1. iPhVWP Polish Presidency, Warsaw October 6 th 2011 Almath Spooner Irish Medicines Board Monitoring the outcome of risk minimisation activities

2. Benefit-Risk Management New EU legislation on Pharmacovigilance: Promote and protect public health by reducing burden of adverse drug reactions through effective risk minimisation and optimising use of medicines. 26/08/2015Slide 2

3. Regulation EU 1235/2010 - 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. ‘ 26/08/2015Slide 3

4. Waller P and Evans S. A model for the future conduct of Pharmacovigilance. Pharmacoepidemiology and Drug Safety, 2003; 12: 17–29 Best Evidence Robust scientific Decision Making Tools for protecting public health Measurable performance in terms of public health benefit Culture of Scientific Development Outcome measures and audit

5. 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. 26/08/2015Slide 5

6. Evaluating the need for Risk Minimisation For each important safety issue, we consider: - Are risk minimisation actions needed? - Is the product information sufficient for this purpose? How do we establish this? - If no, then additional risk minimization required? - Potential for medication error/misuse is considered. 26/08/2015Slide 6

7. Additional risk minimisation Educational materials - Need for critical evaluation of their objective and clear measures of success. - However, potential to be a useful tool. - Should these be considered in the context of the broader risk minimisation strategy rather than as a separate entity? - Can they complement rather than compete with the SmPC? 26/08/2015Slide 7

8. Current EU Guidance

9. Additional risk minimisation measures provision of information and education control the use

10. 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. MSs/EMA shall: ‘monitor the outcome of risk minimisation measures contained in risk management plans and of the conditions’ of Marketing Authorisation. 26/08/2015Slide 10

11. Reflection paper on effectiveness of risk minimisation – some principles Direct measures of the risk being minimised should be employed whenever feasible; Indirect measures of the risk being minimised should be limited to those instances when direct measurement of the effectiveness is not feasible; Surveys and drug utilisation studies using electronic databases are suggested as examples of indirect measures. 26/08/2015Slide 11

12. What are we evaluating? Effectiveness of risk minimisation? Outcome of risk minimisation – intended and unintended? Compliance with recommendations? Scientific validity of the recommendations? Understanding of preventability. - Do we need to provide for a spectrum of approaches to evaluating public health impact? - Could each be valid depending on the circumstances? - How could we accommodate flexibility but ensure underpinned by scientific rigor? 26/08/2015Slide 12

13. Risk Minimisation Activities Risk Minimisation Activities = Public Health Interventions….therefore... - Complex?* (No of elements) - Programmatic? (Implementation is important) - Context dependent? L Rychetnik, M Frommer, P Hawe, A Shiell * Interplay of factors impacting on outcomes. 26/08/2015Slide 13

14. Challenges for the evaluation of RMAs Need to distinguish between the fidelity of the evaluation process in detecting the success or failure of an intervention, and the success or failure of the intervention itself --  scientific rigor/methodology -  GVP should address. If an intervention is unsuccessful, the evidence should help to determine whether the intervention was inherently faulty or just badly delivered  GVP Descriptive information on the intervention and its context is required to assess transferability/ generalisability -  GVP could provide principles? 26/08/2015Slide 14

15. Questions for evaluative research 1. Is the research good enough to conclude on whether the intervention was successful? 2. What are the research outcomes? 3. Are the results transferable? Database study in UK/NL/IT etc…results transferable to IE? 26/08/2015Slide 15

16. 1. Is the research good enough? ‘Good enough’ = helps us to understand why an intervention appears to be effective or not. Contribution of observational studies: - Need to discriminate between observational study designs - Improve our understanding of bias - Consider the importance of the study design relative to other dimensions of quality in evaluation research. - How can the GVP module support the conduct of studies that are ‘good enough’? 26/08/2015Slide 16

17. 2. What are the intervention outcomes? 1. Identify the outcome information needed by regulatory authorities and our stakeholders. 2. Consider both anticipated and unanticipated effects – ‘outcome’ as well as ‘effectiveness’ of RMMs. 3. Implementation successes/failures 26/08/2015Slide 17

18. 3. Are the results transferrable? To determine this require descriptive information: 1. Information on the intervention and its delivery 2. Information on the context 3. Interaction between the intervention and the context 26/08/2015Slide 18

19. 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. 26/08/2015Slide 19

20. Performance Measure: Survey Need for guidance and better understanding of bias? Common considerations: When to survey? Whom to survey? How to survey? Is the sample representative? What will the results tell us? 26/08/2015Slide 20

21. Drug Utilization Studies in Risk Management What is their value? Do they provide a valid option for evaluating the performance of risk minimization measures? Strengths e.g. less biased than survey Limitations e.g. information available on databases Challenges e.g. transferability? Opportunities for developing methodological guidance? Should this be part of a GVP module on this topic? 26/08/2015Slide 21

22. Points to consider What should be the driver for formal evaluation of the effectiveness of risk minimisation? 1. Nature of the safety issue (adverse reaction burden, potential impact on the benefit-risk profile etc) ? 2. Uncertainties regarding the evidence base for the risk minimisation strategy? 3. Concerns regarding how the medicine is used in real life medical practice and implications for benefit-risk. 4. Classification of the risk minimisation activity as routine or additional – how would the contribution of the additional risk minimisation alone be scientifically evaluated? 26/08/2015Slide 22

23. Conclusion Effective risk management requires: Measurable objectives - defined measures of success Evaluation of the risk minimisation strategy for a product in terms of its outcomes and not just its evaluation of its individual elements i.e. scope includes routine and additional risk minimisation measures. If risk minimisation is not working, need to analyse where it is failing – implementation or conceptual failure Drug utilisation studies have an important role. GVP module will need to include methodological guidance Standalone module but needs to be integrated into pharmacovigilance planning, reporting in PSURs etc. Proposals need to be feasible, realistic and underpinned by science. Work to be done on terminology. 26/08/2015Slide 23