Informations- og dialogmøde om den nye lovgivning om lægemiddelovervågning Sundhedsstyrelsen, tirsdag den 11. september 2012

Eftermiddagens program  Velkomst og introduktion til den nye organisation v. Direktør Vagn Nielsen  Pharmacovigilance Risk Assessment Committee (PRAC): Nye tider, nye opgaver v. overlæge Doris Stenver  Status om lovgivningen fra CMD(h) v. sektionsleder Joan Boye  Ændringer i CHMP’s opgaver v. overlæge Jens Heisterberg  Pause  Oplæg og input fra brancheforeningen LIF  Spørgsmål og diskussion  Afrunding 2

Pharmacovigilance Risk Assessment Committee (PRAC): Nye tider – nye opgaver Doris I. Stenver Overlæge, medlem af PRAC

4 Overview  New pharmacovigilance legislation – purpose and expected achievements  Pharmacovigilance Risk Assessment Committee – tasks and responsibilities  EMA Implementation plan  GVP modules – status  Commission Implementing Regulation  Revision of legislation

5 Ancient times…..

6 Impact of thalidomide tragedy in the 1960s  Establishment of drug safety surveillance systems  Involvement of health professionals  Decisions based on national experience  Non-transparent environment

7 European Medicines Agency London, since

8 Present time…..  Internet era  Transparency  Internationalisation  Competitive power  Innovative power  Disease burden  Involvement of patients

9 New pharmacovigilance legislation  In general, overall strengthening of pharmacovigilance  Clear roles and responsibilities  Rational use of ressources  Streamlined procedures (administrative and scientific) with timetables  New ADR definition  New PSUR format and scope  Legal basis for PASS  Transparency  HCP & Patient involvement

10 8 Pharmacovigilance – basic steps Risk detection / signal detection Risk assessment Risk and therapeutic effect assessment Communication of risk and benefit/risk Risk minimisation (regulatory action) and analysis of impact of risk minimisation Pharmacovigilance audit Design and Evaluation of post authorisation safety studies

11 PRAC tasks and responsibilities  Referral procedures for safety reasons  Signals detected from EU spontaneous reporting systems  Risk management plans  PSUR assessments  Post-Authorisation Safety Studies (PASS)  Product-related pharmacovigilance inspections  Safety issues – requested by CHMP or by MS(s)  Organisational, regulatory and methodological matters

12 PRAC agenda September 2012  Referral procedures for safety reasons: None  Signals detected: Thirteen  Risk management plans: One  PSUR assessments: None  Post-Authorisation Safety Studies (PASS): None  Product-related pharmacovigilance inspections: Two  Safety issues – requested by CHMP or by MS(s): None  Organisational, regulatory and methodological matters: Many

13 PRAC agenda September 2012 – new signals  Varenicline - CHAMPIX (CAP)  Signal of seizures  Status: for initial discussion  Regulatory details:  PRAC Rapporteur: Doris Stenver (DK)

14 PRAC recommendation flow Coordination Group CG CHMP European Commission Member States PRAC Recommendations

15 PRAC agenda September 2012 – new signals  Somatropin – NUTROPINAQ, OMNITROPE (CAPs, NAPs)  Signal of convulsions (SMQs – Standardised MedDRA Queries)  Status: for initial discussion and Rapporteur appointment  Regulatory details:  PRAC Rapporteur: to be appointed

16 PRAC agenda September inspections  8.2. On-going or concluded pharmacovigilance inspections  Disclosure of information on results of pharmacovigilance inspections could undermine the protection of the purpose of these inspections, investigations and audits. Therefore such information is not reported in the agenda.

