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1BeAPP pharma.be, Brussels Nov 23 12 Be (pharmaco)vigilant! Important changes in the PV-legislation 23-11-2012.

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Presentation on theme: "1BeAPP pharma.be, Brussels Nov 23 12 Be (pharmaco)vigilant! Important changes in the PV-legislation 23-11-2012."— Presentation transcript:

1 1BeAPP pharma.be, Brussels Nov Be (pharmaco)vigilant! Important changes in the PV-legislation

2 Does a safe environment guaranty safety? M.Sangeleer, MD Medical Affairs Manager, Eli Lilly Benelux Lecturer at the Free University of Brussels (ULB) 2 The Pharmacovigilance legislation after 2012 BeAPP pharma.be, Brussels Nov 23 12

3 09/12/10: BeAPP Cultural event: BeAPP pharma.be, Brussels Nov Does a safe environment guaranty safety? Johan Braeckman: « Evolutionism & creationism »

4 BeAPP pharma.be, Brussels Nov There is always variation 2.There are more organisms that are born that the amount which can survive (struggle for life) 3.The one who survive are the fitests 4.There is natural + sexual selection 5.The process is repetitive from generation to generation (positive feed-back) 6.At the end, adaptations arise Does a safe environment guaranty safety?

5 Pharmacovigilance evolution 5 Computerised system Internationalisation Proactive approach EU reg 1235:risk based regulation Thalidomide Collection of AR Signal detection Worldwide databases MAH Collaboration between states (WHO,…) Risk Management systems/plans Embryo of EU worksharing Ad hoc surveillance& risk management plans Involvement of all staleholders Improvement collaboration BeAPP pharma.be, Brussels Nov 23 12

6 Objectives and Key measures of the new PV law 1.Reinforcement and modernisation of current system (more rapid decisions): Additional Monitoring - signal detection Pro-active Risk Management Plan for all products = CONDITION for registration Harmonisation of decisions and work sharing: reduction of redundancy Harmonisation of post –marketing, non- interventional studies for safety and efficacy (PAES/PASS) Reinforce the link between safety evaluations and regulatory actions 2.Reinforcement of patient protection &engagement - increase the communication and transparency Direct reporting to the Agencies (web portals) Information Available on the webportal of Agencies 3.Introduction of impact of drugs on the environment 6 BeAPP pharma.be, Brussels Nov 23 12

7 More actors ICH CIOMS ECNCAs EMAHCPs MAHs 7 BeAPP pharma.be, Brussels Nov Quality? (faster, better, perceived severity, final outcomes, impact on QOL, motivation?)- Role of Advocacy groups Patients: Awareness and engagement – reporting, acting on information

8 8 Adverse event reporting Expedited reporting of ICSR Periodic reporting Labels updates (4.8) Proactive surveillance Risk management plan Risk assessment Risk minimisation plan Risk minimisation activities Studies: PASS- PAES Labels updates (4.4) MAH operational pharmacovigilance tasks BeAPP pharmabe, Brussels Nov 23 12

9 «OLD» LEGISLATION«NEW» LEGISLATION Patient reporting: no legal basis Electronic reporting:no legal basis Definition of ADR: « under normal conditions » SERIOUS ADRs to EV- 15 days Patient reporting: legal basis Electronic reporting legal basis Definition of ADR: also in case of off label use, misuse,… SERIOUS ADRs to EV- 15 days NON SERIOUS ADRs to EV: 90 days No expectedness Legislation main changes for the MAH AE expedited reporting 9 BeAPP pharma.be, Brussels Nov 23 12

10 Consequences for MAH Volume o Electronic transmission (E2B)- o signal detection o Different timelines Identification and « medical validation » of patient reports o Assessing causality? o Perform follow-up with patients? o What about precription medicines? Effect on treating HCP, if more administration is required? Duplicate reports? 10 Which AE? Resources, Training, adaptations of rules and procedures BeAPP pharma.be, Brussels Nov Which AE?

11 11 Adverse event reporting Expedited reporting of ICSR Periodic reporting Labels updates (4.8) Proactive surveillance Risk management plan Risk assessment Risk minimisation plan Risk minimisation activities Studies: PASS- PAES Labels updates (4.4) MAH operational pharmacovigilance tasks BeAPP pharmabe, Brussels Nov 23 12

12 «OLD» LEGISLATION«NEW» LEGISLATION PSUR PSURs for all MAs PSUR Worksharing on voluntary basis NO central filing Periodic Benefit Risk Evaluation Report submission +cycle in function of risks Worksharing: legal basis Central repository Legislation main changes for the MAH Periodic reporting 12BeAPP pharma.be, Brussels Nov 23 12

13 MORE EXPLICIT EVALUATIONS OF B/R 13 Ad hoc periodicity according to risk close link with RMP Scientific evaluation > data Tabulations> line listings Cumulative data starting +new information of this period Summaries of studies incl in unauthorised indications Extensive chapters on signal detection; benefit/risk evaluation Therefore, MAH is granted 10 extra days for 6 or 12 monthly reports after the datalock point 30 days for reports of a longer frequency after the datalock point On the grounds: more pragmatic approach BeAPP pharma.be, Brussels Nov 23 12

14 PSUR-PBRER: worksharing & simplifications Unique List of Union Reference Dates & frequencies: EURD list Single assessment (variation, suspension, revocation all over EU) Repository for submission of PSURs (Common European Submission Platform) No PSUR anymore for generics and « well established use » medications 14 Less work thanks to worksharing? BeAPP pharma.be, Brussels Nov On the format

15 15 Adverse event reporting Expedited reporting of ICSR Periodic reporting Labels updates (4.8) Proactive surveillance Risk management plan Risk assessment Risk minimisation plan Risk minimisation activities Studies: PASS- PAES Labels updates (4.4) MAH operational pharmacovigilance tasks BeAPP pharmabe, Brussels Nov 23 12

16 «OLD» LEGISLATION«NEW» LEGISLATION Eudrapharm not used- few transparency Transparency: SPC,PIL to be published EudraPharm (EVPMD) to be populated and up to date SPC,PIL and summary of SPC (lay public) +PAR (summary for the public, condition of MA) Legislation main changes Transparency 16 BeAPP pharma.be, Brussels Nov 23 12

17 Scope and timelines Timelines broken down into steps: July 2, 2012 : MAH submit information on ALL medicinal products in EVPDM 2 July 2012 :variations/suspensions/revocations within 15 calendar days >1 Jan 2015 :MAH can submit using the new standard (IDMP ) >31 Dec 2015:All product information must be resubmitted according to ID MP. 17BeAPP pharma.be, Brussels Nov ISO IDMP standards, a set of internationally harmonised specifications for the unique identification of medicines

18 Consequences for MAH 18 Resources to hold timelines Questions from patients? Volume of events ? Risk of induced effects? They state reading the label might harm the eyes BeAPP pharma.be, Brussels Nov 23 12

19 19 Adverse event reporting Expedited reporting of ICSR Periodic reporting Labels updates (4.8) Proactive surveillance Risk management plan Risk assessment Risk minimisation plan Risk minimisation activities Studies: PASS- PAES Labels updates (4.4) MAH operational pharmacovigilance tasks BeAPP pharmabe, Brussels Nov 23 12

20 «OLD» LEGISLATION«NEW» LEGISLATION RMP if required RMP not evaluated PASS/PAES: no legal basis Additional monitoring: no legal basis RMP for all applications (proportionate to risks) Legal basis for evaluation of the RMP-RMAactivities PASS/PAES legal basis Additional monitoring: legal basis Legislation main changes for the MAH: Proactive PV 20 BeAPP pharma.be, Brussels Nov 23 12

21 Consequences of RMP provisions Public summary on the European Web Portal – Readibility for lay reader – Linked with list of products with additional monitoring Art 23 regulation cost + burden for HCP BeAPP pharma.be, Brussels Nov Compulsory assessement of impact: studies, surveys,... MEDIA ATTENTION

22 Media consequences Media trained Resources –Crisis and communication management BeAPP pharma.be, Brussels Nov

23 RMP in Belgium: Introduction of timelines….. PAES-PASS: – Written approval/denial given by belgian authorities/PRAC after 60 days – MAH has 30 days to express its wish to react to PASS/PAES requirement – Need to report on the progress reports ( timing to be agreed) Risk minimisation activities local approval process: 2 months if no Medicines Commission 4 months if Medicines Commission and external expert Clock stops and timelines for MAH too 23 Enough staff needed : reactivity BeAPP pharma.be, Brussels Nov 23 12

24 «OLD» LEGISLATION«NEW» LEGISLATION Detailled Description Pharmacovigilance System Renewal submission 6 month before expiration of validity Signal detection: no legal basis POST MA inspections Free of charges Pharmacovigilance system master file Renewal submission 9 month before expiration of validity Signal detection: legal basis (at least once monthly) PRE and POST MA inspections and more focus on sharing information between CA Fees to be payed at EU and natonial level Legislation main changes for the MAH : Organisation 24BeAPP pharma.be, Brussels Nov 23 12

25 Contributions in Belgium?? Funding for PV resources/staffing at the AFMPS/FAGG: – 58/registration-All products – 0,0118/sold pack / National-MRP products – 650/DSUR for IMPs 25 BeAPP pharma.be, Brussels Nov program law published 06/04/12 (entry into force 17/04/12) Circulars RD 16 jul 2012 on DSURs payments: (effective 18 oct 12)

26 Conclusions: Does a safe environnement guaranty safety? Maximising benefit, minimising risk of medicines, so focus on benefit/risk More pragmatic, risk-based approach Focus on transparency Volume of events – balanced by more efficient signal detection- duplicates? Effect of increased patients/media interactions ? New formats & cycles Processes & workload: will increase at first Simplification/harmonisation: reduce duplicate work at long term Timelines: more dynamic system reactivity will be needed (on demand PASS, PBRER, RMAs) Fees?: will they put staffing at risk? (SME) 26BeAPP pharma.be, Brussels Nov 23 12

