Clinical Epidemiology & Analytics – filling the evidence gap

Clinical Epidemiology & Analytics – filling the evidence gap Woodie M. Zachry, III, PhD Global Lead Clinical Epidemiology and Analytics

The Present – Overview of CE&A activities Establishing the disease profile • Natural history of the disease • Issues in special populations • Incidence/prevalence of the disease • Risk factors of disease Identifying drug safety issues in collaboration with Pharmacovigilance • Safety issues of Abbott products and other current therapies • Subpopulations at higher risk? • Drug-drug interactions? Providing clinical trial support and instrumentation • Identifying biomarkers/surrogate endpoints and its relationship to outcomes Company Confidential© 2009 Abbott

GRADE • The Grading of Recommendations Assessment, Development and Evaluation (GRADE ) • Provides a system for rating quality of evidence and strength of recommendations that is explicit, comprehensive, transparent, and pragmatic and is increasingly being adopted by organizations worldwide • High quality— Further research is very unlikely to change the estimate of effect • Moderate quality— Further research is likely to have an important impact on the estimate of effect and may change the estimate • Low quality— Further research is very likely to have an important impact on the estimate of effect and is likely to change the estimate • Very low quality— Any estimate of effect is very uncertain Company Confidential© 2009 Abbott

RCT Meta-analysis Case-Control Case Series Hierarchy of Evidence Prospective Less Bias Observational Studies Retrospective Less Bias Comparison with bias Uncontrolled Nonsystematic Clinical Experience Company Confidential© 2009 Abbott

Multiple EBM Stakeholders CONSORT Statement RCTs Levels of Evidence Chest EMEA Clinical Practice Guidelines FDA AHRQ NIH Users’ Guides JAMA QUORUM Statement Systematic Review Meta-Analysis HTAs ACP Journal Club Clinical Evidence NICE Cochrane Collaborative Company Confidential© 2009 Abbott

Where we want to be Evidence Summaries across All Phases of Development and Study Designs Identify Evidence Gaps and Propose Ways to Fill Gaps Evidence Based Approach Company Confidential© 2009 Abbott

Case-Control analysis of ambulance, emergency room, or inpatient hospital events for epilepsy and antiepileptic drug formulation changes Woodie M Zachry, III PhD Quynhchau D Doan PhD Jerry D Clewell, PharmD Brien J Smith MD

Background Epilepsy Treatment Disease & Treatment • Incidence: 200,000 cases annually in US, Prevalence: 1% from birth to age 20, then 3% by age 75.6 • Treatment choice dependent upon Partial vs. Generalized presentation, history & secondary causes. • “A-rated” compounds are considered to be therapeutically bioequivalent to the reference listed drug (United States Food & Drug Administration Center for Drug Evaluation & Research) • Generic substitution, observational experience • 65% of US physicians surveyed reported caring for a patient who had a breakthrough seizure after a brand to generic switch.1 • 49.2% of foreign physicians surveyed reported problems when switching from brand alternatives to generics.2 • 67.8% of surveyed neurologists reported breakthrough seizures after a switch.3 • 12.9% of Lamotrigine switches had to be switched back due to medical necessity (v.s 1.5-2.9 for Non-AED).4 • 10.8% of patients switching supplier for CBZ, PHT, & VAL had perceived problems validated by GP.5 • Berg MJ, Gross RA. Physicians and patients perceive that generic drug substitution of anti-epileptic drugs can cause breakthrough seizures - results from a U.S. survey. 60th Annual Meeting of the American Epilepsy Society; Dec 1-5, 2006; San Diego, California. • Kramer G. et al. Experience with generic drugs in epilepsy patients: an electronic survey of members of the German, Austrian and Swiss branches of the ILAE. Epilepsia 2007;48, 609-11. • Wilner AN. Therapeutic equivalency of generic antiepileptic drugs: results of a survey. Epilepsy Behavior 2004;5(6):995-8. • Andermann F, et al. Compulsory generic switching of antiepileptic drugs: high switchback rates ro branded compounds compared with other drug classes. Epilepsia 2007;48(3):464-9. • Crawford P. et al. Generic Prescribing for epilepsy. Is it safe? Siezure 1996;5:1-5. • Centers for Disease Control and Prevention 2007. http://www.cdc.gov/epilepsy/ Accessed October 10, 2007. Company Confidential© 2009 Abbott

