2. General Questions
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2. General Questions
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2.1 Name of Regulatory Authority
The regulatory body in Brazil responsible for the oversight of clinical trials is the National Health Surveillance Agency (Agência Nacional de Vigilância Sanitária (ANVISA).
ANVISA grants permission for clinical trials to be conducted in accordance with the provisions of Resolution No. 9, Resolution No. 61, and Resolution No. 176.
2.2 Name of Ethics Committee
The National Research Ethics Commission (Comissão Nacional de Ética em Pesquisa (CONEP)) is the central body responsible for coordinating the network of institutional ECs, known as Committees of Ethics in Research (Comitês de Ética em Pesquisas (CEPs)) in Brazil, and for registering and accrediting Ethics Committees.
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.
CONEP’s core responsibilities are:
- 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.
2.3 Clinical Trial Application Language
Portuguese.
2.4 Is regulatory approval required from both regulatory authorities and/or EC?
Yes.
2.5 Can regulatory authority and EC submission be done in parallel?
Yes.
2.6 Requirement of any import permit/license before investigational product/study product is shipped from point of origin
Yes. ANVISA is also responsible for authorizing the import of Investigational Products (IPs). The sponsor may request approval to import/export IPs for study purposes at the same time that he/she submits a clinical trial application. Following review and approval of the trial application, 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 his/her trial application is still awaiting review and is within ANVISA’s 90-day approval window, or a Document for Importation of Product(s) under Investigation. The sponsor is required to present one of these ANVISA documents at the location where IPs for import/export are unloaded.
2.7 Biological Specimen Export Requirements
The import or export of biological material for clinical research purposes is regulated by Resolution No. 208 and Resolution No. 613. The process involves electronically submitting ANVISA’s Industry Petition Form to the Integrated Foreign Trade System (SISCOMEX)’s Single Portal.
To obtain an import license, 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
- Institutional ethics committee (EC), CEP approval, and where applicable, National Research Ethics Commission CONEP approval.
2.8 Are studies of GMOs permitted (e.g., GMOs used in vaccines/vaccine manufacture and other modified products)?
Yes. Genetically modified products are regulated by ANVISA. Clinical Trial applications for these products will be reviewed by a specialized group within ANVISA.
2.9 Is in-country sponsor presence/representation required?
Yes, where an applicant has no in-country presence, the role of sponsor may be delegated to a CRO.
2.10 Is there any mandatory requirement to identify a local PI or can a PI be based in a foreign country?
Yes, there needs to be a researcher based in Brazil if the CRO or sponsor is located outside of Brazil.
2.11 Is there any mandatory requirement to identify a local chief or coordinating investigator?
No, there is no mandatory requirement for a Chief Investigator (CI). However, this is normal practice if it is a multicentre study.
2.12 If the applicant is CRO or a third party, does regulatory authority need any authorization or transfer of obligations from the sponsor? Does the authorization letter need to be notarized and/or apostilled?
The sponsor may transfer his/her study-related duties and functions to a contract research organization (CRO). However, he/she is ultimately responsible for the quality and integrity of the study data. 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, a CRO can only submit a clinical trial application on the sponsor’s behalf when the sponsor has no headquarters or subsidiary in Brazil. There is no specific template for the transfer of responsibilities.
2.13 Is there a requirement to register clinical trials on a local registry or database?
It is mandatory for all applicants to register their clinical trials (not non-interventional behavioral/non-biomedical studies) with the World Health Organization’s (WHO) ICTRP or other registry recognized by the ICMJE.
Platformabrasil is a national and unified registry for research involving human participants. Clinical Trials conducted in Brazil must be registered on both the ICMJE and Platformabrasil.
http://conselho.saude.gov.br/plataforma-brasil-conep?view=default
The platform also supports the review and approval processes for ethics submissions. Research applications can be tracked from submission to final approval by the CEP, and when necessary, by CONEP.
2.14 What is the local requirement for clinical study documents archival; minimum of years for the archival, specific format followed (electronic/paper and/or both)?
There is a requirement for sponsors to retain data relating to a clinical trial for a period of five years after the last approval for registration in Brazil. This relates to both physical and electronic records.
2.15 Requirements around periodic safety reporting and timelines on SAEs/AEs/ADRs/SUSARs/DSURs.
The requirements around safety reporting are defined in Resolution No. 9, the Handbook for Notification for Adverse Events and Safety Monitoring in Clinical Trials, and Circular No. 13/2020-CONEP/SECNS/Ms.
The investigator must inform the sponsor within 24 hours of all SAEs/SADRs occurring during the study. The initial 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.
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/CEP) with any additional requested information (e.g., autopsy reports and terminal medical reports).
All AEs/ADRs and SAEs/SADRs should be classified according to the World Health Organization’s Uppsala Monitoring Centre (WHO-UMC) standardized causality assessment. The recommended criterion to categorize each event is as follows: Certain, Probable/Likely, Possible, Unlikely, Conditional/Unclassified, and Unassessable/Unclassifiable.
The sponsor should ensure all relevant information pertaining to fatal or life-threatening SAEs/SADRs occurring in Brazil is documented and electronically reported to ANVISA no more than seven days after first knowledge.
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.
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. 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 (known as the 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.
The sponsor must 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 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 cases where the sponsor temporarily suspends a clinical trial or DDCM as an immediate safety measure, he/she must notify ANVISA within seven consecutive days from the suspension date. The reasons for the suspension, the scope, the interruption of treatment, and the suspension of participant recruitment must be clearly explained in the notification of temporary suspension.
2.16 Requirement on any periodic clinical study update, specific template, and its frequency (e.g., interim or annual progress report and final report, etc.)?
Interim and Annual Progress Reports
The requirements for start-up, end, and follow-up reporting are defined in the following guidance:
The sponsor must file a progress report, known as an annual clinical trial protocol monitoring report, to ANVISA in the form of a secondary petition electronically attached to the respective protocol to which it is linked. 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 the 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. ANVISA does not currently 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.
The PANDRH-GCPs state that the investigator or institution must submit written summaries on the status of the trial to the ethics committee (EC/CEP) annually, or more frequently, if requested by the EC (CEP).
2.17 Does the local regulation require notification of “serious breaches” of GCP or the trial protocol?
Yes, all serious breaches of GCP must be reported to ANVISA.
2.18 Does RA/CA require insurance and indemnity to cover the sponsor and investigator’s potential liability?
Yes. 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.
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