27 27 Basic principle remains unchanged Does a safe environment guaranty safety? ….There is always variation… It is still no rocket science:… There is a human factor

28 Conditions for a safer PV?: Awareness & education of all stakeholders including patients, patients associations and HCP- (manage duplicates) Resources to hold timelines at both MAH/NCA/…PRAC? Sufficient skilled users of signal detection tools Multidisciplinary teams (RMPs) Learn to cope with media 28BeAPP pharma.be, Brussels Nov Learn to cope with « variation »= Mitigating the « Human Factor »

29 29BeAPP pharma.be, Brussels Nov Does a safe environment guaranty safety? Maybe we shouldnt disturb the medical community for such a minor manifestation? Probably,… a fitest pharmacovigilance,…..adapted to the variation

30 Does a safe legal environment guaranty safety? An industry perspective. Impact on SMEs Bart De Greef, pharma.be Katleen Vandeweyer, Biocodex Benelux

31 Stability pact 313/06/2014

32 Stability pact 32

33 Major challenges for SMEs SMEs oriented towards Rx, OTC medicines, MD, food, cosmetics…. – Less complaints – We take our responsibility! Requirements on – Update EUDRAPharm: (European medicines database) Submitting product data =>mandatory from 2 July 2012 EXtended EudraVigilance Medicinal Product Dictionary (XEVMPD) specific tool for SME foreseen in EVWEB – PSMF (audits/inspections, patients support programs, subcontracts,…) – RMP-RMA-PASS/PAES – Patients/public management=>who will manage media reactions? 33

34 IMPACT FOR SMEs Guidance from NCAs - has there been enough and oriented for SMEs? Complying with the Electronic transmission As an SME, I cannot afford to spend tens of thousands of Euro on a PV database and a gateway: – EVWeb: one off-training course, free tool – Contract it out: Stakeholder roles and responsibilities =>importance of well defined contract (detailed description of delegated tasks, data exchange, agreed timelines, definitions,…) MAH retains full responsibility MAH need to ensure an effective quality system =>Evaluate risk/benefit Impact on competitiveness and business profit 34

35 Costs for a SME? Workload…will it be reduced or augmented? Software tools and technology costs? – MEdDRA terms is free to use in EVWEB for Small & micro-sized but not for medium sized Human Resources and training needs – what impact will these have on SME business? Insourcing vs. outsourcing? Fees: EU vs Belgium as NCA Special fee for inspections ? 35

36

37 Agence fédérale des médicaments et des produits de santé Before and after 1235: legislation review Pharma.be/BEAPP Thierry ROISIN – 23/11/2012

38 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Plan New legal framework as regards pharmacovigilance of medicinal products for human use GVPs Legislation : main changes PRAC Union-wide assessment of phvig issues Strengthened transparency and communication Impact for SME

39 Pharma.be afmps/DG Post/Division Vigilance 23/11/ New legal framework as regards pharmacovigilance of medicinal products for human use Regulation (EU) No 1235/2010 of the European Parliament and of the Council of 15 December 2010 amending, as regards Pharmacovigilance of medicinal products for human use, Regulation (EC) No 726/2004 laying down Community procedures for the authorisation and supervision of medicinal products for human and veterinary use and establishing a European Medicines Agency, and Regulation (EC) No 1394/2007 on advanced therapy medicinal products (specific provisions on centrally authorised products and EMA tasks) Directive 2010/84/EU of the European Parliament and of the Council of 15 December 2010 amending, as regards pharmacovigilance, Directive 2001/83/EC on the Community code relating to medicinal products for human use (nationally authorised products and common provisions) Adopted by both Council and EU parliament and publication on 31 Dec 2010 Most of the provisions came into force in July 2012

40 Pharma.be afmps/DG Post/Division Vigilance 23/11/ GVPs

41 Pharma.be afmps/DG Post/Division Vigilance 23/11/ GVPs

42 Pharma.be afmps/DG Post/Division Vigilance 23/11/ GVPs

43 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Legislation : main changes «OLD» LEGISLATION«NEW» LEGISLATION DDPS RMP if required Definition of ADR: under normal conditions SERIOUS ADRs to EV Patient reporting: no legal basis PSURs for all MAs PSUR WS on voluntary basis Pharmacovigilance system master file RMP for all applications (proportionate to risks) Definition of ADR: also in case of off label use, misuse,… SERIOUS and NON SERIOUS ADRs to EV Patient reporting: legal basis PSURs submission in function of risks PSUR WS: legal basis

44 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Legislation : main changes «OLD» LEGISLATION«NEW» LEGISLATION Renewal submission 6 month before expiration of validity Signal detection: no legal basis PASS: no legal basis PAES: no legal basis Additional monitoring: no legal basis PhVWP Renewal submission 9 month before expiration of validity Signal detection: legal basis PASS: legal basis PAES: legal basis Additional monitoring: legal basis PRAC New urgent union procedure More transparency …

45 Pharma.be afmps/DG Post/Division Vigilance 23/11/ PRAC New scientific committee within the Agency Pharmacovigilance Risk Assessment Committee - Reg art. 56(1)(aa) Mandate – Reg. art. 61a §6 All the aspects of the risk management of medicines … having due regard to the therapeutic effect of the medicinal product …: Recommendations to CHMP and CMD(h) on Phvig issues Role in agreement and monitoring of RMPs Prioritisation and review of emerging safety signals Review of PSUR assessments Evaluation of protocols and results of PASS Decision on products under additional monitoring …

46 Pharma.be afmps/DG Post/Division Vigilance 23/11/ PRAC - composition Appointed by each Member State: Appointed by the European Commission following a public call for expressions of interest: 1 member + alternate 27 + EEA countries non voting members 1 patient organisations rep + alternate 1 healthcare professionals rep + alternate 6 members to ensure relevant expertise available

47 Pharma.be afmps/DG Post/Division Vigilance 23/11/ PRAC – activities

48 Pharma.be afmps/DG Post/Division Vigilance 23/11/ PRAC – activities

49 Pharma.be afmps/DG Post/Division Vigilance 23/11/ PRAC Interaction with CHMP and CMD(h) PRAC provides recommendations to CHMP and CMD(h) – Reg. art. 56(1)(aa) CHMP / CMD(h) shall rely on the scientific assessment and recommendations of PRAC for the fulfilment of its phvig tasks, including the approval of risk management systems and monitoring their effectiveness – Reg. art. 5(2) / Dir. art. 27 Explanation on the scientific grounds for differences if opinion / agreement is not in accordance with PRAC recommendation

50 Pharma.be afmps/DG Post/Division Vigilance 23/11/ PRAC Decision-making process PSUR PASS Union procedures (art. 31, 107i) PRAC recommendation: regulatory action CMD(h) (no CAP) CHMP (at least 1 CAP) Position = maint., var., susp., revoc. Opinion = maint., var., susp., revoc. If consensus: agreement NO consensus: position majority COMMISSION Decision modifying MA (CAP) Decision addressed to MS MS: adopt measures MAH: submit variation

51 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Union-wide assessment of phvig issues Two procedures for Union-wide post- authorisation assessment of PhVig issues Dir. art. 107i-l = urgent union procedure ( revision current art. 107 ) Dir. art. 31 in other cases Dir. art. 36 deleted PRAC should always give its recommendation when the reason for taking action is based on PhVig data (regardless of whether centralised or non centralised procedures, urgent or normal procedure) – Dir. Cons (25a) Procedures laid down in Directive 2001/83/EC to be followed, also for centrally authorised products – Reg. cons. (9a)

52 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Union-wide assessment of phvig issues Urgent Union Procedure Triggers - Dir. art. 107i Urgent action necessary, as a result of the evaluation of phvig data. MS / Commission: considers suspending or revoking a MA; considers prohibiting the supply of a medicinal product; considers refusing the renewal of a MA; is informed by the MAH that, on the basis of safety concerns, he has interrupted the placing on the market of a medicinal product or withdrawn a MA, or that he intends to do so; considers that new contraindications, a reduction in the recommended dose, or a restriction to the indications is necessary;

53 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Strengthened transparency and communication European and national (safety) web portals National medicines web-portal – Dir. art. 106 : summaries of RMP (national MA) list of medicinal products referred to in Article 23 of Reg. information on the different ways for reporting suspected ADRs, including the web-based structured forms (Reg. art. 25).. European medicines web-portal – Reg. art. 26 : agendas and minutes from each meeting of the CHMP and PRAC and the CMD(h) as regards phvig activities summary of the RMP (CEP authorised products) Assessment conclusions, recommendations, opinions, agreements and decisions (for PSURs, urgent union procedure, PASS) taken by CHMP, PRAC, Commission, NCA and CMD(h) …

54 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Strengthened transparency and communication

55 Pharma.be afmps/DG Post/Division Vigilance 23/11/ all the provisions of the phv legal framework (obligations for MAHs) are also applicable for SME Consequently, each MA must have a pharmacovigilance system possibility to subcontract certain activities to another organisation or person (cfr I.C.1.5. module I GVP) Impact for SME

56 Pharma.be afmps/DG Post/Division Vigilance 23/11/ In case of subcontract, the MA retains full responsibility for the completeness and accuracy of the PSMF The ultimate responsibility for the fulfilment of all phv tasks and responsibilities and the quality and integrity of the phv system always remains with the MAH The MAH shall ensure that an effective quality system is applied in relation to the subcontracted tasks Impact for SME

57 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Thank You

58 Pharma.be afmps/DG Post/Division Vigilance 23/11/ Agence fédérale des médicaments et des produits de santé - afmps Place Victor Horta 40/ Bruxelles tél fax Contact

59 Vos médicaments et produits de santé, notre préoccupation

60 Federal agency for medicines and health products New pharmacovigilance legislation: How to smoothen the transition period? EU and Belgian bridging measures Goethals Sophie, famhp, vigilance department 23 November 2012

61 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November In this presentation … 1.What has been achieved? What to come? How to smoothen the transition period? EU level Belgium 2.Specific topics where smooth implementation is necessary Additional monitoring and implementation of and standardised statements in SmPC and leaflet Post-authorisation safety studies

62 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Background 2010 Legislation: key achievements / challenges Clear tasks and responsibilities for all parties Improved EU decision-making procedures Proactive and proportionate risk management Higher quality of safety data Stronger link between safety assessments and regulatory action Strengthened transparency, communication and patient involvement

63 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Dir. 2001/83 amended by Dir. 2010/84 Reg. N° 726/2004 amended by Reg. 1235/2010 EC implementing regulation (EU) No 520/2012 Good pharmacoVigilance Practice: 1. PhV + QS, 2. PSMF, 5. RMS, 6. ICSR, 7. PSUR, 8. PASS, 9. Signals Q&A documents, EURD list, list for signal management worksharing, templates, guidance documents on renewals Implement in business processes: new procedure for requesting and assessing RMP, new procedures related to PSURs / PASS for CAPs, signal detection, new referral procedure, … ICT: art. 57 electronic submission of product information What has been achieved? What to come? How to smoothen the transition period? EU level 1. What has been achieved?