17 PSUR Single Assessment – EURD list (11.3.3)  EU Reference Date List for > products  Compiled by EMA, based on EVMPD, PSUR WS and Synchronisation lists  4 consultations with MSs  PRAC consultation September 2012  CHMP & CMD(h) consultation / agreement September 2012  Publication by 30 th September – simultaneously with list on signal WS; becomes binding in April 2013  Monthly updates – dynamic EURD  Process for maintenance under discussion

18 Not all is written in stone!

19 Appointment of PRAC Rapporteurs  Guiding principles – best possible and available expertise, knowledge continuity, “fresh pair of eyes”  Legacy medicines – open up for PRAC rapporteurships to all PRAC delegates  New MAAs – PRAC co-Rapporteur from same MS as CHMP Rapporteur  Gradual phasing in from 4Q2012 in relation to all CAPs due for PSUR assessments of PASS results evaluation in 1Q2013;  Referrals – only non-CAPs  Rapporteur: open to all PRAC delegates  Co-Rapporteur: triggering MS  Referrals – mixture of CAPs and non-CAPs  Rapporteur: PRAC rapporteur for the CAPs  Co-Rapporteur: triggering MS

20 EMA Implementation Plan February 2012  Launched 1 February  Activities in 2012 and beyond 2012 (budget and ressource restrictions)  Activities contributing to public health highest priority, followed by those increasing transparency and improving communication, and with lowest priority those that simplify procedures  4 main topic areas  Collection of key information on medicines  Better analysis and understanding of data and information  Regulatory action to safeguard public health  Communication with stakeholders

21 Collection of key information on medicines  Risk Management Plans (RMPs) (GVP-V)  Strenghtened procedures for submission; beyond 2012 establishment of a risk management effectiveness monitoring system  Periodic Safety Update reports (PSURs) (GVP-VII)  Benefit-Risk evaluation tool; new procedures for submission (CAPs), list of Union reference dates; beyond 2012 focus on PSURs for NAPs  Post-authorisation safety and efficacy studies (PASS/PAES) (GVP-VIII)  Require and enforce PASS/PAES; scientific GL to support delegated act on criteria for PAES

22 Collection of key information on medicines  Electronic submission of core medicine information by pharmaceutical industry (art. 57 requirements)  Extensive requirements – Yes! But in order to conduct effective SD on data in Eudravigilance a comprehensive drug dictionary is a basic requirement; revised legal notice in febr  Reporting by patients  Information to be provided on this new opportunity

23 Better analysis and understanding of data and information  Eudravigilance and Signal Detection  Revised SD process for CAPs; improved access to data on NAPs; improvement of data quality ongoing  Additional Monitoring  First list of medicines subject to additional monitoring  IT systems to support processing and analysis of data  Full development of new IT systems will not begin until after 2012

24 Regulatory action to safeguard public health  Scientific committees and decision-making  Pharmacovigilance Risk Assessment Committee (PRAC) inaugural meeting 19 July 2012 (Bruxelles)  CMD(h) strengthened mandate – will lead on decision- making based on PRAC recommendations  Opinion-making power by either consensus or majority vote  legally binding EC decisions

25 Regulatory action to safeguard public health  Strengthening referral procedures  Urgent Union Procedure  Designed to address significant emerging safety issues with a medicine available in the EU, regardless of authorisation procedure  Systematic involvement of PRAC in providing safety expertice for assessment and to identify appropriate regulatory actions, for subsequent adoption by CHMP or CMD(h)  Increased transparency (publication of information and public hearings)

26 Communication with stakeholders  Publication of  Agendas, minutes, assessments, recommendations and opinions  Scope – PRAC, CMD(h), CHMP  Coordination of safety anouncements  For nationally authorised products  Ensure consistent and coherent safety advice across Europe  Public hearings  In relation to referrals within the Urgent Union Procedure

27 Good Pharmacovigilance Practices (GVP)  GVP Modules – 1 st wave: FINAL June 2012  I PhV Systems and their Quality Systems  II PhV System Master File  V Risk Management Systems  VI Individual Case Safety Reports  VII Periodic Safety Update Reports  VIII Post-Authorisation Safety Studies  IX Signals

