Pharmacovigilance. Major Aims. Drug Safety Knowledge. The Brazilian Experience in Pharmacovigilance REGULATORY RELATIONSHIPS

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1 Drug Safety Knowledge is gained by experience Drug Safety Knowledge Time The Brazilian Experience in Murilo Freitas Dias, MSc Head of Anvisa - Brazil Pre-Marketing Evaluation Phase I Phase II Phase III Toxicity Unexpected effects in in some some patients Clinical Trials Licencing Safety and Efficacy evidences Post-Marketing Evaluation Drug-Related Problems REGULATORY RELATIONSHIPS Pre-Marketing Time Clinical Trials Assessment Laboratory Assays Drug Registration Batch Release Safety Issues Safety/Rational Issues Post-Marketing Time Quality Inspection If quality issues are related with AE Laboratory Assays Major Aims early detection of unknown safety problems detection of increases in frequency identification of risk factors quantifying risks preventing patients from being affected unnecessarily Rational and Safe use of Medicines Laws Framework of Vaccines and Constitution art. 197 Brazilian system WMC/WHO Laws and decrees National National Public Public Health Health Programms Programms National Centre --CNMM Pharmaceutical Pharmaceutical Companies Companies Law 6360/76 creation of Products and Services Public Health Surveillance System MH Resolution (CNS) 3/89 Institution of Pv System National Drug Policy Decree n 3916/98 Law n 9782/99 Anvisa s creation M. Health decree 696/MS 2001 National Centrer creation (CNMM) Anvisa s Service Bulletin nº 16-15/03/2007 institution of Office Anvisa s resolution - RDC N# 04/2009 Pv for Pharmaceutical Industries Reporting Pharmacies Consumers Regionals Reporting Centres Centres Centres Health Professionals Local Local Centres

2 Why do we need Risk Management? - Many new drugs/new technologies in the marketing; - Sub-standard products in the marketing; - A large number of imported products and raw material. Brasil 62º Country (2001) Why Risk Management is a challenge? - Lack of regulatory effort by some Governments - Post-marketing surveillance is not a priority, but license. - Not many resources and structure available for regulation - Human, materials, legal bases, regulatory legislations - Limited expertise in Drug Regulatory Authority - Employees and lack of advisory committees - Drug companies with limited resources - Drug companies lobby - Risk Management resistance - Good formation/information only in English. - courses and literature million of US$ Brazilian Drugs Exportation and Importation data 2500, , , ,00 500,00 0, Importations Exportations Source: Safatle et al. Evolução, Tendências e Características das Importações e Exportações de Farmacoquímicos e Medicamentos IPEA, 2003 Adverse Event Reporting System Brazilian Adverse Event Reporting System Vaccines Clinical Trials Medicines AE Medical products Medical equipment Blood Sanitizer Cosmetics Intoxication Diagnostic reagents Agrotoxic substances

3 NOTIVISA Codes: - Product: - ATC-WHO - ADR: - WHO-ART - MedDRA/WHO-ART Bridge - Therapeutic indications: - ICD 10 SENTINEL HOSPITALS NETWORK Maintenance of 224 high complexity hospital network, able to report adverse drug reactions and other problems SENTINEL HOSPITALS - COMPONENTS Vigilance Aims Technovigilance Hemovigilance -Drugs: - ADR - Medication Errors - Rationality - Quality Deviations -Medical devices, diagnostic kits and Equipaments: - Adverse events - Quality deviations - Trainings -Blood and blood components: - Adverse reactions - Rationality Problems with Medicines? Call for the Pharmacist Brazilian cases exemples of drug-related problems Heavy metals and no Pharmacopoea Reference for Meglumine Anthymonate High alchool concentration Off label use and ADR Criminous counterfit New ADR Irrational Use Brazilian Case Example QUALITY DEVIATION PROBLEM AND REGULATORY INTEGRATION Date: May of 2003 Product: barium sulphate, 150g Use: x-ray for esophagus and stomach Route: Per oral Brazilian Agência Health Nacional Surveillance de Vigilância Agency Sanitária

