Issues driving the EU Regulatory Agenda on Benefit-Risk Management: the Importance of Risk Minimisation Activities.

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1 Issues driving the EU Regulatory Agenda on Benefit-Risk Management: the Importance of Risk Minimisation Activities. ISPE Mid Year Meeting 2011, Florence, Italy Almath Spooner Irish Medicines Board

2 Disclaimer The views expressed in this presentation are the personal views of the presenter and may not be understood or quoted as being made on behalf of or reflecting the position of the European Medicines Agency or it s Pharmacovigilance Working Party.

3 What s driving the EU agenda on B/R management? New EU legislation on Pharmacovigilance: Promote and protect public health by reducing burden of ADRs through effective risk minimisation and optimising use of medicines. 06/05/2011 Slide 3

4 Objectives of the new Pharmacovigilance legislation Clear roles and responsibilities Science based (move up hierarchy) Risk based / proportionate Increased proactivity / planning Reduced duplication / redundancy Integrate benefit and risk Ensure robust and rapid EU decision-making Strengthening EU Network Engage patients and professionals Increase transparency and accountability Better information on medicines 06/05/2011 Slide 4

5 European Risk Management Strategy

6

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8 requires, when appropriate, a detailed description of a risk management system

9 Regulation EU 1235/ Legal basis for Risk Management System Risk Management System: a set of pharmacovigilance activities and interventions designed to identify, characterise, prevent or minimise risks relating to a medicinal product, including the assessment of the effectiveness of those activities and interventions. Risk Management Plan: a detailed description of the risk management system. 06/05/2011 Slide 9

10 Proactive lifecycle management Data collection: Traditional PV Plus post marketing research activities Expanded range of data sources. Benefit Risk Management Planning Life cycle management Risk identification, characterisation, assessment Regulatory decision making Decision Integrated benefit-risk evaluation

11 Waller P and Evans S. A model for the future conduct of Pharmacovigilance. Pharmacoepidemiology and Drug Safety, 2003; 12: Culture of Scientific Development Outcome measures and audit Measurable performance in terms of public health benefit

12 Why this evolution? Information needs of stakeholders (e.g. patients, healthcare professionals, payers). Increased focus on how medicines perform in real life clinical practice and the importance of lifecycle management. 06/05/2011 Slide 12

13 ICH E2E Safety Specification Important identified risks of a drug Important potential risks of a drug Important missing information The safety specification is the basis for the pharmacovigilance plan and the evaluation of the need for a risk minimisation plan. 06/05/2011 Slide 13

14 Risk Minimisation Activities Public health interventions intended to prevent the occurrence of an adverse reaction associated with the exposure to a medicine or to reduce its severity should it occur. Routine Summary of Product Characteristics, Package leaflet, use of product labelling Additional targeted risk communication through healthcare professional or patient education or control of the use of the medicine. 06/05/2011 Slide 14

15 Evaluating the need for Risk Minimisation For each important safety issue: - Are risk minimisation actions needed? - Is the product information sufficient for this purpose? - If no, then risk minimisation plan is needed? - Potential for medication error/misuse is considered. 06/05/2011 Slide 15

16 Current EU Guidance

17 provision of information and education control the use

18 06/05/2011 Slide 18

19 Risk Minimisation Activities 06/05/2011 Slide 19

20 Benefit-risk management Evolution of risk management principles New legislation provides for greater integration of benefits and risks in post marketing evaluations. Maintains focus on proactivity and evidence driven decision making. 06/05/2011 Slide 20

21 The estimation of the benefit-risk balance Major Balance dependent on circumstances HARM Excellent balance Acceptable balance Minor 06/05/2011 Slide 21

22 Dealing with uncertainty Regulatory agencies have access to..sources of data, many of which may not be published, and are thus in a unique position to conduct decision analyses and to evaluate the appropriateness and thoroughness of a specific modelling approach. The relevant question is not whether a model is perfect (none is) but whether it is good enough to provide important insights for authorities making difficult decisions under conditions of uncertainty Hughes, Bayoumi and Pirmohamed 2007 Clinical Pharmacology and Therapeutics, 82,2: /05/2011 Slide 22

