The Brazilian Health Regulatory Agency (Anvisa) is an autarchy linked to the Ministry of Health, part of the Brazilian National Health System (SUS) as the coordinator of the Brazilian Health Regulatory System (SNVS), present throughout the national territory.
Anvisa’s role it to promote the protection of the population’s health by executing sanitary control of the production, marketing, and use of products and services subject to health regulation, including related environments, processes, ingredients, and technologies, as well as the control in ports, airports, and borders.
• “To protect and promote health, ensuring the quality and safety of products and services and taking part in developing access to them.“
Drugs as per ANVISA
What are Drugs?
Anvisa categorizes drugs into the following: new synthetic drugs, generic drugs, similar drugs (a generic drug marketing with a brand name), potentized medicines (homeopathic, anthroposophic, and antihomotoxic), specific medicines, notified medicines (low risk), OTC (over the counter) drugs, herbal medicines, medicinal gases, biologic products, and radiopharmaceuticals.
The maximum timeframes for Anvisa to make a final decision regarding pre-market approvals for drugs are set by Law 13.411/2016: 120 days from the submission date of the prioritization request, for drugs in the prioritized category; and 365 days from the submission date of the request, for drugs in the ordinary category. The aforementioned timeframes may be extended by a maximum of a third.
Pre-market approvals are valid for five years from the date of their publication in the Brazilian Official Gazette and may be renewed for equal and successive periods.
In the case of the Brazilian registration, there are regional specificities and similarities with the CTD format applicable in the ICH countries members. The Brazilian regulation shows that the dossier is structured for product registration in two main parts:
1.Administrative: Compilation of all administrative data, including specific requirements for imported products.
2.Technical: Technical reports, including quality, nonclinical, and clinical information, presenting similarities to the CTD Modules 2, 3, 4, and 5.
Clinical trial in brazil
Procedure and approval procedure of Clinical trials for the pharmaceutical industry in Brazil as follow.
Institutions involved in the approval process
In Brazil, three different institutions:
CONEP (Central) Comissão Nacional de Ética em Pesquisa,
CEP (local committee) Comitê de Ética em Pesquisa , and
ANVISA (Agência Nacional de Vigilância Sanitária),
are responsible for reviewing and approving regulatory documents to initiate a clinical study in this region. The CONEP and ANVISA processes happen in parallel.
1. CONEP, translated from Portuguese as National Committee of Ethics in Research: this committee is the Central Ethics Committee, which is related to the Ministry of Health, is responsible for review and approval of the ethical aspects of a clinical trial in Brazil.
a.The Coordinating CEP is responsible for submission of the clinical trial to the CONEP, and will directly work with the CONEP regarding the study assessment. A written letter will be issued if the CONEP approves the study.
b.Otherwise, CONEP will communicate questions to the Coordinating site through the Coordinating CEP.
Questions are raised in one of three options:
- Questions were raised:
This is the case that the Coordinating CEP receives a set of questions from CONEP and forwards to the Coordinating Site and the Sponsor. The Sponsor will prepare the responses and comments on a question-by-question basis and send back to the Coordinating Site.
- Questions are raised under “approval with the recommendation”:
In this case, the clinical team must provide CONEP recommendations, along with all necessary updated documents to all sites for submission to the CEPS. All CEPs must review and approve the changes before the study starts at the respective sites.
- Questions are raised under “Pending” status:
In this case, the clinical team must provide the recommendations, along with all necessary updated documents to the Coordinating Site only, for submission to the Coordinating CEP. After approval, the coordinating CEP submits the responses to CONEP for review. After CONEP approval of the study, all remaining sites and the respective CEPS must receive the updated approved documents for review and local approval before the study starts at each site.
2. CEP, translated from Portuguese as Committee of Ethics in Research: these are local ethics committees that are registered with CONEP (the central committee). They can review and approve clinical trials conducted at an institution.
a.Each company should have a list of documents and information required for the clinical trial.
b.These documents and information are received from the sponsor and the study sites. These documents may contain templates of forms, documents, and statements required for the study. They also include statements related to general study information. For the first three study sites, one of these sites is selected as Coordinating Site; then its CEP is designated as the Coordinating CEP. All documentation must be provided in Portuguese; any translated document must be accompanied by the corresponding certificate of translation.
