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“PARM 17 th Annual Convention” Marco Hotel, Cagayan De Oro City February 28 – March 1, 2007

“PARM 17 th Annual Convention” Marco Hotel, Cagayan De Oro City February 28 – March 1, 2007. Fracture Reduction in Observational Trials. Broadening the Evidence. Importance of Nonvertebral Fractures. Nonvertebral fractures are approximately… 75% of all osteoporotic fractures and

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“PARM 17 th Annual Convention” Marco Hotel, Cagayan De Oro City February 28 – March 1, 2007

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  1. “PARM 17th Annual Convention”Marco Hotel, Cagayan De Oro CityFebruary 28 – March 1, 2007

  2. Fracture Reduction in Observational Trials Broadening the Evidence

  3. Importance of Nonvertebral Fractures Nonvertebral fractures are approximately… 75% of all osteoporotic fractures and 90% of all osteoporosis related costs Percent Osteoporosis-related Costs Percent total osteoporotic fractures Vertebral Vertebral Nonvertebral Nonvertebral Data source: Medstat Marketscan which is comprised of ~ 45 private & public US health plans. n = 1,009,270: Inpatient and outpatient medical claims for fractures analyzed among women between 50 and 89 years enrolled in managed care programs in the year 2003. Adachi, CTI 2006; 20 (Suppl 1): S125

  4. BONE 8.2% MORE FIT2 FIT1 Liberman Nonvertebral Fracture Risk ReductionAmong Antiresorptives There are no head-to-head fracture studies between antiresorptive therapies PROOF 1.4 1.3 1.2 1.1 --------------------------------------------------------------------------------------------- 1.0 RELATIVE RISK * 0.9 0.8 * 0.7 HIP 0.6 0.5 VERT-MN 0.4 VERT-NA 8.4% 0.3 7 8 9 10 11 12 13 14 15 16 17 18 * stat sig PLACEBO FRACTURE INCIDENCE [%] TREATMENT: Aln Ibn Ris Calcitonin Ral Adapted from Boonen S et al. OI 2005; 16: 1291

  5. Control Risedronate Control Alendronate 14 12 * 36% P=0.002 * 10 * 8 6 4 2 0 0 6 12 18 24 30 36 Time (months) Nonvertebral Fracture ReductionPost-hoc Analyses There are no head-to-head fracture studies between antiresorptive therapies 14 12 59% P=0.002 10 8 % patients with nonvertebral fracture 6 * * * * * 4 * * * * 2 * * 0 6 12 18 24 30 36 Time (months) n= 3658; Patients with a baseline vertebral fracture or femoral neck T score of -2.5 or less. Nonvertebral osteoporotic fractures measured as a composite endpoint (sites are not defined). n=1172; Patients with lumbar spine BMD T-score <-2.5. Nonvertebral fractures based on a composite endpoint of the following: clavicle, hip, humerus, leg, pelvis and wrist. Black JCEM 2000;85:4118 Harrington Calcif Tissue Int 2004;74:129

  6. Broadening the EvidenceThe Role of Observational Studies

  7. Randomized controlled trials (RCTs) are the gold standard for determining drug safety and efficacy and are prerequisite for regulatory approval of new drugs By design, RCTs have strict inclusion and exclusion criteria Evidence Based on Randomized Controlled Trials (RCT) McKee M, et al. BMJ (1999);319:312-315

  8. Applying randomized controlled trial datato clinical practicePatients inclusion in randomized controlled trials Included Patients (%) In these two studies, less than 20% of patients in clinical practice were eligible for inclusion in randomized controlled trials (RCT) Dowd R, Recker RR, Heaney RP. OI 2000;11:533-6. Hlatky MA, et al. Stat Med 1984;3:375-84.

  9. Reasons for Exclusion (%) Barriers to Patient Entry into RCTsReasons patients not eligible for study Age Medications Comorbidity Disease Too Severe Primary reasons that patients are excluded from participating in osteoporosis randomized controlled trials at one center Dowd R, Recker RR, Heaney RP. OI 2000;11:533-6.

  10. Over the past decade, large claims databases have become very common in North America and Europe and are used to conduct effectiveness studies As clinical practice data accumulate over time, outcomes studies can be conducted to complement data generated by RCTs Broadening the EvidenceObservational and Claims Data Studies * Ayanian, JZ Eur Heart J (1999) 20: 1689-91

  11. RCT’s and Observational StudiesConsistent Results Key Findings: • Treatment effects in observational studies and RCT’s were similar for studies published since 1985 Of 19 diverse treatments from 136 reports, 89% showed that estimates of treatment effect from observational studies were not different from RCTs Overall, results from well-designed observational studies show similar treatment effects compared to randomized controlled trials Benson K et al. NEJM 2000;342(25):1878-86.

