Pharmacovigilance Legislation: Brazil in line with international standards

Paper | Open Access | Published: 11 August 2020
https://www.researchgate.net/publication/343588426_Pharmacovigilance_Legislation_Brazil_in_line_with_international_standards
Pharmacovigilance Legislation:
Brazil in line with international standards
1
Fernanda de Lima Ferreira 
Objective
The objective of this paper is to provide a detailed analysis of new pharmacovigilance legislations
in Brazil from a Marketing Authorization Holder (MAH) perspective.
Background
The first pharmacovigilance (PV) legislations have been published in Brazil at national level in
2009 (Resolution RDC 4 10/02/200 and its guidelines). Over a decade later, on 29 July 2020 a
new PV chapter has been established in the South American country with the publication of two
new PV legislations: Resolution of the Collegiate Board of Directors - RDC 406, of July 22, 2020:
Provides for the Good PV Practices for MAHs of Medicinal Products for Human Use, and other
arrangements and the Normative Instruction - IN 63, of July 22, 2020: Provides for the Periodic
Benefit-Risk Assessment Report (PBRER) to be submitted to The Brazillian Health Surveillance
Agency (Agencia Nacional de Vigilancia Sanitaria - ANVISA) by Marketing Authorization Holders
(MAH). These integrate the commitments assumed by Brazil when becoming one of the member
countries of the International Council for Harmonization of Technical Requirements for
Pharmaceuticals for Human Use (ICH).
Good Pharmacovigilance Practices established on RDC 406 22/07/2020 compared to
previous PV legislation RDC 04/2009 and its guidelines
Table 1. New PV requirements on RDC 406 22/07/2020
Main topic Description
Responsibilities
of MAH (RFV)
Changed that the National PV Responsible Person (“RFV”) should contribute to the
preparation of regulatory actions when in response to safety issues to must be
endowed with sufficient authority and autonomy to promptly respond to the HA
regarding the safety of products under the responsibility of the Marketing
Authorization Holder (MAH) (article 7)
Added that for companies of the same group, it is necessary the maintenance of 1
RFV and their deputy for each company of the group (article 10, paragraph 4)
Added that the RFV must be available full-time (article 16) [meaning their
responsibility under PV cannot be shared with other departments
Responsibilities
of MAH
(outsourcing/RFV)
Added the RFV and their deputy may not be outsourced (article 10, paragraph 1)
Responsibilities
of MAH
(outsourcing)
Added specific information that in cases of outsourcing of PV activities, the MAH
remain responsible for the legal and health requirements related to the product
(article 10, paragraph 2)
Staff Added specific information that the MAH must have a number of qualified
employees compatible with the PV activities (article 18)

2
Added there shall be no unjustifiable overlaps, as well as gaps in the responsibilities
of those involved in the MAH PV System (article 19)
Training In addition to previously mentioned sales department, added that teams involved in
PV including customer service and any other function interfaced with information
involving product safety must be properly trained so that their functions and
responsibilities are properly exercised (article 20, sole paragraph)
Added the MAH must have duly approved the training programs as well as the
respective training execution schedules (article 21)
Added the trainings records must be kept by the MAH for PV Inspection purposes
(article 21, sole paragraph)
Documentation Added documentation as a new topic, describing it is an essential part of the PV
System to cover all activities related to it (article 22)
Added the documents and information related to the PV System must be drafted,
approved and distributed exclusively by persons expressly designated (article 23,
paragraph 2)
Added the documents and information related to the PV System shall only be made
available to employees duly authorized and previously trained in the application of
such documents (article 23, paragraph 3)
Added SOPs or any other type of document that defines the activities related to PV
must be legible and clear in order to avoid divergent interpretations during their
execution (article 24, paragraph 1)
Added as new topics that must covered in SOPs or any other type of document: a)
regular analysis process to capture AE information from several sources of scientific
literature, accessing systematic reviews or reference databases; b) preparing and
implementing a Risk Management Plans; c) management of Corrective Actions and
Preventive Actions (article 24, paragraph 2)
Documentation Added the list of activities to be covered in SOPs is not exhaustive and it is up to the
MAH to assess the need to prepare additional documents that contemplate other
activities (article 24, paragraph 3)
Database Added database as a new topic, replacing the previous mention from “system” to
“database”, where MAHs must complete a systematic, updated and routine
registration of activities and information related to the Adverse Events Notifications
received (article 25)
Changed ICSRs submission format, from previous manual entry at HA webpage to
electronic notification system made available by HA [VigiMed] (article 26, paragraph
1) [it is being requested narratives and AE fields in local language (no English info
on these should be forwarded] for the companies which cannot comply with these
requirements, single ICSR manual submission at HA webpage can still be made]
Added the MAH may generate files in XML format compatible with the HA electronic
notification system, in accordance with the requirements defined by ICH-E2B in a
grouped or even individual manner (article 26, paragraph 2)
Self-Inspection Changed self-inspection timeline from at least once a year to preferably one (1) self-
inspection per year not exceeding the period of two (2) years (article 28)
Changed the duration the self-inspection record must be to be maintained by the
MAH from at least 3 years to at least 5 years (article 28, paragraph 1)
Added PV self-inspections shall also include the activities and facilities of third
parties, in cases of outsourcing of PV activities (article 28, paragraph 2)

