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Better protecting the patients Be aware of the system and your role
Inhoud presentatie 9Introductie 9Wetgeving Verordening Richtlijn Implementatie maatregelen 9Belangrijke veranderingen
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Regulering geneesmiddelen
1937 Elixir Sulfanilamide
1956-1963 Softenon, thalidomide
1906 Pure Food and Drugs 1938 Food, Act Drug, and Cosmetic Act
1963-64 UK, NL, US etc 4
Directive 65/65/EEC provisions laid down by law, regulation and administrative action relating to medicinal products 17-11-2011
Pharmacovigilantie
Spontaneous reports 2004 Vioxx
2001 cerivastatine
1995 PSURs
2005 RMPs 5
2006 EU consultation 17-11-2011
Pharmacovigilantie Spontaneous reports
2001 cerivastatine
2004 Vioxx
2010 Regulation 2005 Directive 2006 EU
1995 PSURs
RMPs 8
consultation
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Inhoud presentatie 9Introductie 9Wetgeving Verordening Richtlijn Implementatie maatregelen 9Belangrijke veranderingen
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European Commission schatting • 5% of all hospital admissions due to ADRs • 5% of all hospital patients experience an ADR • ADRs 5th most common cause of hospital death • 197,000 deaths per year in EU caused by ADRs • Total societal cost €79 billion
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Regulation/verordening 1235/2010 Focus op EU procedures en de taken van EMA Directive/richtlijn 2010/84/EC Focus op farmacovigilantie activiteiten in de lidstaten met het oog op nationale registraties De verordening is geen herhaling van de richtlijn , maar cross referenties Maatregelen gelden voor de centrale (CAPs) en niet centrale producten (non CAPS) Moeten samen gelezen worden, beiden treden in werking juli 2012 12
Implementing measures (7)
1. Verdere uitwerking van pharmacovigilance system master file 2. Kwaliteits systeem bij de registratiehouder, EMA, nationale agentschappen 3. Gebruik van internationaal afgesproken termen bij PhV activiteiten; 4. Monitoren van de gegevens in de Eudravigilance data base 5. Formaat en inhoud voor de rapportage van bijwerkingen; 6. Formaat en inhoud electronische PSURs (periodic safety update reports) en RMPs (risk management plans); 7. Formaat en inhoud van protocols, abstracts en studie verslagen van post- authorisation safety studies. 13
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http://ec.europa.eu/health/human14 use/pharmacovigilance/developments/index_en.htm
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Inhoud presentatie 9Introductie 9Wetgeving Verordening Richtlijn Implementatie maatregelen 9Belangrijke veranderingen
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Wat gaat de wet veranderen?
Registratie eisen Risk management plan
Literatuur monitoring Additional monitoring
Referrals/union procedures Post authorisation safety studies renewal
PSURs Bijwerkingen
Meten effecten risk minimisation
Wetenschappelijke committees /PRAC
webportals Signaal detectie
Farmacovigilantie master file Farmacovigilantie inspecties
Transparantie Worksharing 16
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Inhoud sub presentatie 9Introductie Mediator 9Wetgeving 9 stress test 9 wijzigingen
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opdracht
Inleidende voordracht waarin het juridisch kader wordt uiteengezet aan de hand van de Mediator case als ‘stress-test’ (klik hier voor het rapport van de Franse Inspection générale des affaires sociales) en waarin specifiek aandacht wordt besteed aan de nieuwe farmacovigilantiewetgeving (Richtlijn 2010/84/EU en Verordening (EU) nr. 1235/2010) en de betekenis van de nieuwe wetgeving voor industrie, overheid, LAREB, beroepsbeoefenaren en consumenten Vragen: - Op welke punten wijzigt de nieuwe wetgeving echt iets? - Wordt hiermee voldaan aan de doelstellingen van de wetgever? - Wat is de betekenis van de wijzigingen in het perspectief van de volksgezondheid? - Wat zijn de gevolgen voor de praktijk? 18
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Mediator= benfluorex
1976: Add on therapy for hyperlipidemia, diabetes with obesity Rapport van de Franse IGAS 2011 Servier beschuldigd van: Relentlessly marketing at odds with the medical properties Undue lobbying pressure on regulators Pressure on the medical community AFFSAPS Inexplicably tolerant of a drug with no real therapeutic value Overworked bureaucracy Entangled in cumbersome and complex legal procedures Restrained by fear of litigation Medical and scientific community: unresponsible behaviour
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Mediator (benfluorex) Serviers development program: appetite suppression fenfluramine dexfenfluramine benfluorex
sixties
Fenfluramine: Ponderal Dexfenfluramine: Isomeride Anorexigens for obesity Benfluorex on the market
Add on therapy for hyperlipidaemia, diabetes with obesity 1990
1976
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Fenfluramines Scrutiny increased risk of pulmonary heart disease
Benfluorex, MA not renewed in Spain and Italy by Servier
Benfluorex,
close relation, appetite suppressing properties, remains unaffected
2003
1997
1995 Use restricted by AFFSAPS
1998
Fenfluramine withdrawn Serious cardiovascular risks 21
Benfluorex, close PhV surveillance by AFFSAPS concern in Italy
2007 Benfluorex, new PhV surveillance by AFFSAPS 17-11-2011
Mediator (benfluorex) AFSSAPS suspended in November 2009, after results of 2 studies indicating increased cardiovascular risk (valvular anomalies) became available
IGAS concluded : 9Agressive marketing 9Complex bureaucracy at AFSSAPS 9Fear of litigation 9Unhealthy ties between industry and regulators 9Reverse precautionary principle
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Inhoud sub presentatie 9Introductie Mediator 9Wetgeving 9 stress test 9 wijzingingen
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Key measures proposed
1. Clear roles and responsibilities for key parties 2. Strengthening transparancy and communication on medicines safety issues 3. Strengthening companies Pharmacovigilance System 4. Risk management planning for each (new) medicinal product 5. Strengthening reporting system for adverse reactions 6. Pro active and proportionate collection of high quality data
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Stress test 1
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Stress test 2
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Other new provisions, strengthening PhV