3. ANVISA: this is the Brazilian Regulatory Agency. This group is responsible for reviewing all technical aspects and issuing the Import License for a clinical trial. Two types of dossiers are reviewed by ANVISA:
a.Processo de Anuência (Consent Process): the main application dossier for initial submission. This dossier will receive a unique specific number from ANVISA to be used for all updates.
b.Processo de Inclusão de Centros (Inclusion Centers Process): the dossier for adding sites when every site other than the one submitted in the Processo de Anuência. This document will carry the same number as the one previously assigned.
ANVISA prefers to have all information submitted entirely in the dossiers. However, it is acceptable to submit the dossier with part of the information pending and then update the remaining documents as they are available. Responses will be made to address each question that ANVISA raises.
Several documents submitted are briefly described below:
a.Brazilian Informed Consent Form (ICF) template that must be translated into Portuguese and adapted to the local government. There are three different types of ICF that one may find:
- Master ICF is the primary document that is submitted
- Revised ICF is done whenever the changes affect any local requirement.
- Revisions to site-specific ICF is any revision to a site-specific ICF.
b. Importation which includes documents related to Import License request. This document consists of any updates to the list of materials to be imported. It consists of all study drug documentation (such as Certificate of Analysis, BSE Certificates, and documents). This request is valid during one year of the clinical trial and multiple shipments. If the length of the clinical trial or quantities needed exceeds the approved terms, then an extension to cover the extra needs must be done.
c.All master labels for study drugs and materials to ensure they contain all the expected information. These labels are in the English language, and also in its translation to Portuguese.
d.Any advertisement or announcement for the study that will be distributed to the sites.
e.Data protection requirements to be met in the confidentiality and data handling section of the ICF.
f. Insurance and Indemnity assessed as the Sponsor must provide a Medical Assistance Letter for injuries related to the study.
g. Amendments included in the protocol. These amendments needed to be approved by each CEP before the implementation and notified to ANVISA. CONEP approval is not mandatory but can be requested.
h. Safety report must be done according to local requirements. This document is received from the Sponsor in both English and Portuguese.
i. Progress and annual reports are prepared and submitted following local requirements. The study staff must submit an interim report to its CEP every six months.
j. End-of-trial notification is similar to the Progress and Annual Reports at sites and with ANVISA.
k. Clinical trial reports are prepared and submitted to ANVISA only as required by the Sponsor.
The regulatory approval process typically passes through 2 ethical evaluations: the institutional CEP and CONEP. The Coordinating Ethics Committee (EC) submits the multicenter research center research protocol for CONEP for review, and approval would apply to all sites.
CONEP submission requires
- the protocol,
- the ICF, investigator’s brochure,
- Power of Attorney,
- the protocol approved a letter from Coordinating EC, and
- all other documents submitted to the Coordinating EC.
Bioavailability / Bioequivalence Centers
The International CROs that intend to be certificated by Anvisa, must contact a national company to represent them at Anvisa. . The selected national company will be responsible for the submission of specific application forms for first certification or certification renewal.
It is recommended that the application form for certification renewal be submitted at least 180 days before the expire date.
All necessary guidelines, documents and application forms are available below.
RDC nº 56/2014
The Centers that carry out Bioavailability/Bioequivalence studies for the purpose of medicine registration shall observe the rules and technical regulations in force.
Bioavailability / Bioequivalence Report
This report must be filled in by the CRO for each study performed, informing the status of each phase. The reports filled in must be sent to Anvisa (by mail: [email protected]) every three months (4 reports sent annually).
1. ANVISA: an introduction to a new regulatory agency with many challenges By Kim Huynh-Ba & Alexandra Beumer Sassi.
2. Agência Nacional de Vigilância Sanitária – Anvisa
Mr. Shiv Kumar is the Author and founder of pharmaceutical guidance, he is a pharmaceutical Professional from India having more than 14 years of rich experience in pharmaceutical field.
During his career, he work in quality assurance department with multinational company’s i.e Zydus Cadila Ltd, Unichem Laboratories Ltd, Indoco remedies Ltd, Panacea Biotec Ltd, Nectar life Science Ltd. During his experience, he face may regulatory Audit i.e. USFDA, MHRA, ANVISA, MCC, TGA, EU –GMP, WHO –Geneva, ISO 9001-2008 and many ROW Regularities Audit i.e.Uganda,Kenya, Tanzania, Zimbabwe. He is currently leading a regulatory pharmaceutical company as a head Quality. You can join him by Email, Facebook, Google+, Twitter and YouTube