3
ICSR notification
to HA
Changed previous ICSR notification timelines (7d for fatal / LT, 15d for serious
[calendar days]) to all SAEs (expected and unexpected), reported spontaneously or
requested (solicited) within 15d [calendar days]) occurring in the national territory
(article 30)
Added cases of therapeutic ineffectiveness that represent a risk to life, according to
the own evaluation of the MAH, as well as all those related to vaccines and
contraceptives, must be notified to HA within the period established in the given
ICSR timelines (article 30, paragraph 30)
Added additional information should be sought on notifications requiring follow-up,
with priority for serious and unexpected, followed by serious and expected and,
finally, non-serious and unexpected” (article 30, paragraph 3) [impact on non-
serious unexpected requirements, that should now be followed up]
Valid ICSR Added valid case concept never mentioned on previous rule (in order to be
considered valid and reportable, the notification must contain as much information
as possible, including at least identification of the notifier and patient, AE description
and suspect drug) (article 32)
Valid ICSR/
ICSR Follow-up
Added the absence of any of the valid case criterion makes the initial report
incomplete, generating for the MAH the obligation to actively search the missing
data (article 32 sole paragraph)
ICSR Follow-up Added when additional clinically relevant information is received for a previously
reported case, the deadline for submission of the Follow-up Notification is reset
(article 33)
Alerts Added that [only] “emergency situations related to the use of its products that affect
the patient's safety must be reported to HA within 72 h” (article 34, paragraph 1),
against previous rule (to notify in 72h [any] actions taken by the company itself in
relation to products affecting patient’s safety including those taken by international
regulatory agencies).
Medical dictionary Changed the medical dictionary for the description of medical terms and AEs when
sending reports and notifications to the HA from WHO-ART to MedDRA (article 35)
ICSR assessment Added that in addition to the mother, the child must also be monitored after the
evaluation of all cases of exposure to medication of pregnant patients and their
children after birth by the MAH (article 36)
Added in view of pre-gestational exposure, MAHs are also responsible for
monitoring and evaluating the case, also taking into account the half-life of the
substance or its metabolites, as well as the long-term effects (article 36, sole
paragraph)
Aggregate
Reporting
Changed Periodic Safety Report format from PSUR to o ICH-aligned format Periodic
Benefit-Risk Evaluation Report (PBRER) (Section II)
Benefit-Risk
Assessment
Added a Benefit-Risk Assessment topic covering
a) The MAH must maintain a routine assessment of the Benefit-Risk
Relationship of its products (article 41)
b) Any change in the balance between the benefits and risks of its products
must be informed immediately to HA, including new data that may exist from
post-marketing studies, indicating the occurrence of Signals or changes in
the Benefit-Risk Relationship of the medicines (article 41 sole paragraph)

4
RMP Changed reference by HA to the document previously designated as
“Pharmacovigilance Plan & Risk Minimization Plan” to the ICH-aligned format “Risk
Management Plan” (RMP) (Section IV)
Emphasized that the RMP writing must be carried out with special attention and
precision in all requirements previously provided in previous legislation (new
products, upon HA request, etc…) (article 43)
Updated requirements to submit RMPs to HA (article 43):
a) newly added: biological products registered by the class of development by
comparability;
b) previous requirement complemented: in cases of significant changes in the
registration, which impact the safety of the product
Added the MAH must consider the need to update the RMP when obtaining new
data related to safety, as well as the use of the drug in populations not studied in the
pre-registration phase (article 45)
Added the updated version of the RMP must be electronically forwarded to HA via
electronic petitioning (article 45, sole paragraph)
Added that situations in which the drug has a probable use not properly studied in
the pre-registration period must be contemplated in the Risk Minimization Plan
(article 46 Paragraph 2)
Inspections
Updated previous rule by adding that any inspections to MAHs from HA to asses
compliance with this legislation may be announced or not (article 47)
Labelling
RDC No. 47*, of September 8, 2009, is hereby effective with the following
amendments provided by this RDC 406 within Appendix 1 – Adverse Reactions
template texting [01 making reference to HA’s website [VigiMed] and 02 new
warning messages] (article 49).
* establishes rules for the preparation, harmonization, updating, publication and
availability of package inserts for patients and health professionals.
New Periodic Reports requirements on IN 63 22/07/2020 compared to previous legislation
RDC 04/2009 and its guidelines
Table 2 – New Period Reports requirements on IN 63 22/07/2020
Format
Changed Periodic Safety Report format from PSUR to o ICH-aligned format
Periodic Benefit-Risk Evaluation Report (PBRER) (Section II)
Periodicity
Added the PBRER must be submitted to the HA respecting the periodicity
available on HA’s webpage [HA list harmonized with international PBREs is
currently under preparation with planned expected release until the effective date
of this rule] (article 18)
Periodicity
Added the HA may request the MAHs if necessary, to present PBRERs at
different periods and periods than those previously defined by the HA including
those resulting from important changes in the initially approved clinical use, such
as: a) new clinical indication; or b) new approval for patients from special

