Title: Pharmacoepidemiology in clinical drug development

1. Pharmacoepidemiology in clinical drug development Presenter: Dr David E Neasham Company logo here

8. Study design

9. Study design: Measuring disease risk Slide © Imperial College London Types of error: study bias, chance variation, confounding

10. Study design hierarchy + Bradford Hill causality criteria 

11. A typical scenario: identifying risks INCIDENCE OF COMMONLY OCCURRING EVENT FROM CLINICAL TRIALS Background Epidemiology Risk management strategy  INCIDENCE OF EVENT IN GENERAL POPULATION IDENTIFICATION OF RISK FACTORS POTENTIAL SIGNALS OF RARE EVENTS Spontaneous Reports Observational Studies Other Activities 1/1,000 1/500 1/100 1/10,000 1/5,000 1/1,000 1/100,000 1/50,000 1/10,000 HYPOTHESIS TESTING 1/1,000,000 1/500,000 1/100,000, Clinical trial Data Insufficiently powered Evidence base Self-report bias Best study design….

17. Cohort Formation INGENIX Research Database Women (10-59 yrs) n = 959,482 Propensity score matching of 12 initiator cohorts (n = 22,429) New dispensing of Yasmin (n = 31,149) New dispensing of other OCs (n = 360,505) ≥ 6 months continuous enrollment (n = 22,887) ≥ 6 months continuous enrollment (n = 227,596) Propensity score matching of 12 initiator cohorts (n = 44,858) 1:2 Ratio

19. Yasmin Launch Q3 Time Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 2001 2002 2003 2004 Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow-Up Follow-Up Yasmin Control P Follow Follow Yasmin Control P 2005 Q1 Q2 Q3 Q4 Claims-Based Outcomes Chart-Based Outcomes Apr. Report Oct. Report Apr. Report Oct. Report Apr. Report Oct. Report Apr. Report Final Report

20. Blinded Chart Reviews to Confirm Outcomes Claims Based Abstraction Medical Chart Abstraction Screen Claims Data Medical Review

21. Rate Ratios Some outcomes may be continuations of pre-existing conditions * No rate ratio calculated as no case in Yasmin Cohort ** Composite hyperkalemia outcome comprised of chart-confirmed cases of arrhythmia, syncope, electrolyte disturbance, hyperkalemia, and myocardial infarction. Syncope Arrhythmia Hyperkalemia Other Electrolyte Disturbance Dialysis* Myocardial Infarction* Hospitalization with Hyper/Hypokalemia* Death Composite Hyperkalemia** 0 0 0 0 Incidence Rate Ratio –Yasmin versus Other OC (95% CI) 5.0 1.0 2.0 4.0 3.0 0.5 0.25 0.33 0.2 0.1

27. Evolution of Lipid Management ATP Guidelines* ATP I (1988) ATP II (1993) ATP III (2001) Diet; low-dose, non-statin monotherapy High-dose statin, combination therapy Low- to moderate-dose statin monotherapy Increasing aggressiveness of cholesterol-lowering therapy * The National Cholesterol Education Program Adult Treatment Panel (ATP)

31. Pharmacoepidemiology program

33. Pooled person-time and outcomes

38. Pharmacoepidemiology in clinical drug development Dr David E Neasham [email_address] +44 (0)1628 408442 Questions & answers Company logo here