28 Good Pharmacovigilance Practices (GVP)  GVP Modules – 2 nd wave: Ongoing  III Audits Public Consultation until 21 September 2012  IV Inspections Public Consultation closed; time table for finalisation awaited  X Additional Monitoring Public Consultation closed; time table for finalisation awaited  XI Public Participation Drafting ongoing  XII Continuous phv, B/R evaluation, communication planning and decision-making for regulatory action Drafting ongoing  XV Safety Communication Consultation until 21 September 2012  XVI Risk Minimisation Measures Drafting ongoing  XIII Incident management (scope tbc)  XIV International collaboration (scope tbc)

29 Good Pharmacovigilance Practices (GVP)  GVP Considerations for product- and population-specific pharmacovigilance  Biological medicinal products incl. biosimilars  Vaccines (Review drafting ongoing)  Pregnancy  Children  Elderly

30 Commission Implementing Regulation (EU) No 520/2012  I. Pharmacovigilance System Master File  II. Minimum requirements for quality systems  III. Minimum requirements for Eudravigilance database, details on signal management  IV. Terminology, formats, standards  V. Individual Case Safety Reports  VI. Risk Management Plans  VII. Periodic Safety Update Reports  VIII. Post-Authorisation Safety Studies  IX. Final provisions

31 All is written in stone - almost!

32 Revision of legislation  Art. 23 of the Regulation concerning the list of medicinal products subject to additional monitoring  Medicinal products where a PASS is a condition for the MA  Medicinal products approved in exceptional circumstances and subject to specific obligations (art. 14 (7) and (8) REG, art. 22 DIR); MAH with stricter obligations to register / report suspected ADRs  Strengthened obligations for MAHs to inform regulatory authorities about causes underlying withdrawals of medicinal products, request for withdrawal of MA or decision on not to apply for renewal of a MA. MAH shall in particular declare if such actions are based on any of the grounds set out in art. 116 and 117(1) of Directive 2001/83  Art. 107i of the Directive, Urgent Union Procedure  …when urgent action is considered necessary… deleted; Except art. 107i(1), point e (new contraindication, reduction in recommended dose or a restriction to the indications)

Status om lovgivningen fra CMDh Sundhedsstyrelsens informations- og dialogmøde for industrien 11. september 2012 Joan Boye Sektionsleder Enhed for Markedsføringstilladelser og Lægemiddelregulering

34 Procedure/dossier/format relaterede overgangsordninger er publiceret af Kommissionen/EMA/CMDh : Kommissionen: Questions and answers on transitional arrangements concerning the entering into force of the new pharmacovigilance provisions in July 2012 ( EMA: Questions and answers on practical transitional measures for the implementation of the pharmacovigilance legislation ( p&mid=WC0b01ac05804fa031) p&mid=WC0b01ac05804fa031 CMDh: Questions and answers from CMDh: MRP/repeat use and variations a new RMP/update RMP (

CMDh’s hensigt Article 5-Recommendation for classification Publiceret ( :  Introduction or change of the Pharmacovigilance system Master file(PSMF) IA IN  Change in the QPPV, including contact details, and/or the location of the PSMF as part of the summary of the pharmacovigilance system for medicinal products for human useIA IN  Evt. Andre: sorte symbol, standardsætning underkastet supplerende overvågning 35

CMDh Best Practice Guides, 1 Publiceret udkast: CMDh Best Practice Guide on the processing of renewals in the MRP/DCP - draft revision 7 (April 2012) - LinkLink Afventer svar fra Kommissionen i hvilke situationer, er det nødvendigt at rejse PRAC (article 107i)? eller CHMP henvisning? f.eks. hvis ikke-renewal 36

CMDh Best Practice Guides, 2 Offentlig evalueringsrapport incl. resumé i lægmandssprog Resumé for generika:  Tager udgangspunkt i indlægssedlens anvisninger og sprogbrug  Overskrift som spørgsmål/afsnit med svaret Hvorledes virker X? Hvad er fordele/ulemper ved X? Samarbejde med EMA 37