5
populations (children, pregnant women and the elderly) (article 18, sole
paragraph)
Special
situations I
Added MAHs are held responsible for submitting the RPBR for their products
(article 9) and when companies are bound by contractual relationships of a
certain product, the respective actions for the preparation of the PBRER must be
clearly specified in written agreements (article 9 sole paragraph)
Special
situations II
Added specific instruction for PBRER submission of product combination and
clones in addition to single-active ingredient (subsections II and III and I,
respectively)
Medical
dictionary
Added the compulsory use of MedDRA is hereby adopted (article 14)
IBD
Changed National Birth Date to International Birth Date (IBD) as a criterion for
preparing periodic safety reports (article 16 and its sole paragraph)
Submission
intervals
Changed the intervals between the datalock point and the PBRER submission: a)
70 days for PBRERs of up to 12 months; b) 90 days for PBRERs with a period
exceeding 12 months; c) 90 days for exceptional PBRERs unless another term is
determined by HA (article 19).
Report
template
Added PBRERs submitted to Anvisa must follow the template contained in the
updated version of the E2C Guide of the International Conference on
Harmonization (ICH) (article 20)
Conclusion
These new requirements impact from minor to major changes for MAHs. From all of them, the
biggest impacts fall on:
• the national adoption of the Upsalla Monitoring Center (UMC) Safety database to the
National Pharmacovigilance Program (locally named as Vigimed)
• the implementation of Medical Dictionary for Regulatory Activities (MedDRA) in an
exclusive Brazilian Portuguese version
• ICSR reporting method change from manual to electronic submission format
• the official use of the Periodic Benefit-Risk Evaluation Report (PBRER) as the officially-
accepted aggregate reporting format now following the adoption of the International Birth
Date (IBD) calendar.
There is a long step to be taken between publication and implementation by MAHs who must
comply with the new requirements and relay on the HA to supplement it with the required
guidelines and clarifications as well as with the alignment with local / state HAs, but definitely the
publishing of this new rules aims at a more robust national PV system and puts Brazil in line with
international standards as was long expected.

6
References
1. Resolution of the Collegiate Board of Directors - RDC No. 406, of July 22, 2020:
Provides for the Good PV Practices for MAHs of Medicinal Products for Human Use, and
other arrangements. Anvisa website. Accessed 29/07/2020.
http://portal.anvisa.gov.br/documents/10181/4858873/RDC_406_2020_.pdf/c62cdded-
e779-4021-858d-852edbd90178
2. Normative Instruction - IN No. 63, of July 22, 2020: It provides for the Periodic Benefit-
Risk Assessment Report (RPBR) to be submitted to Anvisa by holders of Human
Medication Registration. Brazilian Government website. Accessed 29/07/2020.
https://www.in.gov.br/en/web/dou/-/instrucao-normativa-in-n-63-de-22-de-julho-de-2020-
269155503
3. Guias de Farmacovigilância para Detentores de Registro de Medicamentos. Anvisa
website. Accessed on 29/07/2020.
http://portal.anvisa.gov.br/documents/33868/2894051/Guias+de+Farmacovigil%C3%A2n
cia+para+Detentores+de+Registro+de+Medicamentos+-
+documento+completo/f3fc06a5-97e6-4bbc-848d-750bcefb99e0
4. Huynh-Ba, K., Beumer Sassi, A. ANVISA: an introduction to a new regulatory agency
with many challenges. AAPS Open 4, 9 (2018). https://doi.org/10.1186/s41120-018-
0029-x. Accessed on 29/07/2020.
5. MedDRA. Anvisa website. http://portal.anvisa.gov.br/vigimed/meddra. Accessed on
29/07/2020.
6. Vigimed: notificação fácil de eventos adversos. http://portal.anvisa.gov.br/noticias/-
/asset_publisher/FXrpx9qY7FbU/content/vigimed-notificacao-facil-de-eventos-
adversos/219201. Accessed on 29/07/2020.
Author information, Affiliations and Correspondence
Fernanda de Lima Ferreira, Registered Pharmacist, PgDip. Pharmacovigilance&Medical Writing
Independent Researcher. Sao Paulo, Brazil.
Correspondence to: nandacrfsp@hotmail.com
Funding
The paper received no fundings.
Ethics declarations / Competing interests
The author declares that this is their sole opinion on the topic as an independend researcher and
area expert, without content relation or competing financial interests of any employer.

Pharmacovigilance Legislation: Brazil in line with international standards

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