64 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Dir. 2001/83 amended by Dir. 2012/26 Reg. N° 726/2004 amended by Reg. N° 1027/ Fees Regulation 2. Delegated act on efficacy studies (may provision) 3. EC Reports on readability of product information 1. GVP: 2 nd wave modules 2. Scientific guidance for PAES Update Q&A documents, EURD list, list for signal management worksharing, templates, Phvig training, Implement in business processes: EMA literature monitoring, PSUR single assessment, programme for monitoring of effectiveness RMM ICT: validation of received art. 57 information, PSUR repository, EudraVigilance enhancement,.. What has been achieved? What to come? How to smoothen the transition period? EU level 2. What to come? Oct ? Jan 2013 Beyond 2013 June 2013

65 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November What has been achieved? What to come? How to smoothen the transition period? EU level 2. What to come? GVP second wave modules Module III – InspectionsPublication Dec 2012 Module IV – Pharmacovigilance AuditsPublication Dec 2012 Module XV - Safety communicationPublication Dec 2012 Module X - Additional monitoringPublication Q1/Q Module XI - Public participationPublic consultation Q Module XII - Continuous pharmacovigilancePublic consultation Q Module XIII - Incident managementUnder discussion Module XIV - International collaborationPublic consultation Q Module XVI - Risk minimisation measuresPublic consultation Dec 2012 / Q1 2013

66 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November What has been achieved? What to come? How to smoothen the transition period? EU level 2. What to come? The 2012 legislation: Pharmacovigilance II Background: Stress test of the 2010 legislation detected certain areas where legislation could be further strengthened 25 October 2012 new amending legislation adopted: – Directive 2012/26/EU of 25 October 2012 amending Directive 2001/83/EC as regards pharmacovigilance; Applicable from 28 October 2013 – Regulation No 1027/2012 of 25 October 2012 amending Regulation No 726/2004 as regards pharmacovigilance; Applicable from 4 Dec 2012 / 5 Jun 2013 Filling gaps: – Clarification of scope of referral procedures and events that will lead to the initiation of the procedures (especially Urgent Union procedure) – Modified Union interest procedure will allow Member States to take provisional measures – Voluntary withdrawal – MAH to state reasons – Increased transparency: List of products subject to additional monitoring

67 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November What has been achieved? What to come? How to smoothen the transition period? EU level 3. How to smoothen the transition period? ECs Q&A on transitional arrangements ance/2012_02_qa_phv.pdf EMA/ NCA Q&A on practical transitional measures – November updated awaited ment_library/Regulatory_and_procedural_guid eline/2012/05/WC pdf CMDh Q&A List of nationally approved substances for which PSURs are required for generic medicinal products during the transitional period Reporting requirements of ICSRs applicable to MAHs during the interim period ment_library/Regulatory_and_procedural_guid eline/2012/05/WC pdf NCAs requirements for PSUR submission during the transitional period ment_library/Regulatory_and_procedural_guid eline/2012/05/WC pdf To come: Q&A on EURD list?

68 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November What has been achieved? What to come? How to smoothen the transition period? Belgium 1. Achievements : programmawet van 29 maart 2012: herziening retributies wet dd. 3 augustus 2012 tot wijziging van de wet van 25 maart 1964 op de geneesmiddelen, gepubliceerd op 11 september 2012 in Belgisch Staatsblad Safety board, patient reporting,.. 2. Expected soon: ontwerp KB tot wijziging KB 14 dec > advies Raad van State circulaire -> consultatie met industrie 20 nov Transition period: MAHs can apply European new legislation, guidelines, transitional measures, although new directive has not been fully transposed into national law [http://www.fagg-afmps.be/nl/geneesmiddelenbewaking/] a combination of old and new legislation shall not be accepted.

69 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November What has been achieved? What to come? How to smoothen the transition period? Belgium Patient reporting in Belgium

70 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November What has been achieved? What to come? How to smoothen the transition period? Belgium Patient reporting in EU

71 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 1. Background [Reg 726/2004 whereas clause 17] … some medicinal products are authorised subject to additional monitoring. This includes all medicinal products with a new active substance and biological medicinal products, including biosimilars, which are priorities for pharmacovigilance. Competent authorities may also require additional monitoring for specific medicinal products that are subject to the obligation to conduct a post-authorisation safety study or to conditions or restrictions with regard to the safe and effective use of the medicinal product. Medicinal products subject to additional monitoring should be identified as such by a black symbol and an appropriate standardised explanatory sentence in the summary of product characteristics and in the package leaflet. A publicly available list of medicinal products subject to additional monitoring should be kept up to date by the European Medicines Agency ……

72 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 1. Background Mandatory scope [Article 23 (1) of the Regulation] Two categories of medicinal products shall be automatically included in the list : a) Medicinal products authorised in the Union that contain a new active substance which, on 1 January 2011, was not contained in any medicinal product authorised in the Union; b) Any biological medicinal product not covered by point (a) that was authorised after 1 January New regulation 1027/2012 amending Reg. 726/2004: extends mandatory scope products subject to specific conditions will be included under mandatory scope cfr. red text on next slide

73 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 1. Background Optional scope [Article 23 (2) of the Regulation] There is also the possibility to include in the list medicinal products subject to conditions, not falling under the mandatory scope. This can be done at the request of the EC or the NCA, as appropriate, following consultation with the PRAC. conditions or restrictions with regard to the safe and effective use [Reg Art 9(4)(c), Dir Art 21a(d)]; to take certain measures for ensuring the safe use of the medicinal product to be included in the risk management system [Reg Art 9(4)(ca), Dir Art 21a(a)]; to conduct post-authorisation safety studies (PASS) / post-authorisation efficacy study (PAES) [Reg Art 9(4)(cb) (cc) and Art 10(a), Dir Art 21a(b)(f) and Art 22a]; stricter reporting of ADRs [Reg Art 9(4)(cb), Dir Art 21a(c)]; conditional approval, i.e. authorisation is granted subject to certain specific obligations (e.g. the performance of further studies), to be reviewed annually by EMA [Reg Art 14(7)]; marketing authorisation under exceptional circumstances [REG Art 14(8), DIR Art 22]; the existence of an adequate pharmacovigilance system [DIR Art 21a(e)]. when a competent authority imposes an obligation on a marketing authorisation holder to operate a risk management system for a medicinal product approved before 2 July 2012 [REG Art 21(2)] or 21 July 2012 [DIR Art 104a].

74 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 2. Creating and maintaining the list of product under additional monitoring EMA and NCAs will be responsible for (automatic) inclusion of substances on the list products will normally remain on the list for 5 years – for mandatory scope products removal will be tied to the renewal procedure – for optional scope products removal will be tied to fulfillment of conditions List to be published on EMA + NCA web portals: Q1 2013? publication of list to be aligned with ECs selection of black symbol (2 July 2013) ? Will MAHs know in advance of publication of their products? ? Will national schemes co-exist?

75 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 3. Implementation of and standardised statements in SmPC and leaflet The SmPC and the package leaflet shall include the statement This medicinal product is subject to additional monitoring. That statement shall be preceded by a black symbol which shall be selected by the Commission following a recommendation of the PRAC by 2 July 2013* [Reg. 2012/xx to be published], and shall be followed by an appropriate standardised explanatory sentence [Art. 11 and 59 of Directive 2001/83/EC and Art. 23(5) of Regulation (EC) No 726/2004]. a.Selection of black symbol: PRAC recommendation (Oct 2012): inverted black triangle ( ) Commission Decision (before 2 July 2013): Q ? EC public consultation on phasing-in launched 21 Nov till 10 Jan 2013 [http://ec.europa.eu/health/files/pharmacovigilance/2012_11_09_pb__black.pdf] b.Standardised statements for SmPC and leaflet: CHMP endorsement of the QRD template / translation /.. Implementation plan Publication by March / April 2013 (once black symbol is selected by EC)

76 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 4.Wording of standardised statements for additional monitoring SmPC Package Leaflet

77 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Additional monitoring and implementation of and standardised statements in SmPC and leaflet 5.Wording of standardised statements - encouragement ADR reporting for all medicinal products SmPC (end of section 4.8) Package Leaflet (end of section 4.)