Increased transparancy about safety issues Webportals Publication of all decisions Public access to Eudravigilance List of prodcts under addtional monitoring Risk Management Adverse drug reactions also off label use Continuous benefit risk assessment All products a risk management plan Reports from HCP and patients Pharmacovigilance procedures Minimum requirements forquality system Audits of PhVS
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Key measures proposed 1. Clear roles and responsibilities for key parties 2. Strengthening transparacy and communication on medicines safety issues 3. Strengthening companies Pharmacovigilance System 4. Risk management planning for each (new) medicinal product 5. Strengthening reporting system for adverse reactions 6. Pro active and proportionate collection of high quality data
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Tot slot
PRAC PSUR RMP+ PhV MF ADR
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Pharmacovigilance Risk Assessment Committee (PRAC)
Mandate (R61a6) All aspects of the risk management of the use of medicinal products including the detection, assessment, minimisation and communication relating to the risk of adverse reactions, having due regard to the therapeutic effect of the medicinal product, the design and evaluation of post-authorisation safety studies and pharmacovigilance audit
303
0
PRAC expertise
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and the MAH shall
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Periodic Safety Update Reports PSURs Requirements for PSURs have changed substantially – When to submit – Where to submit – What to submit – How to assess – How to implement – How to prepare
PSURs
• For generics and traditional herbal medicines PSURs will no longer be routinely required • On the basis of PhV concerns PSURs can be required • MAHs shall submit electronically to the EMA (repository, where Member States access) – following audit of IT system
PSURs content Will not contain line listings – ADR data already in Eudravigilance But will contain • Company integrated assessment of benefit risk + exposure •
Structured data using controlled terminologies
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Safety specification (focussing on important identified and potential risks and important missing information)
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Signals/signal detection/signal management (newly identified, ongoing or closed, changed)
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Newly identified important risks
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Evaluation of the Effectiveness of Risk Minimisation.
PSURs • Periodicity specified in the MA, established by EMA (binding list on website) • For MA same active substance the frequency may be amended and harmonised • MAH may submit a request to adjust submission frequency • For established substances, single EU assessment • EMA will PSUR Assessment Report to MAH (after new repository implemented) • Assessment leads to automatic regulatory action: maintenance, variations, suspension, revocation
Decision-making for PSURs “No CAP concerned”
Single AR prepared by the Member State appointed by the CMD
PRAC to adopt the AR If any regulatory action results from the AR, CMD to reach a position: maintenance, variation, suspension or revocation according timetable for implementation MS =
CMD ≠ PRAC
MS ≠ Detailed explanations to be annexed. Decision sent the MAHs and MSs CMD has the legal power concerned Position of the majority of MSs to be sent to the Commission which will adopt a decision 4 1
Decision-making for PSURs Single AR prepared by the Rapporteur appointed by the PRAC
“At least 1 CAP concerned” PRAC to adopt the AR
If any regulatory action results from the AR, CHMP to adopt an opinion: maintenance, variation, suspension or revocation according timetable for implementation
Commission to adopt a decision concerning the regulatory action(s)
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DDPS- PHVS master file
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Adverse Reaction reporting
• • • • • • •
Definition Reporting lines Serious and non serious Patient reports E forms Data quality Transparancy
Better ADR Reporting Adverse Reaction definition (Dir art 1) “A response to a medicinal product which is noxious and unintended” 9Medication errors that result in an ADR 9EV shall contain information an ADRs also during abuse misuse and off label use 9ADRs that arise from error associated with the use of medicinal product are also made available to competent authorities/bodies/organisations at a national level
Better ADR reporting Eudravigilance to be the single point of receipt for ADRs All ADRs from MAHs and from Member States are sent to Eudravigilance Additional reporting arrangements should not be imposed (dir 107a.6 unless..) Member States are ‘auto-forwarded’ their national data Eudravigilance to be fully and permanently accessible with appropriate access levels MAHs access reports in Eudravigilance Functional specification and time-lines to be drawn up with Member States Transitional arrangements will be put in place 47
Better ADR reporting MAH shall record all suspected adverse reactions spontaneously and PA study and submit electronically to the EV database 9 all serious suspected adverse reactions that occur in the Union and in third countries within 15 days. 9 all non- serious suspected adverse reactions that occur in the Union, within 90 days 9 All patient reports 9 MAH shall not refuse ADR reports from patients of HCPs (received electronically or by any other appropriate means)
Signal detection
-For 1st time the concept is recognised in legislation -roles and responsibilities for EMA and Member States stated in the legislation -MS and EMA shall monitor the data in the Eudravigilance database to determine whether there are new risks or whether risks have changed and whether those risks impact on the risk benefit balance’ -PRAC performs initial analysis and prioritisation of signals of new risks or risks that are changing or changes to the risk-benefit balance.
EU ≠ the United States of Europe
EU legislation:
27 different sets of national legislation
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Volume 9A wordt : GVP Modulair van opzet Ontwikkeld door EMA samen met lidstaten Uit voor pubieke consultatie ( 8 weken) Planning: gefaseerd
Thank you! Questions?
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