CMDh Best Practice Guides, 3 CMDh juli 2012 mødet: Sammendrag af risikostyringsplanen(RMP) Engelsk version publiceres MRI Product Index’et 38

CMDh Best Practice Guides, 4 Ingen EU Single assessment for NAPs(nationalt godkendte lægemidler), foreløbig: CMDh Best practice Guide for transitional arrangements for PSUR worksharing (concerning the assessments of PSUR’s of Products for which an EU harmonised virtual birth date and related harmonised data lock point have been agreed) PSUR WS med P-RMS fortsætter for en tid! Publicering af resultatet/anbefaling af ændringer af PRS(generika opdatering) 39

Coordination Group for Mutual Recognition and Decentralised Procedures (human) (CMDh) Standard Operating Procedure Process for adopting CMDh position and timelines for implementation of Pharmacovigilance Risk Assessment Committee (PRAC) recommendations 30 dages proceduren i CMDh: Praktiske aflevering fra PRAC til CMDh Hvem er Leading CMDh Member States Uret starter ved førstkommende CMDh møde 40 CMDh Best Practice Guides, 5.1

CMDh Best Practice Guides, 5.2 A reference to the CMDh adopted positions on PRAC recommendations to be included in the monthly CMDh press release. The CMDh positions, together with the PRAC AR outlining the PRAC recommendation, to be published on the EU web-portal / EMA website on a monthly basis, with links / sign posts to the CMDh website and the various NCA websites Oversættelser, MAH –NCA? 41

CMDh Best Practice Guides, 5.3 Hvorledes:  Jf. Artikel 107g, stk.2: Når de medlemsstater, som er repræsenteret i koordinationsgruppen, til enighed om de foranstaltninger, der skal træffes, registrerer formanden, at der er enighed, og sender den fastlagte holdning til indehaveren af markedsføringstilladelsen og medlemsstaterne. 42

Procedural Advice on Referral Procedures for Safety Reasons(artikel 107 i)  Ikke en del af GVP-modulerne  Projektteams forslag til proces diskuteret i CMDh  NCA har haft mulighed for kommentering Afventer Kommissionen del af Notice to Applicants? 43

Andre tiltag med baggrund i PhV  Forslag til revideret ansøgningsskema er sendt til Kommissionen  EMAs WG on Quality Review of Documents (QRD), opdatering af templates følges (rev. templates er endnu ikke godkendt) 44

CMDh møde september 2012 Konklusion: Nok at tage fat på! Forhåbentlig hurtig afklaring samt publicering 45

CHMP’s opgaver fremover Overlæge Jens Heisterberg Sundhedsstyrelsen Medlem af CHMP Dialogmøde med industrien, 11. september 2012

Vandtætte skotter 47 PRAC = Pharmacovigilance Risk Assessment Committee CHMP Godkendelse Vedligeholdelse CHMP Verden efter 1. juli

Bliver skotterne helt vandtætte? 48

Den engelske udgave: Fresh pair of eyes 49

Ikke helt  Der bliver en adskillelse mellem det beslutningsorgan, som godkender lægemidler, og det, som efterfølgende vurderer safety- signaler  Adskillelsen vil i praksis kun være på komité- niveau og delvis på Rapporteur-niveau  De nationale lægemiddelmyndigheder vil formentlig anvende de samme eksperter  CHMP skal sanktionere PRAC-indstillingen  Men uenigheder bliver offentliggjort 50

Hvad skal CHMP så lave nu?  Godkendelser af nye lægemidler i den centrale procedure  Indikationsudvidelser  Videnskabelig rådgivning (Scientific Advice)  Videnskabelige og regulatoriske guidelines  Appelinstans (arbitration) ved uenigheder i ikke- centrale procedurer (MRP og DCP)  Safety-spørgsmål (men nu efter indstilling fra PRAC) 51