4 CASE EXAMPLE QUALITY DEVIATION PROBLEM (CELOBAR) ADR: hypokalemie, cardiac and pulmonary arrest possibly leading to death Number of cases: Around 200 disabilities reported and 22 deaths. Geographic distribution: 6 states involved Reaction onset: 10 minutes to 3 hours (mean 30 min) (e.g) Adverse Drug Reaction Stevens-Johnson Syndrome INVESTIGATION: Celobar = 21g barium carbonate (7 times lethal dose) First Death Patient and Celobar body concentration = 143 mg/kg Lethal dose = Around 3 grams* *Source: POISINDEX, THOMSON MICROMEDEX, 2003c Brazilian Health Surveillance de Vigilância Agency Sanitária (e.g) Medicine Quality Problems Brazilian Risk Management Documentation Development of Brazilian Guideline for Risk Management in Health Authorities Document; from 2006 to Regional Seminars; Creation of Macro flow for Brazilian System; New rules for Industries Phv Regulatory Resolution including Phv Plan and RMP Risk Management for Health Authorities Macro flow 60% - Actions (retctangle boxes) 33% - Decisions (diamond-shaped boxes) 07% - Other boxes Key points of new brazilian regulation in pharmacovigilance (RDC N# 04/2009) Source: ISoP2008 Poster - Development of Guideline and Macro Flow for : Basis for decentralization

5 New brazilian regulation in pharmacovigilance New brazilian regulation in pharmacovigilance - Having a system of pharmacovigilance located in Brazil; - Coordination of professional demonstrably qualified; - Structure physical and documentary organization that meets the implementation of proposed activities; - Have detailed document describing its system of pharmacovigilance implanted in the company. - There must be on pharmacovigilance communications without prior or simultaneous information to Anvisa; - The actions adopted in Brazil or by regulatory agencies in respect of pharmaceutical product, safety should be communicated; - Encourage Health professionals and consumers to be notified; - Must do Risk Management Plan when asked for New brazilian regulation in pharmacovigilance New Brazilian regulation in pharmacovigilance Deadline for report: - Life threatening and death adverse reaction to drugs, which occurred in national territory: 7 days run from their knowledge; - Other serious adverse reactions, occurred in national territory: 15 days run from their knowledge; - Non-serious adverse reaction expected to be incorporated into the PSUR Primary Sources: - Health professionals; - Users with evaluation by a health professional; - Users without individual assessment, but that generated safety signal. New Brazilian regulation in pharmacovigilance Periodic Safety Update Report (PSUR): -When asked by Anvisa; - New Drugs: - Every six months, the first two years of granting registration; - Each year by the first renewal (three years); -At the time of renewals thereafter. Chapter 6 - Plan and Risk Minimization Plan Article 11. Anvisa may request at the time of licensing, or at any time, the Plans for pharmaceutical companies, describing the actions of routine or description of additional actions proposed for the monitoring of medicines. Article 12. May be required at the time of licensing, or any time for any product, in addition to the Plan, a Risk Minimization Plan, where the situations that require additional action. In this plan the company should explain how will evaluate the effectiveness of their actions to minimize the risks of their products. 1. The RMP referred to in this article aims to management of new risks in the postregistration or even monitoring of known risks in populations already studied. Also they aim to implement in situations where the product will likely use one that has not been studied adequately in pre-registration; 2. In addition to routine pharmacovigilance, the PMR should submit a proposal based on methods pharmacoepidemiological for the assessment of critical points related to security medicine.

6 New Brazilian regulation in pharmacovigilance The knowledge-driven model of decision-making - Inspections: programmatic or sporadic; - It should be made selfinspection at least once a year; Data Collection Information Knowledge Sorting/ selection Understanding Analysis Judgement Interpretation Decision Weighing options Valuation Source: Design and Implementation of Health Information Systems. WHO, p. 35 Thank you! Thank you! Brasília DF during sunset Murilo.freitas@anvisa.gov.br