Confidence in Treatment-Effect Relationship Low High 1Mednick D, Day D. JMCP 1997;3(1):66-75. 2Hennekens, C. Epidemiology in Medicine. 3Harris S. J Cont. Ed. In Health Prof 2000;20:133-45. Company Confidential© 2009 Abbott

Methods • Objective: To determine if patients who received epilepsy care in an inpatient setting, emergency room, or ambulance have greater odds of having had a change between A rated AED medication alternatives in the past 6 months when compared to epileptic patients with no evidence of receiving epileptic care in similar settings. Company Confidential© 2009 Abbott

Methods • Retrospective claims database analysis utilizing the Ingenix LabRx database • Case-control study • Unmatched & Matched 1:3 for age within 5 years and epilepsy diagnosis type • Index date for case patients: 1st seizure event requiring inpatient admission, emergency room visit, or ambulance during 3Q2006 – 4Q2006 • Index date for control patients: 1st office visit during 3Q2006 – 4Q2006 • Index primary ICD-9 diagnosis of 345.xx excluding 345.6 • 12 and 64 years of age • No inpatient admission, emergency room visit, or ambulance in 6 months prior to index date • Possess at least 145 day supply of AED medication for 6 months prior to index event • Continuous eligibility for 6 months prior to index. Company Confidential© 2009 Abbott

Siezure type Generalized Convulsive 345.0 Non-convulsive 345.1 Petite mal status 345.2 Grand mal status 345.3 Partial Complex partial 345.4 Simple partial 345.5 Epilepsia partialis continua 345.7 Other Other forms 345.8 Epilepsy unspecified 345.9 Modifier XXX.X0 – without mention of intractable epilepsy XXX.X1 – with mention of intractable epilepsy Diagnosis Categories Company Confidential© 2009 Abbott

Matched Case-Control Patients Excluding Patients Who Changed Dosage Schedule • Odds of a change between A rated alternatives Odds ratio = 2.011 (95% CI, 1.189 – 3.4) Company Confidential© 2009 Abbott

Discussion • This study tested a hypothesis and found a relationship between emergent and inpatient care visits and previous AED formulation switching. This is concordant with problems identified in the survey and case study literature. • surveyed physicians believe there may be potential safety problems associated with switching between AED formulations for the same medication • There is some evidence of a significant percentage of patients who must switch back to a branded formulation after trying a generic formulation. Company Confidential© 2009 Abbott

Discussion • This study assumes that patients experiencing break-through seizures will seek care in emergency and inpatient settings more often than ambulatory settings. • Study subjects seeking care for break through events in an ambulatory setting may have attenuated the true magnitude of the significant relationship found in this study. • Attempts were made to strengthen the assumption that subjects were taking AEDs. However, claims data only records the date a prescription was filled, not when or if the patient took the medication. • Subtle differences in formulations may take time to accumulate and effect outcomes. However, the majority of formulation changes occurred within 2 months of the index event. Company Confidential© 2009 Abbott

Discussion • Several factors may play a role in break through seizures that were not controlled for in this analysis (e.g., sleep deprivation, alcohol intake, hormonal influences). These effects may be additive to or even supersede formulation changes in precipitating break-through seizures. • Zonisamide became available as a generic during the study time period. The high percentage of zonisamide formulation changes may have played a role in the significant relationship discovered. • Case-control studies cannot establish a temporal association between AED formulation switches and outcomes. Company Confidential© 2009 Abbott

Conclusions • This analysis has found an association between patients who utilized an ER, ambulance or inpatient hospital for epilepsy and the prior occurrence of AED formulation switching involving “A” rated generics. • After matching by age and epilepsy diagnosis, Cases had 81% greater odds of prior “A” rated switches compared to matched controls. • The case population had significantly more Medicaid patients. • Post hoc analyses excluding patients who had a dosage change and Medicaid patients did not change the significance of the original analysis. • Further investigations are warranted to better understand a possible cause-effect relationship. Company Confidential© 2009 Abbott

RCT Meta-analysis Case-Control Case Series Hierarchy of Evidence Prospective Less Bias Observational Studies Retrospective Less Bias Comparison with bias Uncontrolled Nonsystematic Clinical Experience Company Confidential© 2009 Abbott

Clinical Epidemiology & Analytics – filling the evidence gap