78 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Non-interventional post-authorisation safety studies (PASS) 1.Scope of dir. 2001/83, chapter 4 supervision of PASS a post-authorisation study should be classified as a PASS, when the study includes one of the following objectives [GVP, VIII.B.3]: to quantify potential or identified risks to evaluate risks of a medicinal product used in patient populations for which safety information is limited or missing (eg pregnant women, specific age groups, patients with renal or hepatic impairment) to provide evidence about the absence of a risk to assess patterns of drug utilisation that add knowledge on the safety of the medicinal product (eg indications, dosage, co-medication, medication errors) to measure the effectiveness of a risk minimisation activity. PASS initiated, managed or financed by a MAH n on-interventional If a PASS is a clinical trial: dir. 2001/20/EC and Vol. 10 of Eudralex shall be followed

79 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November … voluntarily or pursuant to obligations non-interventional PASS; initiated, managed or financed by MAH applicable legislation Pursuant to an obligation imposed by a competent authority: condition to the MA [Dir. art. 21a and art. 22a / Reg. art. 10 and art. 10a] exceptional circumstances MA [Dir. Art. 22 / Reg. art. 14, §8] Dir. 2001/83 art. 107 m: cfr. infra Dir. 2001/83 art. 107 n-q: regulatory supervision by competent authority (protocol and final study report) Implementing Reg. 520/2012, art format of protocol, abstract and final study report Voluntarily: studies required in RMP any other PASS Dir. 2001/83 art. 107 m: no promotional character, payments to HCP restricted to compensation of time and expenses incurred protocol and progress reports: may be requested by MS in which the study is conducted final report to MS where study conducted, monitor data and impact on BR GVP: legal requirements applicable to studies conducted pursuant to obligation are recommended, where appropriate, to studies conducted voluntarily [GPV, VIII.B.1] Non-interventional post-authorisation safety studies (PASS)

80 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Management of study (PASS with MAH involvement ) Imposed as an obligationConducted voluntarily no promotional character payment to HCP restricted … [Dir. Art. 107m] Legal obligation Monitor data generated in the study with consideration to benefit-risk of product concerned [Dir. Art. 107m] Legal obligation Use of standard formats for protocol and study report [Reg. 520/2012] Template for protocol [http://www.ema.europa.eu/docs/en_GB/ document_library/Other/2012/10/WC pdf] Legal obligation (10 Jan 2013)GVP recommendation Prior protocol approval [Dir. Art. 107n-q] regulatory supervision and assessment of study results [Dir. Art. 107n-q] Legal obligation: PRAC supervision National supervision for PASS imposed after authorisation by 1 MS, and conducted only in that MS (if in RMP) Registration in EU PAS registerLegal obligationGVP recommendation Quality systemLegal obligationGVP recommendation Non-interventional post-authorisation safety studies (PASS)

81 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Reporting of study information (PASS with MAH involvement ) Imposed as an obligation Conducted voluntarily Any new information which might influence the evaluation of B/R balance to be reported to NCAs of MS where the product is authorised [Dir. Art. 107m] Legal obligation Protocol to be submitted upon request to NCA of MS where study is conducted [Dir. Art. 107m + art. 107 n (3)] Legal obligationcfr. Annex to GVP module VIII Progress reports to be submitted upon request to NCA of MS where study is conducted [Dir. Art. 107m] cfr. Annex to GVP module VIII Final report to be sent to the NCA of the MS where the study is conducted, within 12 months of the end of data collection [Dir. Art. 107m] Legal obligation Reporting of suspected ADRs in studies with primary data collection with 15 days (serious ADRs) or 90 days (non- serious ADRs) [See interim and final arrangements in GVP Module VI, C.4 ] Legal obligation Final manuscript of article to be transmitted to NCAs of MS where product is authorised within 15 days after acceptance [GVP] recommended Non-interventional post-authorisation safety studies (PASS)

82 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Annex to GVP module VIII: MS' requirements for transmission of information on non-interventional PASS with PRAC oversight Belgium: famhp, vigilance department, Non-interventional post-authorisation safety studies (PASS)

83 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Annex to GVP module VIII –Member States' requirements for transmission of information on non-interventional PASS, conducted voluntarily Non-interventional post-authorisation safety studies (PASS)

84 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November famhp requirements for transmission of information on non- interventional PASS with famhp oversight Protocol (CD-rom), progress reports and final study report incl. abstract to be submitted to famhp, R&D Non-interventional post-authorisation safety studies (PASS)

85 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November EU PAS Register EU electronic register of post-authorisation studies [GVP, VIII.B.4] repository of all non-interventional PAS conducted in the EU, irrespective of the source of funding and status of investigators (MAH, academia, regulatory or public health authorities, …) will be developed as upgrade of ENCePP study registry transitional period: ENCePP study registry to be used supports EMA to fulfil its obligation to make public protocols and results of PASS imposed as an obligation [Reg. art. 26 (h)] For imposed studies: will not replace regulatory submission For studies conducted voluntarily: accepted by MS (and Belgium) as means for submitting study information (Annex 1 of GVP Module VIII) Non-interventional post-authorisation safety studies (PASS)

86 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November EU PAS Register Non-interventional post-authorisation safety studies (PASS)

87 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November ICSR reporting requirements for MAH during interim period 1.Serious EU ICSRs [http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_procedural_guideline/2012/05/WC pdf]

88 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November ICSR reporting requirements for MAH during interim period 2.Serious non-EU ICSRs and non-serious EU ICSRs

89 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November ICSR reporting requirements for MAH during interim period 2.Serious non-EU ICSRs and non-serious EU ICSRs

90 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November PSURs: List of Union reference dates and PSUR frequency Comprehensive list of active substances and combinations of active substances, authorised in more than one member state, for which PSURs shall be submitted as determined Harmonisation of DLPs and frequency of submission of PSUR for products subject to different marketing authorisations –> enable single assessment based on substances EURD list used to control PSUR submission for generics; grounds for requesting PSURs for generics: concerns based on phvig data / lack of data Agreed by the CHMP/CMDh after consultation of the PRAC [DIR Article 107c (paragraphs 4 and 7), and REG Article 26(g)] Publication on EMA website on 1 October 2012: d5c1 Legally binding as of April 2013 [DIR Article 107c (7)]. Until then, follow currently agreed PSUR submission frequency and DLP. The list overrules the routine submission schedule and any condition laid down in the MA of the products concerned.

91 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November PSURs: List of Union reference dates and PSUR frequency

92 15/05/2012 FAMHP/Vigilance/gss92 PSURs: overview Old legislationNew legislationTransitional provisions? Situation since July 2012 PSUR requirement: for all MAs Derogation: no routine PSUR for generics, WEU, THMP, homeopathic registration Noderogation for routine PSURs applicable PSUR frequency: routine PSUR cycle for most MAs 1) Risk based PSUR cycle, through comprehensive URD List 2) Condition to MA 3) Routine PSUR cycle No 1) List URD legally binding 6 months after publication (publication Oct > April 2013) 2) July ) July 2012 Timelines for submission : Within 60 days > DLP Within 70 or 90 days > DLP (GVP) NoIrrespective of old / new PSUR format: 70 or 90 days > DLP PSUR submission: to MS / EMA (centralised) [Annex 6.2 of Vol. 9 A] E-submission to EMA PSUR repository From 12 months after repository is operational PSUR submission to MS / EMA (centralised)

93 15/05/2012 FAMHP/Vigilance/gss93 PSUR: overview Old legislationNew legislationTransitional provisions? Situation since July 2012 Assessment: centralised procedure informal PSUR work sharing MRP Purely national procedures Clear legal basis for: Assessment of single centrally authorised medicinal product Single EU assessment Purely national procedure No Assessment of centralised products following new procedure (PRAC) Informal PSUR work sharing Mutual Recognition Procedures Purely national procedures Content: Focus on presentation of safety data Structured risk evaluation Benefit evaluation Integrated benefit risk evaluation module Transitional period of 6 months in Implementing Measures - draft Between July 2012 and January 2013 old and new formats will co-exist

94 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November PRAC phasing-in For complete new MAAs for CAPs starting as of December 2012: – 1 Status-quo with current situation – 2 X = open to all PRAC delegates, the selection criteria being the best possible scientific expertise and, where possible, from a different MS compared to the CHMP Rapporteur (A) and CHMP Co-Rapporteur (B) For new MAAs for CAPs under CHMP review or procedures starting in Aug / Sept / Oct / Nov 2012: PRAC Rapp/Co-Rapp stays aligned with CHMP Rapp/Co-Rapp Member States For generics, the PRAC Rap is from the same delegation as the CHMP Rap of the reference medicinal product

95 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November PRAC phasing-in For Legacy centrally authorized medicines (= authorised and on-going), while awaiting formal reappointment from Q onwards and if PRAC needs to be consulted: PRAC Rapp/Co-Rapp stays aligned with CHMP Rapp/Co-Rapp Member States Referrals (only non-CAPs involved): Co-Rapporteur: Member State triggering the referral. Rapporteur: open to all other Member States, and criterion of best possible and available expertise to be taken into account. Referrals (mixture of CAPs and non-CAPs): Rapporteur: PRAC Rapporteur for the CAP(s). Co-Rapporteur: Member State triggering the referral (whereby also the involvement of the PRAC Co-Rapporteur for the CAP(s) needs to be considered).

