Better protecting the patients. Be aware of the system and your role

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2 Better protecting the patients Be aware of the system and your role

3 Inhoud presentatie Introductie Wetgeving Verordening Richtlijn Implementatie maatregelen Belangrijke veranderingen 3

4 Regulering geneesmiddelen 1937 Elixir Sulfanilamide Softenon, thalidomide 1906 Pure Food and Drugs Act 1938 Food, Drug, and Cosmetic Act UK, NL, US etc Directive 65/65/EEC provisions laid down by law, regulation and administrative action relating to medicinal products

5 Pharmacovigilantie Spontaneous reports 2001 cerivastatine 2004 Vioxx 1995 PSURs RMPs 2006 EU consultation

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8 Pharmacovigilantie pontaneous reports 2001 cerivastatine 2004 Vioxx 1995 PSURs RMPs 2010 Regulation Directive 2006 EU consultation

10 European Commission schatting 5% of all hospital admissions due to ADRs 5% of all hospital patients experience an ADR ADRs5 th 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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12 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

13 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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16 Wat gaat de wet veranderen? Registratie eisen Literatuur monitoring Risk management plan Additional monitoring Referrals/union procedures Post authorisation safety studies PSURs renewal Bijwerkingen Meten effecten risk minimisation Wetenschappelijke committees /PRAC webportals Farmacovigilantie master file Farmacovigilantie inspecties Transparantie 16 Signaal detectie Worksharing

17 Inhoud sub presentatie Introductie Mediator Wetgeving stress test wijzigingen 17

18 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

19 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 19

20 Mediator (benfluorex) Serviers development program: appetite suppression fenfluramine dexfenfluramine benfluorex Fenfluramine: Ponderal Dexfenfluramine: Isomeride Anorexigens for obesity Benfluorex on the market Add on therapy for hyperlipidaemia, diabetes with obesity 1990 sixties

21 Fenfluramines Scrutiny increased risk of pulmonary heart disease Benfluorex, close relation, appetite suppressing properties, remains unaffected Benfluorex, MA not renewed in Spain and Italy by Servier Use restricted by AFFSAPS Fenfluramine withdrawn Serious cardiovascular risks Benfluorex, close PhV surveillance by AFFSAPS concern in Italy Benfluorex, new PhV surveillance by AFFSAPS 21

22 Mediator (benfluorex) AFSSAPS suspended in November 2009, after results of 2 studies indicating increased cardiovascular risk (valvular anomalies) became available IGAS concluded : Agressive marketing Complex bureaucracy at AFSSAPS Fear of litigation Unhealthy ties between industry and regulators Reverse precautionary principle 22

23 Inhoud sub presentatie Introductie Mediator Wetgeving stress test wijzingingen 23

24 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 24

25 Stress test 1 25

26 Stress test 2 26

27 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 27

28 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 28

29 Tot slot PRAC PSUR RMP+ PhV MF ADR 29

30 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

31 PRAC expertise 31

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36 and the MAH shall 36

37 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

38 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

39 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 Safety specification (focussing on important identified and potential risks and important missing information) Signals/signal detection/signal management (newly identified, ongoing or closed, changed) Newly identified important risks Evaluation of the Effectiveness of Risk Minimisation.

40 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

41 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 Decision sent the MAHs and MSs Detailed explanations to be annexed. concerned CMD has the legal power Position of the majority of MSs to be sent to the Commission which will adopt a decision 4 1

42 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) 4 2

43 DDPS- PHVS master file 43

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45 Adverse Reaction reporting Definition Reporting lines Serious and non serious Patient reports E forms Data quality Transparancy

46 Better ADR Reporting Adverse Reaction definition (Dir art 1) A response to a medicinal product which is noxious and unintended Medication errors that result in an ADR EV shall contain information an ADRs also during abuse misuse and off label use ADRs that arise from error associated with the use of medicinal product are also made available to competent authorities/bodies/organisations at a national level

47 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

48 Better ADR reporting MAH shall record all suspected adverse reactions spontaneously and PA study and submit electronically to the EV database all serious suspected adverse reactions that occur in the Union and in third countries within 15 days. all non- serious suspected adverse reactions that occur in the Union, within 90 days All patient reports MAH shall not refuse ADR reports from patients of HCPs (received electronically or by any other appropriate means)

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50 Signal detection -For 1 st 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.

51 EU the United States of Europe EU legislation: 27 different sets of national legislation 51

52 Volume 9A wordt : GVP Modulair van opzet Ontwikkeld door EMA samen met lidstaten Uit voor pubieke consultatie ( 8 weken) Planning: gefaseerd

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54 Thank you! Questions? Better protecting the patients Be aware of the system and your role

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