1. © Safeguarding public health Innovation; issues for regulators, society and industry. Overview of Conference topics Alasdair Breckenridge Medicines and Healthcare products Regulatory Agency London 23 September 2008

2. © “It is a frustrating aspect of benefit-risk evaluation that there is no defined and tested algorithm or summary metric that combines benefit and risk data that might permit straightforward quantitative comparisons of different treatment options, which in turn might aid decision making” CIOMS, 1998.

3. © Current perceptions Approval thresholds heightening Increased focus on safety Regulators dislike uncertainty Increasing cost of drug development Demand for increased transparency Negative perceptions of pharmaceutical industry and regulators

4. © What information do regulators and industry need to enable them to undertake benefit : risk assessments? Are available frameworks adequate? How can we best communicate benefit : risk to the general public?

5. © Benefits of an agreed framework Shared understanding of issues between industry and regulator. Consistency in expressing benefit and risk. Transparency of regulatory decisions Tool to compare products

6. © Methods of assessing benefit Nature of disease-incidence natural history impact of treatment consequences of no intervention Purpose of treatment-prevention prevention of recurrence symptomatic treatment cure Assessment of benefit-morbidity mortality symptoms quality of life

7. © Methods of assessing risk Development or post marketing ADRs affecting different systems Seriousness of ADRs

8. ©  Under-reporting Reporting bias Quality of reports Cannot estimate frequency of events Spontaneous reports of ADRs

9. © Knowledge Time

10. © Knowledge Time Timing of market authorisation MA

11. © Knowledge Time Earlier to market? MA Post-licensing assessment

12. © “A systematic approach to population based drug safety surveillance which seeks to ascertain the number of adverse events by means of a continuous pre-organised process.” Active Surveillance

13. ©  Record of drug exposure Record of outcomes Access to detailed information about individual cases Data requirements for active surveillance

14. ©  Computerised databases of users and non users Medical records Sources of information for active surveillance

15. © British Society of Rheumatology Biological Register(1) For patients with severe RA prescribed anti TNF α medicines. To receive drug, patient must be entered on central register. Short and long term ADRs documented. Cohort of similar patients prescribed conventional DMARDs

16. © British Society for Rheumatology Biological Register(2) Rheumatologists contacted 6 monthly about specific patients Data on severe infections and hospital admissions obtained Patient diaries Patients flagged with ONS to ascertain new cases of cancer and deaths Over 20000 patients on register

17. © GPRD: population figures Contains 6.1 million acceptable patients from 464 active practices Currently collecting data on 3.58 million active patients from 405 up to standard practices >45% of patients have 5 or more years of follow-up, >60% have at least 3 years Contains over 40 million patient-years data Geographically representative

18. © Safeguarding public health RISK major minor The worst balance For restricted use only Balance may require further study Acceptable balance Excellent balance minormajorBENEFIT The Benefit-Risk Spectrum

19. © Principle of three Seriousness, duration, incidence as applied to adverse reactions Seriousness, chronicity, extent of control or cure as applied to benefit Describe verbally or numerically

20. © Aspirin DiseaseEffectiveness of the drug Dominant reaction Seriousness133 Duration132 Incidence302 TOTAL567 3 = high, 2 = medium, 1 = low, 0 = no effect

21. © Shortcomings of models Do not enhance objectivity of benefit-risk decision making Time consuming Conflict between stakeholders in assessment

22. © Benefit-risk : outstanding issues Need for lexicon of terminology Framework for benefit: risk assessment in which different models might be used Different models for different situations Agreed framework would improve underlying science of innovation Importance of taking patient preferences into account Learning from other disciplines, including HTA Communication difficult but crucial