96 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Back up slides –

97 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Back up slides –

98 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Back up slides –

99 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Back up slides –

100 Beapp Famhp/DG Post/Vigilance Department-Pharmacovigilance 23 November Federal agency for medicines and health products - famhp Place Victor Horta 40/ Bruxelles tel fax Contact

101 Your medicines and health products, our concern

102 Federal agency for medicines and health products How to qualify for quality in the near future and be audit ready Nele Matthijs

103 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 103 -What do we expect from industry in relation to safety reporting of drugs. How to be prepared for an inspection ? - How to ensure the effectiveness and correctness of our pharmacovigilance system How to qualify for quality in the near future and be audit ready

104 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 104 A journey of quality

105 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 105 Journey of PhV Legislation Good Vigilance Practices Implementing Measure Regulation & Directive Increasing level of detail

106 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 106 GVP : Good Pharmacovigilance Practice Apply to marketing-authorisation holders, the Agency and medicines regulatory authorities in EU Member States Cover both centrally authorised and nationally authorised medicines Comprise 16 modules, each of which covers one major process in pharmacovigilance

107 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 107 Just a flavour of the changes Pharmacovigilance System Master File (PSMF) Expedited reporting (new requirements!) PSUR and the new format (to submit or not to submit?) Risk Management Plans required for all products- effectiveness of risk minimization activities needs to be assessed Inspections and the role of the Supervisory Authority Inspections of contractors

108 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 108 How to qualify for quality in the near future and be audit ready - Quality – Quality systems GVP Module I - Inspections GVP Module III -Audits GVP Module IV - Written for a broad public : basic principles specific details - take out what you need / implement where needed - Risk-based approach

109 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 109 Module I: Pharmacovigilance systems and their quality systems - Legal requirement for quality systems introduced by Directive 2010/84/EU and Regulation (EU) No 1235/2010 -The minimum requirements of these quality systems are set out in the Commission Implementing Regulation (EU) No 520/2012 on the Performance of Pharmacovigilance Activities - C onsistent with the general principles of the ISO 9000 Standards on good quality management practices, Guidance for the establishment and maintenance of quality assured pharmacovigilance systems for MAHs, CAs of MSs and the EMA

110 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 110 Quality cycle: planning, QC, QA, improvements Responsibilities of the MAH regarding EU-QPPV - EU-QPPV qualification – ensure he has acquired adequate theoretical and practical knowledge for the performance of PhV activities - EU-QPPV role and responsibilities : oversight over the functioning of the system in all relevant aspects, including its quality system - Each PhV system can have only one QPPV. 1 QPPV can work for more than 1 MAH for shared of separate PhV systems or act as QPPV for more than 1 PhV system of the same MAH, provided that the QPPV is able to fulfil all obligations. Module I: Pharmacovigilance systems and their quality systems

111 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 111 Training Facilities and equipment Compliance management Record management Documentation of the quality system Monitoring performance & effectiveness of the PV system & its quality system Module I: Pharmacovigilance systems and their quality systems

112 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 112 To ensure that all PhV processes are controlled : Case translation : in which time period, correct translate? Does MAH check when sending a case to global, there is always an acknowledgment of receipt sent to local? Does the MAH verify the timelines of compliance for transmission of ICSRs, PSURs,..? Check internal timelines for reporting SPC updates RMP compliance and effectiveness : - monitoring compliance and effectiveness of RMP and RMA - is the compliance monitoring performed at regular basis Why and how perform quality control Are SOPs up-to-date ?

113 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 113 -In many cases, error is made to implement QC only at the end of the implementation of a whole of processes RISK that an error is made at basic level (f.e. : translation (local level), Meddra coding (global level)) A MAH may have a perfect functioning system on signal detection and PSUR evaluation, but when an error occurs at first level or case processing big impact on the whole process Start QC at each stage as soon possible and for each individual sub process. Why and how perform quality control

114 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 114 There is broad support for quality systems for pharmacovigilance, but also some concern over the burden to implement them, in particular for smaller marketing authorisation holders or for medicinal products with low risks to patients and public health. every risk, low or high, is a risk quality is needed implement step by step risk-based planning Module I: Pharmacovigilance systems and their quality systems

115 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date Module provides transparency to the inspection process and gives MAH and NCA guidance on the expectations during inspections - Public consultation finished - Final Module III publication in December 2012 Module III : Pharmacovigilance inspections

116 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 116 New concepts in addition to the elements included in vol. 9A: Supervisory Authority PSMF location Pre-authorization inspections Information sharing on inspections planned and conducted Communication of non-compliance Module III : Pharmacovigilance inspections

117 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 117 Contact person for pharmacovigilance issues at national level : National nominated persons should report to the QPPV. Reporting in this context relates to pharmacovigilance tasks and responsibilities and not necessarily to line management - Availability 24/24 and 7/7 - Employed in Belgium - Dispose the appropriate qualifications for the performance his responsibilities as also have the linguistic properties to talk with his interlocutors in the national language of his choice - Circular 520/544/545 related to PhV local QPPV 1 new circular related to the local contact person Module III : Pharmacovigilance inspections

118 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date Publication December Provides clear guidance on planning and conducting audits which will help promote standards and harmonisation throughout the European network. - Welcome the development of the risk-based approach requested in the Implementing Measures Module IV : Audits

119 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 119 INDEPENDENCE ( legal requirement, see auditing standards) TRAINING AND QUALIFICATIONS ( In line with Module I- I.B.7 ) EVALUATION OF AUDIT WORK (quality assessment of the auditors work is a professional requirement) Module IV : Audits

120 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 120 Why Perform Pharmacovigilance System Audits? To ensure compliance with company procedures and local / global regulatory requirements To ensure company regulatory obligations / commitments are met Increasing Regulatory Inspections –Internal detection of risk is essential To identify process / quality deficiencies and improvements MOST IMPORTANTLY, PHARMACOVIGILANCE AUDITS ACT AS ONE MECHANISM TO ENSURE THE SAFETY OF PATIENTS IS MAINTAINED Module IV : Audits

121 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 121 Types of Pharmacovigilance System Audits Global Pharmacovigilance (QPPV – Global Systems and processes) Company Affiliates (i.e., Country Office, Local Operating Company, Marketing Company) Marketing (Licensing) Partners Module IV : Audits

122 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 122 Global Pharmacovigilance System Audits QPPV : qualification, availability, 24u/7, back-up procedures, training Focus on central Pharmacovigilance processes –Safety Case Processing –Expedited Reporting –Signal Detection / Safety Surveillance –Aggregate Reports (e.g., PSUR, etc.) –Literature Search –Office of the QPPV responsibilities Module IV : Audits

123 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 123 Assess compliance with company procedures and global Pharmacovigilance regulations Sample of products across therapeutic areas and a defined timeframe (vehicle to assess the system / process) Systems approach focused on processes Global Pharmacovigilance System Audits

124 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 124 Company Affiliates Primary focus on local contact person (qualifications// job description, availability – back up procedure, training,.. local Pharmacovigilance responsibilities Assess compliance with local and global company procedures and regulatory requirements (as applicable) Evaluate the flow of safety information (from all applicable sources) from initial receipt to reporting to external parties : AE collection Involves many functional groups that impact the Pharmacovigilance system -Pharmacovigilance -Sales -Regulatory Affairs -Product Quality -Medical/Clinical -Information Technology -Marketing -Medical Information Not just an audit of local affiliate but also of global processes to support local affiliates

125 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 125 Reconciliation with Product Quality Complaint handling and medical questions Local quality systems (including compliance monitoring) Regulatory functions (e.g., Aggregate reports submission, Labeling, Regulatory Authority query management, etc.) Contracts and Agreements (Marketing Partners, CROs, consultancy, etc.) : e.g. to verify if resources are sufficient for the required activities as described in the contract (internal/external audit) Promotional Material Company Affiliates

126 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 126 Standard Operating Procedures (SOPs) Training Verification of respect of RMAs and their tracking Management of PSP (contracts, collect and management of AEs/ARs,…) Document Retention / Archive Electronic systems used to support the Pharmacovigilance system Business Continuity / Disaster Recovery Company Affiliates

127 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 127 Marketing (Licensing) Partner Audits Includes in-licensed and out-licensed product agreements Focus on compliance with Marketing Partner agreement –Ensure Pharmacovigilance roles and responsibilities are defined and performed –Ensure appropriate exchange of safety information Assess compliance with local and global company procedures and regulatory requirements (as applicable) May be performed independently by company, as a joint audit between companies, or by an agreed upon consultant

128 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 128 Global Pharmacovigilance Inspection Trends Past Site based Product safety data specific Independence between Regulatory Authorities globally Limited frequency Mostly FDA Inspections Present Systems based with safety and /or compliance data as a potential trigger Focused on Pharmacovigilance system –across sites / operations / products Scope includes linkages and relationships across the company to perform Pharmacovigilance responsibilities Increased collaboration across regulatory authorities globally

129 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 129 Examples of deficiencies related to the quality system Lack of quality control in key processes (local as global processes) - lack in FU of cases : has it been performed, how, when,.. - no control on translation, reporting from sales reps - literature reporting : has it been performed, when, how Missing or incomplete SOPs in key processes - back-up procedure, - quality control, - business continuity) No or incomplete job descriptions - reflection of Management - defines necessary skills and training

130 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 130 Examples of deficiencies related to the quality system Deficiency on the performance of audits (local affiliates/ global activities) - risk-based approach - audits of contract companies - skills auditors Lack in interaction between departments - reconciliation of PhV data (medical and quality department) - regulatory affairs : update SPCs, variations, PSURs, implementation of referrals (MRP/DCP/NAT) - interaction global / local : awareness of safety issues / RMP / … Lack in responsibilities of the QPPV - incomplete overview - insufficient back-up system

131 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date Steps You Can Take to Help Ensure Quality in the near future -1 Define the impact of the new legislation on the processes and process documents / database / … -2 Update processes / documents (SOPs, guidance, working instructions, …) / tools as appropriate risk-based planning -3 Get the concerned people trained in time -4 Perform quality control on the : - training - the performance on PhV activities - the correctness/efficacy of the PhV activity -5 Performance of audits on global and local activities

132 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 132 A journey of improved quality

133 How to qualify for quality in the near future and be audit ready? famhp/DG Inspection/Division Industry Date 133 Federal agency for medicines and health products - famhp Place Victor Horta 40/ Bruxelles tel fax Contact

134 Your medicines and health products, our concern

135 Federal agency for medicines and health products The Belgian consensus on Risk Minimisation Activities New process M.L.Bouffioux - 23th November 2012

136 RMA New process famhp/DG Post/Division Proper use of medicine Date 136 Reminder Legal basis: Article 6 § 1stocties of the law of 25th March 1964 on medicines, as amended by the law of 3 rd August 2012 (MB 11th September 2012) Some marketing authorisations are granted on condition that the MA holder develops additional risk minimization activities (RMA). Justified if essential for the safe and effective use of the medicinal product The need for such possible measures belongs to the risk management plan (RMP) now mandatory in marketing authorization applications. These RMA activities often require that the marketing of the medicinal product is accompanied by materials, educational or informative programmes or services for healthcare professionals and / or patients.

