1 / 48

OsteoporosisWRAP SlideCAST

OsteoporosisWRAP SlideCAST. Complexities and Challenges of Measuring Fracture End Points Interpreting the Results of Existing Trials. Steven T Harris MD FACP Clinical Professor of Medicine University of California, San Francisco.

arnaud
Download Presentation

OsteoporosisWRAP SlideCAST

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. OsteoporosisWRAPSlideCAST Complexities and Challenges ofMeasuring Fracture End Points Interpreting the Results of Existing Trials Steven T Harris MD FACP Clinical Professor of Medicine University of California, San Francisco

  2. Regulatory approval of existing medications has been based on fracture reduction, rather than changes in surrogates such as bone mineral density (BMD) alone The most common fracture endpoint has been the reduction in vertebral fracture Vertebral fracture has most often been defined on the basis of morphometric changes, including both “new” and “worsening” fractures “Clinical” vertebral fracture—defined as fracture associated with back pain—has usually been identified as a secondary endpoint Fracture Endpoints

  3. “Non-vertebral fracture” has most commonly been identified as a secondary endpoint as well Varying definitions of “non-vertebral fracture”: all fractures vs fragility fractures vs a particular composite endpoint Hip fracture has sometimes—but not always—been identified as a separate endpoint of particular interest Fracture Endpoints, con’t

  4. Fracture reduction has most often been expressed —both clinically and commercially—as relative risk reduction, rather than absolute risk reduction The rapidity with which fracture protection occurs has been of clinical—and commercial—interest There are no head-to-head randomized trials with fracture as the primary endpoint The pivotal fracture trials recruited patients with a certain “sameness”—but there were notable differences in demographics, baseline fracture status and baseline BMDs nevertheless There were obvious differences in observed fracture rates—both vertebral and non-vertebral Fracture Endpoints, con’t

  5. RLX ALN RIS IBN Calcium CT ZOL Vertebral Fracture Effects In Prospective Trials Direct Comparisons Among Trials Cannot Be Made 49% 30 40% % = Relative Fracture Risk Reduction % of Patients With New Vertebral Fractures Over 3-5 Years 25 30% 20 41% 47% 15 70% 52% 10 50% 50% 5 0 PROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFA With Prevalent Vertebral Fractures ± Vert Fx Without Vert Fx Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637 Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077 Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83 Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356:1809

  6. RLX ALN RIS IBN Calcium CT ZOL Nonvertebral Fracture Effects In Prospective Trials Direct Comparisons Among Trials Cannot Be Made * 30 % = Relative Fracture Risk Reduction 25 % of Patients With New Nonvertebral Fractures Over 3-5 Years 33% p = 0.06 12% p = n.s. 20 20% p = 0.06 12% p = n.s. 15 25% p < 0.001 10% p = n.s. 39% p < 0.05 p = n.s. 10 5 0 PROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZON * Patient demographics and the definition of nonvertebral fracture varied among studies Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637 Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077 Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83 Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356:1809

  7. If existing randomized clinical trials cannot reasonably address all issues of clinical relevance, then additional insights can be gleaned from: Additional—post hoc—analyses of existing trial data Meta analyses of existing trial data Observational data Fracture Endpoints

  8. Nonvertebral Fracture ReductionPost-hoc analyses 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) 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=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. 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). Harrington Calcif Tissue Int 2004;74:129 Black JCEM 2000;85:4118

  9. Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis (PMO): results of a meta-analysis of Phase III studies Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  10. Study Objectives • To evaluate the nonvertebral and clinical fracture efficacy of different doses of ibandronate using a pooled analysis of data from 4 pivotal phase III clinical trials: BONE,1 IV Dose Fracture,2 MOBILE,3 and DIVA4 • To estimate the fracture rate over time using the Kaplan-Meier method 1oral iBandronate Osteoporosis vertebral fracture trial in North America and Europe. Chesnut CH, et al. Curr Med Res Opin. 2005;21:11-18. 2Recker R, et al. Bone. 2004;34:890-899. 3Monthly Oral iBandronate In LadiEs. Reginster JY, et al. Ann Rheum Dis. 2006;65:654-661. 4Dosing IntraVenous Administration. Delmas PD, et al. Arthritis Rheum. 2006;54:1838-1846.