  12. Broadening the EvidenceObservational Studies Diversity of population and health care providers in category Health Care Database Health Care Database RCT RCT Product A Product B Time in category • Health Care Database studies can be conducted to create insights in the disease state, real world safety, treatment patterns, resource utilization and population-based effectiveness • Complements RCT findings in larger and more diverse patient-types within therapeutic category • Can provide basis for therapeutic comparison in real world patients

  13. Patient Observation Based on Claims Data Health plans with millions of people Provide service Record diagnosis, procedure, prescription Billing of service for patient Entry of ICD-9 coded diagnosis, NDC coded prescription Dates of service Claim payment by insurance company Collects all billing info, which can be used for research purposes

  14. Effectiveness of Bisphosphonates on Nonvertebral and Hip Fractures in the First Year of Therapy: The Risedronate and Alendronate (REAL) Cohort Study Delmas PD, Silverman SL, Watts NB,Lange JL, Lindsay R J Bone Miner Res 2006;21(Suppl 1):S180 Presented at: the Twenty-Eighth Annual Meeting of the American Society for Bone and Mineral Research, Philadelphia, PA; September 15-19, 2006

  15. To evaluate the onset of fracture reduction by by measuring the incidence of hip and non-vertebralfractures among women 65+ in the first year following initiation of either once-a-week dosing of risedronate or alendronate Study Objective Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  16. Ingenix Lab/Rx MedStat Marketscan Contain patient-specific data including: Demographic information Clinical encounters Outpatient pharmacy dispensing Data SourcesTwo real-world medical practice databases 12 million people in 100 health care plans Shaded states have patients covered by MedStat and/or Ingenix databases Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  17. History Period Exposure Period Observation PeriodTreatment initiation between July 2002 and Sept 2004 1stRx Up to 12 months At least 6 months Observation of risk factors for fracture Observation of fracture outcomes(nonverterbral fractures and hip fractures) Direction of inquiry Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  18. Inclusion Criteria: All Women ≥65 years of age Once-weekly bisphosphonate (BP) use between Jul-02 and Sep-04 Exclusion Criteria: <6 months of health plan enrollment before first BP use <3 months of health plan enrollment after first BP use Any BP use during 6-month history period Diagnosis of Malignancy or Paget’s disease Discontinuation of BP therapy with first 3 months of exposure period Study Population Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  19. Retrospective Cohort Design Eligible women ≥65 Years With Fracture Once-weeklyrisedronate Without Fracture With Fracture Once-weeklyalendronate Without Fracture Population Exposure Outcome

  20. Nonvertebral Fractures Collectively (hip, wrist, humerus, clavicle, pelvis, leg) Hip Fractures The rate of fracture incidence was compared through 1 year between cohorts of risedronate and alendronate patients during therapy Proportional hazard modeling to adjust for measurable differences in fracture risk factors Fracture OutcomesFracture sites and analysis methods Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  21. Baseline CharacteristicsDeterminants of fracture risk Characteristic Risedronate Alendronate Cohort size (n) 12,215 21,615 Age (years) at study entry (mean)* 74.8 74.6 Medication – 6 month history Concomitant meds (mean)* 4.0 3.6 Gastrointestinal med use (%)* 26.2 20.1 Estrogen use (%) 17.2 16.5 Glucocorticosteroid use (%)* 10.3 8.5 Medical – 6 month history Hospitalization (%) 8.2 8.2 Office visits (mean)* 5.6 5.1 Rheumatoid arthritis diagnosis (%)* 2.7 2.3 * p<0.05 between cohorts Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  22. 0.58 alendronate 0.50 0.40 0.30 % of cohort with a hip fracture risedronate 0.20 0.10 0.00 Baseline Month 6 Month 12 Cumulative Hip Fracture Incidence ↓43% * at Month 12 *Adjusted Relative Rate Reduction, p = 0.01, 95% CI: 13% - 63% Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  23. Cumulative Incidence of Hip Fractures During Therapy Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  24. 2.3 2.0 1.5 1.0 0.5 0.0 Cumulative Nonvertebral Fracture Incidence alendronate ↓18%* at Month 12 risedronate % of cohort with a nonvertebral fracture Month 6 Month 12 Baseline *Adjusted Relative Rate Reduction, p = 0.03, 95% CI: 9% - 32% Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  25. Cumulative Incidence of Nonvertebral Fractures During Therapy Delmas PD et al. J Bone Miner Res 2006;21(Suppl 1):S180

  26. Internal validity (systematic error) Information bias Selection bias Validation of data analysis Sensitivity analyses Validation of statistical analysis Consistency with other studies Biological plausibility How can I assess the comparability of the cohorts and the relevance of the results?