137 RMA New process famhp/DG Post/Division Proper use of medicine Date 137 Prior Approval Educational and informational materials, programmes or services shall be subject to the prior approval of the Minister or his delegate (CEO of the FAMHP) - National MAs, DCP, MRP - Centralized marketing authorization - Modification of the RMA without modification of the terms of the marketing authorizations - Variation of the MA-> with new RMA conditions -> with modification of the RMA conditions Implementation should be no later than at the time of the marketing of the medicinal product or, if conditions change, within the time allowed if specified in the MA.

138 RMA New process famhp/DG Post/Division Proper use of medicine Date 138 Approval procedure Working group with industry -> consensus on a proposal for an approval procedure which should be implemented in a modification of the Royal Decree of 14th December 2006 (future Article 65 quater)

139 RMA New process famhp/DG Post/Division Proper use of medicine Date 139 Introduction of the approval application Contents of the file: - Standard application form (already available on the FAMHP website) - 2 copies - Copy of the MA and any annexes (conditions – key elements of RMA) - SPC, leaflet (latest approved version) - Copy and / or complete description of the material, programme or service - Copy of the part of the RMP justifying the implementation of the RMA - Terms of implementation – circulation plan - Possibly, in the case of modification, termination terms or removal procedures of the old material

140 RMA New process famhp/DG Post/Division Proper use of medicine Date 140 Application validation Within 15 days the FAMHP checks if the file is complete If OK -> acknowledgment If not OK -> the MA holder is informed by the FAMHP -> 15 days to complete the file If file not complete after 15 days -> application unacceptable -> MA holder informed

141 RMA New process famhp/DG Post/Division Proper use of medicine Date 141 Application assessment Within 45 days from the date of validation of the file the FAMHP sends the applicant the results of its assessment. The FAMHP can consult the Commission for medicines for human use (cfr current circular 532 bis to be adapted). The delay is then extended to 90 days. In exceptional circumstances (e.g. to consult an external expert) the delay period may be extended by 15 additional days The MAH is informed.

142 RMA New process famhp/DG Post/Division Proper use of medicine Date 142 Assessed items Compliance with the SPC, leaflet, approved items within the MA fulfilled conditions – key elements Necessary, sufficient, appropriate materials, programmes or services to promote the safe and effective use of medicine: - evaluation of the appropriate design and form, of the content, of rules of implementation (adapted to the health care system in place in Belgium) Lack of promotional aspects. Information should be clearly focused on the risk minimisation goals

143 RMA New process famhp/DG Post/Division Proper use of medicine Date 143 Conclusions of the assessment 1. Positive conclusions -> intention of RMA approval 2. Unfavourable provisional advice Reasons: - Objections to envisaged materials, programmes or services - Request to modify the form and / or content and / or procedures for implementation - Request to complete the file Timing suspended: - The holder responds within a maximum of 60 days - If> 60 days: request denied Conclusions: - intention of (modified )RMA approval - Refusal (to reintroduce an application)

144 RMA New process famhp/DG Post/Division Proper use of medicine Date 144 Introduction of the final material Within 60 days of the letter of intended approval the applicant shall submit a copy of: - The final presentation of the approved version - Translations with a declaration of conformity of these translations

145 RMA New process famhp/DG Post/Division Proper use of medicine Date 145 Approval decision Within 5 days of receipt of the final material and translations the FAMHP - Verifies that the documents are complete - Sends the letter with the decision of approval

146 RMA New process famhp/DG Post/Division Proper use of medicine Date 146 Implementation at the time of the marketing - maximum 90 days after approval - if imposed after MA - if modified unless the Minister determines a different timing The MA holder is responsible for the implementation of the RMA and its consistency with the approved dossier

147 RMA New process famhp/DG Post/Division Proper use of medicine Date 147 References -> Usage humain->Médicaments -> Bon Usage -> Additional RMA Usage humainMédicamentsBon UsageAdditional RMA Menselijk gebruik -> Geneesmiddelen -> Goed gebruik -> Additional RMA Circular 532 bis will be adapted to the new procedure Standard Form of application EMA Guideline on good pharmacovigilance practices – Module V – Risk management systems (V.B11.2 ) – further extensive guidance on additional risk minimisation measures will be provided in Module XVI 10 focus points published on the FAMHP website Guidelines for the content and form published on the FAMHP website Need for on-going dialogue during the procedure between the file manager and the applicant, in particular to avoid having to appear several times before the medicines commission Keep in mind the goal of public health

148 RMA New process famhp/DG Post/Division Proper use of medicine Date 148 Federal agency for medicines and health products - famhp Place Victor Horta 40/ Bruxelles tel fax Contact

149 Your medicines and health products, our concern

150 Does CT-3 provide more operational transparency ? An industry perspective J. Van Rampelbergh Head of Clinical Study Unit sanofi-aventis Belgium Info session: Be (pharmaco) Vigilant - 23/11/2012

151 What s CT-3?

152 Circular letter National Application of the Revised CT-3 guidance To implement revised CT-3 in national practice Replaces Circular Letter 460 and provides short term improvement and updated information on management of adverse event/reaction reports arising from Clinical Trials Aim – Brightening – Clearing – Clarifying 152

153 Definitions (1) IMP NIMP In the scope but….. an untoward or unintended response to a non-IMP which does not result from a possible interaction with an IMP is, by definition, NOT A SUSAR Circ Letter 586: only a definition of NIMP. 153

154 Definitions (2) SUSAR – Suspected unexpected serious adverse reaction Reference Safety Information (RSI) – If SmPC available: most appropriate (with reference to subject safety) version should be selected – Otherwise most recent version of RSI (mostly in the Investigators Brochure) – Will serve to determine and report SUSARs – An update/change of the RSI will influence the number of adverse reactions that are reported as SUSAR 154

155 Application (1) – Interventional clinical trials with Investigational Medical Products or with nonIMP – Post marketing Pharmacovigilance rules are not applicable, even if marketed drugs are used in the clinical trial – Non-interventional trials – Compassionate Use and Medical Need Programs follow post-marketing PV rules But CUP are conducted with medicinal products without marketing authorization 155

156 Application (2) – Non-commercial trials Instructions for electronic or paper submission ? Deadline for mandatory reporting through EudraVigilance ? – Investigator Sponsored Trials Avoid double reporting by sponsor and investigator? Recommended: Technical agreement in order to delegate to pharma company or an external consultant to perform safety reporting for the investigator without being considered as the sponsor. Quid: non-EudraCT studies ? 156

157 SUSAR Reporting Sponsor to CA (1) All unblinded SUSARs occurring in clinical trials – Authorized in the EU or by the FAMPH – Performed exclusively in a third country or another Member State when the active substance was authorized in the EU Timelines – unchanged – 7 days vs 15 days Reporting obligation ends with treatment completion all subjects enrolled in that MS 157

158 SUSAR Reporting Sponsor to CA (2) Format – Indirect reporting through EMA EudraVigilance DB (ICHE2B format) Belgian Affiliate or Corporate PV Local studies: Agreement with delegation of power (audits) Double reporting to avoid – Direct reporting: Non-Commercial trials Individual case safety reports (ICSR) by paper with waiver Direct reporting possible in Belgium until when ?

159 SUSAR Reporting Sponsor to LEC Sponsor of a clinical trial conducted in Belgium should send Belgian SUSAR report to LEC No 6-monthly line listings to LEC needed Format – Not specified – Electronic if accepted by LEC – + CIOMS in attachment = unprotected – Encourage secured company portal system? 159

160 SUSAR Reporting Sponsor to investigators (1) Sponsor should also inform all other investigators by means of periodical line listing of SUSARs together with an updated safety profile of the IMP – No timelines – To be specified by sponsor depending on type of trial ? – Drivers to define periodicity ? – All SUSARs vs only Belgian cases to LEC? Confusing for investigators and EC – Standardize by sponsor in procedure or in protocol (audit) – Do investigators need to receive individual cases ? 160

161 SUSAR Reporting Sponsor to investigators (2) – Scientific, medical value and transparency of line- listing of all SUSARs to investigators and no longer to (L)EC ? SUSARs with no (direct) consequence on Risk/Benefit – no timelines? SUSAR with change of Risk/Benefit – reporting by Urgent Safety Notification to all parties? 161

162 Unblinding - GENERAL (1) – CA Belgian unblinded cases through EudraVigilance – LEC Belgian unblinded cases – format not specified – Why unblinded to LEC ? – Guarantee investigators will receive unblinded information ? 162

163 Unblinding - GENERAL (2) Investigators – Should only receive blinded information unless unblinding necessary for safety reasons – Blinded individual SUSARs or line-listing – Format not specified – Periodicity: not specified or standardized – Use of abbreviated DSUR?

