sequence of that specimen)
Furthermore, the RevComRule delineates the requirements of broad consent—an alternative consent process—for the storage, maintenance, and secondary research use of private information or identifiable biospecimens. Broad consent requires that the following information be provided to the participant and/or the legal representative(s) or guardian(s):
- Certain basic elements from the normal consent process related to risks, benefits, confidentiality, voluntary statement, commercial profit, contact information, and whole genome sequencing elements
- Types of research that may be conducted
- A description of the information or biospecimens that might be used in future research, whether sharing might occur; and the types of institutions or researchers that might conduct research
- A description of the length of time that the information or biospecimens may be stored, maintained, and used
- A statement that participants will or will not be informed of the details of any specific research studies that might be subsequently conducted
- A statement that research results either will or will not be disclosed to participants
- An explanation of whom to contact for answers to questions about the subject's rights and about storage and use of the subject's identifiable private information or identifiable biospecimens, and whom to contact in the event of a research-related harm.
The RevComRule does allow the use of identifiable information or biospecimens in instances where the institutional ethics committee (EC) (institutional review board (IRB) in the United States (US)) determines the research could not practicably be carried out without the information in that form. Furthermore, it removes the requirement for the investigator to seek a waiver of informed consent to obtain information or biospecimens to screen, recruit, or determine eligibility of prospective participants. See USA-54 for more information on broad consent and informed consent waivers.
The HHS’ G-StoredData-Tissues and USA-2 recommend that the following be included in informed consent documents for biospecimen collection:
- A clear description of the operation of the biospecimen resource including details such as whether identifiable information will be maintained by the biospecimen resource and/or whether research results will be linked to the biospecimen
- Conditions under which samples and data will be released to recipient investigators
- Procedures for protecting the privacy of human research participants and confidentiality of data
- Specific descriptions of the nature and purpose of the research
- Information about the consequences of DNA typing if human genetic research is anticipated
(See the Required Elements and Participant Rights sections for additional information on informed consent).
Requirements
Additional Resources
Form