23 Evolution of knowledge on benefit-risk throughout the lifecycle Time 06/05/2011 Slide 23

24 Supports for EU Benefit-Risk Management Pharmacoepidemiological resources e.g. ENCePP (European Network of centres for Pharmacovigilance and Pharmacoepidemiology). Benefit-risk research IMI PROTECT (Pharmepi Research on Outcomes of Therapeutics by EU ConsorTium). ICT developments facilitate risk identification and evaluation signal detection (data mining), electronic healthcare records. 06/05/2011 Slide 24

25 Estimated benefit risk At launch At maturity Negative Positive Estimated benefit risk 06/05/2011 Slide 25

26 Changes in benefit-risk Benefit-risk profile may vary depending on perspective Benefit-risk profile may change as pharmacovigilance data emerge. Benefit-risk profile may be influenced by the availability of alternative products. Date Insert on Master Slide Slide 26

27 Ongoing benefit-risk management Objective is to optimise safe and effective use throughout the lifecycle of the product The benefit-risk margin can be managed by: - Reducing the burden of ADRs through effective risk minimization - Enhancing benefit through patient selection, on treatment management etc 06/05/2011 Slide 27

28 Monitoring the effectiveness of RMAs Additional risk minimisation activities required when considered essential for the safe and effective use of the product Measures should be accompanied by proposals to evaluate their effectiveness The rationale for the additional risk minimisation measures should be clearly reflected in the EPAR to support HCPs understanding and adherence to risk minimisation measures. Transparency RMP (summary and AR) at website 06/05/2011 Slide 28

29 Monitoring the effectiveness of risk minimisation in the context of a RMS Direct measures of the risk being minimized should be employed whenever feasible; Indirect measures of the risk being minimized should be limited to those instances when direct measurement of the effectiveness is not feasible; Surveys and drug utilization studies using electronic databases are suggested as examples of indirect measures. 06/05/2011 Slide 29

30 New legal basis for monitoring the effectiveness of risk minimisation Regulation (EU) No 1235/2010 (Article 28a) and Directive 2010/84/EU (Article 107h(a)) New legal requirement. EMA/MSs shall: monitor the outcome of risk minimisation measures contained in risk management plans and of the conditions of Marketing Authorisation. 06/05/2011 Slide 30

31 Monitoring the effectiveness of risk minimisation Effectiveness is a measure of the extent to which a specific intervention fulfils its objectives when deployed in routine clinical practice. The assessment of effectiveness of risk minimisation is central to the benefit risk management cycle. Assessment of evidence should differentiate between implementation of an additional risk minimisation activity and achievement of its final objective. 06/05/2011 Slide 31

32 Performance Measure: Survey When to survey? Whom to survey? How to survey? Is the sample representative? What will the results tell us? 06/05/2011 Slide 32

33 Surrogate outcome measures RMA should have a clearly defined objective Has the educational material affected doctors behaviour? Drug utilisation studies are useful performance (surrogate) measures 06/05/2011 Slide 33

34 What to measure? Teratogenic drug No children with congenital abnormalities born No women on the drug becoming pregnant 06/05/2011 Slide 34

35 Effective risk management Measurable objectives - defined measures of success If risk minimisation is not working, need to analyse where it is failing implementation or conceptual failure. 06/05/2011 Slide 35

36 Pharmacoepidemiology and benefit-risk management Strengthened methodologies Evaluating new signals Quantifying risk Monitoring the effectiveness of risk minimisation Monitoring the impact of regulatory action 06/05/2011 Slide 36

37 06/05/2011 Slide 37

38 Future vision for benefit-risk management Bringing together all available evidence on effectiveness and harms in clinical use Clearly identifying limitations of evidence and uncertainty Better justified regulatory decisions Better public understanding of benefit risk Effective risk minimization is a key element of benefit-risk management. Monitoring its effectiveness requires health outcomes research. 06/05/2011 Slide 38