164 Unblinding (2) After unblinding by the sponsor – Case is unexpected = SUSAR – Report according to specified rules – Case is expected or placebo related = No SUSAR – Comparators Sponsor to report SUSAR through EudraVigilance Information towards MAH? How to define a SUSAR with a comparator? RSI? SmPC? 164

165 DSUR reporting (1) Format – Reference ICH E2F, DSUR (previous ASR) – To be prepared after first authorization of a clinical trial in Europe Reference Safety Information – RSI applicable at the start of reporting periods and to be attached in appendix – RSI serves as reference during reporting period RSI changes/updates – Substantial amendment to LEC and CA – Alignment of DSUR, Investigators Brochure and/or RSI update = alignment reporting period and reference doc 165

166 DSUR reporting (2) Content Listing all SUSARs (yearly basis) and Safety Summary To LEC and CA. Quid non LEC ? Start of DSUR submission to CA After first authorization by CA of a clinical trial with this IMP – Most recent DSUR to submit with initial CTA dossier, if study start in Belgium is later than first authorization – Line listing unblinded SUSARs to fill possible gap? End of reporting Until LVLP in Belgium = End of exposure Or until End of Trial criteria as specified in the protocol

167 DSUR reporting (3) No DSUR required for trials < 1 year The Clinical Trial Report (CSR), as a part of the End of Trial notification, will serve as DSUR in this case – CSR is not a part of the EOT notification – CSR issued max. 1 year later after worldwide EOT – No local EOT, only worldwide EOT Recommended to submit DSUR if more short studies < 1 year with same IMP – Recommendation or obligation ? 167

168 Operational Transparency ? Conclusion Questions ? Ideas ? 168

169 Federal agency for medicines and health products The Belgian implementation of CT3 (circ. 586 & 593) Kristof Bonnarens – 23/11/2012

170 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 170 Revision of CT-3 guidance Revised detailed guidance on the collection, verfication and presentation of adverse reaction reports arising from clinical trials on medicinal products for human use (CT-3) was published in the Official Journal on 11/06/2011 Replaces old guidance documents CT3 and CT4 (Detailed guidance on the European database of SUSARs – Eudravigilance /Clinical Trial Module) Aimed to provide short term improvements and clarifications for safety reporting, awaiting the revision of the current Clinical Trial Directive 2001/20/EC

171 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 171 SUSAR = SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION CT3 revision and circular letter 586 (2)

172 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 172 SUSAR = SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION Causality between event and IMP «reasonable causal relationship» Definitions (1)

173 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 173 SUSAR = SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION it results in death it is life-threatening it requires hospitalisation or prolongation of existing hospitalisation it results in persistent or significant disability or incapacity it is a congenital anomaly or birth defect An important medical event is also serious if it jeopardises the clinical trial participant or requires an intervention to prevent a serious outcome Definitions (1)

174 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 174 SUSAR = SUSPECTED UNEXPECTED SERIOUS ADVERSE REACTION Adverse reactions should be considered as unexpected if the nature OR severity of the reaction(s) is not consistent with the reference information for the IMP. Definitions (1)

175 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 175 RSI: Reference Safety Information The expectedness of an adverse reaction is determined in the reference safety information (RSI). This should be done from the perspective of events previously observed, not on the basis of what might be anticipated from the pharmacological properties of a medicinal product The RSI is contained in the Summary of product characteristics (SmPC) or the Investigators Brochure Absence of the RSI is the most frequent validation question in 2012 Definitions (2)

176 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 176 Scope Scope CT-3 : Interventional clinical trials falling under Directive 2001/20/EC Responsibilities regarding safety reporting determined only by Directive 2001/20/EC: Whether IMP has a marketing authorisation or not Provisions on pharmacovigilance as set out in Directive 2001/83/EC and Regulation (EC) No 726/2004 are not applicable, even for NIMPs

177 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 177 SAE reporting by the investigator Investigator should report all serious adverse events immediately to the sponsor except those specified in the reference safety information Timelines: Immediate reporting <24h Non immediate: appropriate time Other critical safety issues: as specified in protocol Causality and seriousness are assessed by the investigator Expectedness assessment by sponsor

178 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 178 Sponsor should report all SUSARs Occuring in a clinical trial authorised in the EU Occuring in trials performed exclusively in a third country or another Member State when the active substance was authorised in the EU Timelines: Fatal or life-threatening: initial report within 7 days + follow-report within additional 8 days Other SUSARs: initial report within 15 days Format Indirect reporting: through EV-CTM Direct reporting: individual case safety report (ICSR – ICH E2B) SUSAR reporting by the sponsor (1)

179 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 179 Sponsor should equally send the SUSAR report to the EC that issued the single opinion in the memberstate where it occurred No line listings to Ethics Committees needed Sponsor should inform all other investigators by means of a periodical line listing together with an updated safety profile of the IMP SUSAR reporting by the sponsor (2)

180 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 180 Annual Safety Report (1) Should be prepared after the first authorisation of a clinical trial worldwide Development International Birth Date – DIBD: First authorisation of a clinical trial worldwide with this IMP DIBD = International Birth Date for authorised drugs: date of the first marketing authorisation in any country worldwide Data lock point – DLP: last day before the anniversary of the DIBD Covered reporting period: 1 year or shorter for aligning purposes

181 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 181 Annual Safety Report (2) Content and format of the annual safety report should be in line with ICH guideline E2F: Note for guidance on development safety update reports (DSUR) Common standard for periodic reporting on drugs under development among the ICH regions (EU, USA, Canada and Japan) A DSUR should present a comprehensive annual review and evaluation of pertinent safety information related to an IMP, whether it is marketed or not

182 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 182 Implementation of CT-3 revision in Belgium Circular letter 586: Submission of SUSAR reports and annual safety reports Circular letter 593: Submission fee for annual safety reports

183 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 183 Circular 586: SUSAR reporting in Belgium SUSARs to be reported to FAMHP: Occuring in a clinical trial authorised by the FAMHP Occuring in trials performed exclusively in a third country or another Member State when the active substance was authorised by the FAMHP Only unblinded SUSARs Indirect reporting through EVCTM Reporting obligation ends with the last visit of the last patient (LPLV) in Belgium

184 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 184 Circular 586: SUSAR reporting in Belgium SUSARs to be reported to Ethics committee All SUSARs occurring in Belgium for the clinical trials authorised by the Ethics Committee Should not be submitted: 6 monthly SUSAR line listings

185 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 185 Circular 586: submission of ASR Start of ASR submission to FAMHP after first authorisation of a clinical trial by FAMHP with this IMP An ASR should be submitted until the last visit of the last patient in Belgium or until the End of Trial criteria in the protocol are met for the last ongoing trial with this IMP in Belgium No ASR submission required for trials shorter than 1 year In unprotected pdf format (allowing search and copy/paste functionality) on CDrom with cover letter

186 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 186 Circular XXX : guidance on ASR submission Royal Decree on ASR submission fee published on 08/10/2012 – entry into force on the 18th of October Practical instructions in the circular letter that will be drafted asap Revision and evaluation of the process after 6 months with stakeholders. Goal = better follow-up of the safety in clinical trials by a risk-appropriate evaluation of the annual safety report (in the DSUR format).

187 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 187 Federal agency for medicines and health products - famhp Place Victor Horta 40/ Bruxelles tel fax Contact

188 Your medicines and health products, our concern

189 Federal agency for medicines and health products How to qualify for quality in IMP safety in the near future Sarah TKindt – 23/11/2012

190 Subject famhp/entity/Division-Unit-Cell Date 190 Presentation topics Overview of a GCP inspection Why is it important to focus on reports from clinical trials? Overview of safety topics during a GCP inspection at the sponsor site Safety findings from previous GCP inspections Legislation

191 Subject famhp/entity/Division-Unit-Cell Date 191 Overview of a GCP inspection Topics to be discussed during a systemic GCP inspection at the sponsor site: The organization & personnel : qualification and training Outsourcing & contract management Project / trial management The IMP Data management Sample management Safety reporting & evaluation Statistics & study reporting Quality management

192 Subject famhp/entity/Division-Unit-Cell Date 192 Why is it important to focus on reports from clinical trials? For some products, a high proportion of adverse event reports and other safety information comes from clinical trials Reports and other safety information from clinical trials are (usually) high quality data Relevant additional information can be easily obtained (medical history, other AEs, lab values, etc.) Information can be retrieved in more controlled settings

193 Subject famhp/entity/Division-Unit-Cell Date 193 Overview of safety topics during a GCP inspection at the sponsor site Preceding a sponsor site inspection there is usually an investigator site inspection of a specific trial from the sponsor to be inspected: The training on site of the study persons concerning the safety reporting process Reconciliation of data between the source, the CRF and the (serious) adverse events that are reported Delegated safety aspects mentioned on the delegation duty log The quality of the monitoring on site The up to date safety information on site

194 Subject famhp/entity/Division-Unit-Cell Date 194 Overview of safety topics during a GCP inspection at the sponsor site (cont.) Follow up information Information on concomitant medication Evaluation of the SAE form Update of safety information leads to an update of the informed consent form (ICF) The update of the ICF is signed in time by the subjects Confirmation of receipt from the sponsor for the reported information Findings from the investigator site inspection will be further discussed during the sponsor site inspection.

195 Subject famhp/entity/Division-Unit-Cell Date 195 Overview of safety topics during a GCP inspection at the sponsor site (cont.) The set-up of the trial: A clear description of the safety reporting process in the protocol A non confusion definition of the severity grade A defined time period for reporting Expedited reporting according to the requirements The reference safety information (RSI): To indicate the expectedness Usually in the Investigator Brochure (IB) Reference information allocated and updated as per regulation requirements

196 Subject famhp/entity/Division-Unit-Cell Date 196 Overview of safety topics during a GCP inspection at the sponsor site (cont.) The DSMB (Data Safety Monitoring Board) The discision making process for the need of a DSMB Documentation of the discisions of the DSMB The written reports of the DSMB Safety procedures: Clear overview of the timelines and the responsibilities for the safety reporting from collection to reporting Flow of distribution of safety information to the concerned investigators: IB – DIL Emergencies The writing of the DSUR The writing of the CSR …

197 Subject famhp/entity/Division-Unit-Cell Date 197 Overview of safety topics during a GCP inspection at the sponsor site (cont.) Minutes of the safety management team meetings Communication between the safety (PhVig) department and the Clinical trial unit and involvement of the PhVig department in critical trial processes/document review: Confirmation of the expedited reporting Protocol Case Report Form Clinical Study Report The trial statistician should be a member of the team responsible for the clinical study report, and should approve the clinical report.