  27. There are known knowns. There are known unknowns. But there are also unknown unknowns. Information BiasAvailable data within claims databases Age, glucocorticoid use, rheumatoid arthritis, recent fracture history BMD, smoking, maternal fracture history, lifetime history of fracture Many fractures occur in persons with no obvious risk factors Donald Rumsfeld on a briefing on the IRAQ campaign

  28. Selection BiasFractures in pre-exposure history period Fracture diagnosis in pre-exposure period (%) * * 6-month pre exposure 12-month pre exposure (Subset (81%) of patients with 12-month history) * p<0.05

  29. Internal validity (systematic error) Information bias Selection bias Validation of data analysis Sensitivity analyses Validation of statistical analysis Consistency with other studies Biological plausibility Are these observations real?Criteria for a causal association

  30. 1.0 0.8 Rate ratio and 95% confidence interval for fracture (risedronate:alendronate) 0.6 3 2 1 0.4 Sensitivity AnalysisEffect of fracture risk differences between cohorts Hip fracture primary analysis ● • Exclude subjects with prior estrogen use (n - 9505) 2) Exclude subjects with prior glucocorticoid use (n - 3086) 3) Exclude subjects with history of fragility fracture in the past 6 months(n - 2235) Primary analysis (n = 33,830), using a proportional hazard model for statistical adjustment of differences in baseline fracture risk

  31. Rate ratio and 95% confidence interval for fracture (risedronate:alendronate) 4 Sensitivity AnalysisEffect of history period differences between cohorts Hip fracture primary analysis ● • Included subjects with less than 6 months history period (n + 43,032) 1.0 0.8 0.6 0.4 Primary analysis (n = 33,830), using a proportional hazard model for statistical adjustment of differences in baseline fracture risk

  32. Rate ratio and 95% confidence interval for fracture 5 (risedronate:alendronate) Sensitivity AnalysisEffect of therapy adherence differences between cohorts Hip fracture primary analysis ● 1.0 5) Included all patients initiating bisphosphonate therapy regardless of therapy adherence (intent-to-treat) (n+17,329) 0.8 0.6 0.4 Primary analysis (n = 33,830), using a proportional hazard model for statistical adjustment of differences in baseline fracture risk

  33. The authors jointly developed the study plan The authors had full access to all data and validated the analyses independently Validation of Statistical Analysis

  34. Internal validity (systematic error) Information bias Selection bias Validation of data analysis Sensitivity analyses Validation of statistical analysis Consistency with other studies Biological plausibility Are these observations real?Criteria for a causal association

  35. Control RCT Risedronate RCT Control RCT Alendronate RCT 14 59% P=0.002 Risedronate REAL 12 * * Alendronate REAL 10 * 36% P=0.002 8 % patients with nonvertebral fracture 6 * 14 * * * * 4 * 12 * * * 2 * * 10 0 8 6 12 18 24 30 36 0 6 12 18 24 30 36 6 Time (months) Time (months) 4 2 0 Nonvertebral FracturesConsistency of results between REAL study and post-hoc analysis of pooled clinical trial data n= 3658; Patients with a baseline vertebral fracture or femoral neck T score of -2.5 or less. Nonvertebral osteoporotic fractures measured as a composite endpoint (sites are not defined). n=1172; Patients with lumbar spine BMD T-score <-2.5. Nonvertebral fractures based on a composite endpoint of the following: clavicle, hip, humerus, leg, pelvis and wrist. Black JCEM 2000;85:4118 Harrington Calcif Tissue Int 2004;74:129 Based upon published data. Not from a head to head study

  36. Internal validity (systematic error) Information bias Selection bias Validation of data analysis Sensitivity analyses Validation of statistical analysis Consistency with other studies Biological plausibility Are these observations real?Criteria for a causal association

  37. Biologic PlausibilityDistinct differences among bisphosphonates Differential Binding to Hydroxyapatite • Affects uptake and distribution in bone • Affects duration of response and reversal of effect Differences in Inhibition of FPP Synthase • More potent BPs (eg risedronate) bind to FPPS more tightly • Cause conformational changes in the enzyme • Producing essentially irreversible inhibition

  38. In the REAL study, patients using risedronate had an earlier and lower incidence of non-vertebral and of hip fractures in the first year of therapy than those using alendronate. This cohort study is consistent with the results of previous randomized controlled clinical trials. Conclusion

  39. Maraming Salamat Po !

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