Hvad sker der med CHMP’s sammensætning?  Ingenting  Fortsat et medlem og en suppleant fra hvert EU- medlemsland samt Norge og Island  Op til fem co-optede medlemmer  Ingen repræsentanter fra patientorganisationer  Beslutninger tages ved fortsat simpelt flertal  Norge og Island tæller ikke med 52

Hvad er på tapetet i CHMP lige nu?  Få den nye pharmacovigilance-lovgivning til at fungere  Samarbejde med PRAC  Forbedre assessment-rapporter  Mere gennemskuelighed i vurderingen af benefit-risk  Kvalitet  Åbenhed  Anvendelighed for andre interessenter, fx HTA 53

Hvad er på tapetet i CHMP lige nu?  Mere fokus på gamle patienter  Mere effektiv udnyttelse af tilknyttede ekspertgrupper  SAGs  Ekstern konsultation  Bedre håndhævdelse af post authorisation measures  Bedre forståelse for GCP-funds betydning for vurderingen af benefit-risk  Etik i kliniske forsøg 54

FUMerne forsvinder  CHMP vil gerne kunne håndhævde, at firmaerne rent faktisk udfører de studier og andre aktiviteter, som de lover ved godkendelsen  Instrumenterne hertil er for nylig forbedret  Annex II  RMP  Firmaer, som ikke overholder Annex II- eller RMP-betingelserne, vil kunne straffes 55

56 Behov for flere studier eller data? Skal det være en forpligtelse i forbindelse med Conditional eller Exceptional Authorisation Er det en safety bekymring? Kritisk for benefit-risk? Ja Annex II Condition (+ RMP) + CHMP AR Er det vigtigt? Ja Nej RMP + CHMP AR Nævnes kun i CHMP AR (recommendations for development) Ja Nej

Tolkning af GCP-fund 57 GCP-inspektørerKliniske assessorer GCP-fund

GCP-fund og benefit-risk  Nogle fund kompromiterer safety, well-being and rights of participating subjects, fx  Manglende informeret samtykke  Forsinket indrapportering af SAE’er  Andre rejser spørgsmålstegn ved resultaterne af kliniske studier og gør det vanskeligt at vurdere benefit-risk, fx  Ufuldstændig blinding af forsøgsmedicin  Problemer med randomiseringen  Mangelfuld drug accountability  Fejl i data management 58

GCP-fund og benefit-risk  Begge sidsnævnte kategorier af fejl kan resultere i negativ CHMP-afgørelse  Men visse GCP-fund er mindre betydende og påvirker hverken forsøgspersonerne eller studiets validitet  Mere CHMP-fokus på analyse og kvantitering af GCP-funds betydning for B/R og den endelige godkendelse 59

60 Benefit Risk Effekt Convenience Effekt og sikkerhed i forhold til andre markedsførte produkter Tolerabilitet Sikkerhed Lægemiddel- interaktioner Hvor alvorlig er sygdommen? Særlige populationer Etik Men ellers indgår de samme komponenter i benefit-risk balancen som tidligere Pris

Besvarelse af spørgsmål fra LIF v. Lægemiddelinspektør Lisbeth Bregnhøj

Detaljer for lokation af PSMF og QPPV Sektion 1.8.1:  Notice to Applicants punkt :  Medlemsland hvor QPPV bor og udfører sine opgaver.  Kontaktdetaljer for QPPV.  En reference til PSMF location GVP Modul II: "The required location information for the PSMF is a physical office address of the marketing authorisation holder or a contracted third party". 62

Detaljer for lokation af PSMF og QPPV  Vi afventer Classification guideline vedrørende variationer (ultimo 2012?).  Det foreslåede detaljeniveau for informationer i dossieret er sandsynligvis ikke tilstrækkeligt.  Vedrørende QPPV detaljer i artikel 57 databasen: Der er en række oplysninger, som alle er obligatoriske, herunder navn, titel, gade, by, postnummer, land, telefonnummer og . 63