198 Subject famhp/entity/Division-Unit-Cell Date 198 Overview of safety topics during a GCP inspection at the sponsor site (cont.) Compliance of the information in the safety database and the safety information in the DSUR and the CSR Reconciliation of the information in the CT database and the safety database The database(s) used for the storage of safety information A risk level QC of the safety database A documented validation of the database(s) Database ready for demonstration and search of specific topics during inspection

199 Subject famhp/entity/Division-Unit-Cell Date 199 Overview of safety topics during a GCP inspection at the sponsor site (cont.) The blinding and unblinding process Clear unblinding rules for SUSARs An independant safety monitor ISM for blinded trials for which the IMPs are manipulated in the hospital pharmacy Adequate safety training of the monitors Training and revision training of the safety procedures Training on the discision management of issues and protocol deviations Training of new important information during the trial

200 Subject famhp/entity/Division-Unit-Cell Date 200 Overview of safety topics during a GCP inspection at the sponsor site (cont.) The use of a common adverse event dictionary The role of the local affiliates in the safety process and the communication with global. Is there a local database? Are the procedures in line with the global ones? Qualified employees for the review of the events and the medical writing

201 Subject famhp/entity/Division-Unit-Cell Date 201 Safety findings from previous GCP inspections No confirmation of receipt from the sponsor of the reported SAE from the investigator site No prove of attendance of the concerned study staff on the site initiation visit and/or the investigator meeting Not all adverse events are recorded, only those that the investigator classifies as clinical significant, although the protocol describes that all adverse events must be recorded

202 Subject famhp/entity/Division-Unit-Cell Date 202 Safety findings from previous GCP inspections (cont.) SAEs that are reported long after the first aknowledge by the PI and no note to file from the monitor. The procedures are not complete of the way of working doesnt fit with the procedures Day zero not clear from the SOP No identification of the responsible persons during the safety flow Only the safety reporting on paper is explained, while the reporting is now done via E2B No quality control of the information mentioned in the DSUR and CSR

203 Subject famhp/entity/Division-Unit-Cell Date 203 Safety findings from previous GCP inspections (cont.) The subject identification at the sponsor site contains the name of the subject AEs that are crossed out on the AE list without any further explanation or indication of the person responsible for this cross out No audit of the CRO whos responsible for the safety reporting Very poor documented monitoring reports The use of a non-validated local safety database

204 Subject famhp/entity/Division-Unit-Cell Date 204 Legislation Safety reporting falls either under Directive 2001/20/Ec or under the provisions on PhVig as set out in Directive 2001/83/EC and Regulation (EC) No 726/2004. AEs may not be reported under both regimes! Law of 07 May 2004: Art. 27 en 28 & the implementing orders Directive 2001/20/EC Directive 2005/28/EC: The IB shall be validated and updated by the sponsor at least once a year Detailed Guidance CT-3: Note: the PhVig rules laid down in Directive 2001/83/EC and Regulation (EC) No 726/2004 do not apply to IMPs and non-IMPs.

205 Subject famhp/entity/Division-Unit-Cell Date 205 Legislation ICH E6: Note for Guidance for Good Clinical Practice CPMP/ICH/135/95 ICH E3: Note for Guidance on Structure and Content of Clinical Study Report CPMP/ICH/137/95 ICH E2A: Note for Guidance on Clinical Safety Data Management CPMP/ICH/377/95: Definitions and standards for expedited reporting ICH E2F: Note for Guidance on Development safety Update Reports

206 Subject famhp/entity/Division-Unit-Cell Date 206 Federal agency for medicines and health products - famhp Place Victor Horta 40/ Bruxelles tel fax Contact

207 Your medicines and health products, our concern

208 Agence fédérale des médicaments et des produits de santé PRIORITIES OF THE DGs FOR THE NEAR FUTURE AND TAKE AWAY MESSAGES Pharma.be/BEAPP Vanessa BINAME, Director General DG Post – 23/11/2012

209 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ RECOGNITION AT NATIONAL, EUROPEAN AND INTERNATIONAL LEVEL Active participation in: – QRD WG, Variations WG and European Council meetings – Recast medical devices and European WG (MDEG, CIE, …) National coordination medical devices (MD) Development network safety experts

210 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ DEVELOPING PARTNERSHIPS WITH THE HEALTHCARE SECTOR To improve communication with stakeholders (i.a. industry via WG) Human phv/MD : to develop network with HCPs Veterinary phv: to improve feed-back SAM and active participation to the eHealth roadmap Publication withdrawn MA

211 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ PERFORMING CORE TASKS IN A PROFESSIONAL MANNER Monitor of the timelines and deadlines for DG POST processes SOPs (TQM) and corrective actions based on BEMA III MD: plan Capacity planning RMA

212 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ INFORMING THE PUBLIC OPTIMALY Publication SPC/PIL Website FAHMP Campaign concerning proper use medicines for children To develop information concerning MD Information for patients

213 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ DEVELOPING TRANSVERSALITY intra and inter DG, i.a. between Vigilance division and DG PRE/DG Inspection

214 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ EALISING AND ESTABLISHING A LEARNING ORGANIZATION CULTURE Development cycles Knowledge management Quality system for pharmacovigilance CAF

215 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ To improve quality of services Transparency and communication IMPORTANT MESSAGE DG POST 2013

216 Priorities of the DGs for the near future and take away messages afmps/DG Post 23/11/ Agence fédérale des médicaments et des produits de santé - afmps Place Victor Horta 40/ Bruxelles tél fax Contact

217 Vos médicaments et produits de santé, notre préoccupation

218 Federal agency for medicines and health products DG PRE Priorities Greet Musch – 23/11/2012

219 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 219 EU Strategy Clinical Trial Regulation Equal and Early Access ( availability of drugs ) Public Health Needs – early authorisation in restricted population – elderly people – cooperation with HTA – bodies in early stage of drug/device development Anti-Microbial Resistance ( Human and Veterinary) Better Regulation ( Veterinary ) Selection/Reconfirmation of Centres of Excellence Funding IT

220 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 220 Regulatory expertise Scientific expertise Strengthen the basic layers - Focus on Clinical expertise - B/R methodology ( Clinical trials, Unmet need, Marketing authorisations, Self Care, Medical Devices : Clinical Investigations and Evaluations - Co ö rdination and integration of EU Scientific Committees (COMP-SAWP-CAT-CHMP-PDCO and PRAC )within the FAMHP … Introducing the concept of TAC s Therapeutic Area Co ö rdinators UNEXPECTED SERIOUS ADVERSE REACTION Expertise

221 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 221 With National Institutions ( RIZIV, KCE, HGR, FOD VVVL ( WIV-CODA ), FAVV … ) Within the FAMHP With DG Post - B/R : Clinical assessors and Vigilance assessors - VHB Pre and VHB Post - CI and CE of medical devices ; combined products… With DG Inspection -Triggers for Inspection -Outcome of Findings : impact ? -Ad Hoc dossiers : Veterinary division, Traditional Use, ATMPs HE, Active Pharmaceutical Ingredients … UNEXPECTED SERIOUS ADVERSE REACTION Interfaces

222 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 222 Per process and intra process Review of role and responsabilities of the Commission for medicinal products for human and veterinary use Although dreaming of ancient times … QA of the decision making process

223 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 223

224 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 224 Optimisation of platforms - ad hoc for existing platforms - sufficient ? compilation ? Opportunities for improvement ? Your Priorities ? Future views (i.e. Role of Be as RMS for human and veterinary medicinal products ? ) Stakeholders

225 The Belgina implementation of CT3 famhp/DGPRE/ R&D Date 225 Federal agency for medicines and health products - famhp Place Victor Horta 40/ Bruxelles tel fax Contact

226 Federal agency for medicines and health products Priorities of DG Inspection in the near future and take away messages Josiane Van der Elst Director General

227 Organisation chart

228 Directorate General Inspection 2013: Autocontrol becoming a reality

229 229 The Switch to Make AS IS: Gothic TO BE: Art Nouveau Authority – only driven Authority – driven supracontrol in combination direct linear control with sector – driven delegated autocontrol of which selfevaluation can be part co-regulation Vertical link Curvilinear, Linkage with environment Cartesian, dissection of system into parts Holistic, treating systems as a whole Limited interface with operators, one –one interactionStrong Interface with operators Mainly rulesRules and guides Ressources boxed, strictly dedicated to one task More rational use of capacity Low trustHigh trust Authority keeps right of final decision and power of sanction

230 Co-regulation Showing the relationship to a central idea Emphasizes both information in the center circle and how information in the outer ring of circles contributes to the central idea Co- regulation

231 Develop further the concept AND Develop one concrete model to start with: Medical Devices is an opportunity to develop a model and put it to the test AND Work in parallel in different other domains of inspection where concrete actions are foreseeable and feasible already Publicity Certification of persons: f.i. QPPV, oxygenotherapy AND Design Coordinator (s) at DG Inspection Action Plan Autocontrol / Co-regulation

232 Directorate General 2013: The Veterinary Experience

233 Veterinary issues coming up Fight against antimicrobial resistance is high on the agenda in view of an holistic approach « The Depot » Lacunes in legislation Good Veterinary Practices to be introduced Better Transversal Coordination needed within FAMHP Autocontrol/co-regulation: first steps to be considered Invite stakeholders at our FAMHP house

234 Directorate General 2013: The New Structure

235 235 DG Inspection: current structure Director General Division Industry Planning of inspections Execution of inspections Issuing of authorisations Division Dispensing Planning of inspections Execution of inspections Issuing of authorisations Special Investigation Unit Control policy 235

236 236 DG Inspection: new structure to be in line with new vision Director General Division Industry Operational Planning of inspections Execution of inspections Division Dispensing Operational Planning of inspections Execution of inspections Special Investigation Unit Division Autorisations Issuing of autorisations Staff Inspection management including Control Policy Strategic modelling of inspections Including co/regulation 236

237 Autocontrol / co-regulation as a new style of inspection is going to the test Veterinary inspection will take up its rightfull place and leave the position of « underdog » for the benefit of public health A new style structure, a new structure The new structure of DG Inspection sticks with the new vision on inspection Take Away Messages for 2013

238 days to go till

239 Your medicines and health products, our concern


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