  11. Cox regression analyses were adjusted for variables to allow for meaningful comparisons among trials Age Previous clinical fracture Baseline BMD Lumbar spine BMD for models with all clinical fractures Hip BMD for models with nonvertebral fractures (NVFs) or key NVFs Kaplan-Meier methods were used to: Plot survival curves for time to fracture Compare rates using a log-rank test Pooled Fracture AnalysisMethods Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  12. Fracture rates were determined by tabulating the proportion of all ITT patients with at least 1 fracture Doses were pooled based on annual cumulative exposure (ACE) ACE was calculated by multiplying the drug strength by the number of annual doses and by an absorption factor (0.6% for oral dosing and 100% for IV dosing) For example, the ACE for oral BONIVA 150 mg once-monthly would be 10.8 mg = 150 x 12 x 0.006 Pooled Fracture Analysis Methods (cont.) Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  13. IV and oral ibandronate annual cumulative exposure across studies 12 mg 12 10.8 mg 8 mg 8 5.5 mg Annual cumulative exposure (mg) 4 mg 4 0 Quarterly IV Oral daily Quarterly IV Oral monthly Quarterly IV MF43801 BONE2 IRIS3 MOBILE4 DIVA5 1. Recker R, et al. Bone. 2004;34:890-899. 2. Chesnut CH, et al. J Bone Miner Res. 2004;19:1241-1249. 3. Adami S, et al. Bone. 2004;34:881-889. 4. Miller PD, et al. J Bone Miner Res. 2005;20:1315-1322. 5. Data on file (Reference #161-153), Hoffman-La Roche Inc, Nutley, NJ 07110

  14. Fracture risk reductions for high dose of ibandronate (≥10.8 mg/yr), by fracture type Nonvertebral fractures Key nonvertebral sites All clinical fractures 0 -10 % † -20 -30 Relative risk reduction, -40 -50 28.8%* 29.9%* 34.4%* -60 *P<0.05 +/- 95% Confidence Intervals †Relative risk reduction adjusted for age, baseline BMD, and fracture history.

  15. ACE ≥10.8 mg Placebo Pooled Ibandronate Fracture Analysis 10 8 6 4 2 0 Relative Risk Reduction28.8% P<0.05† Estimated Clinical Fracture Rate, % 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Days †Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo.Kaplan-Meier plot (2-year data). Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  16. ACE ≥10.8 mg Placebo Pooled Ibandronate Fracture Analysis, con’t 10 8 6 4 2 0 Relative Risk Reduction 29.9% P<0.05† Estimated Nonvertebral Fracture Rate, % 0 50 100 150 200 250 300 350 400 450 500 550 600 650 700 750 Days †Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo.Kaplan-Meier plot (2-year data). Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  17. Not all studies were placebo-controlled A limited number of baseline patient characteristics (age, previous fracture, baseline BMD) were available for use in multivariable models This was an exploratory, post hoc analysis with no adjustment for multiple comparisons Limitations Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  18. In this pooled analysis, doses of ibandronate resulting in an ACE of ≥10.8 mg—which include the marketed doses of 150 mg monthly oral and 3 mg IV quarterly—significantly reduced the risk of clinical fractures and non-vertebral fractures compared to placebo The high ACE group (≥10.8 mg) had a longer time to fracture compared to placebo for all clinical fractures, non-vertebral fractures and key non-vertebral fractures Conclusions Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  19. Strengths Treatment patterns are those in “real world” clinical practice A large number of patients can be followed over time Limitations No chart review available to validate the ICD-9 codes Selection bias is possible—if not probable Cannot assess the use of samples or OTC products Extraneous variables are not controlled Observational StudiesStrengths and Limitations of Claims Data

  20. RIS vs. ALNRR=0.46(p=0.067) RIS vs. ALNRR=0.41(p<0.05) 59% 54% Protocare Sciences DatabaseNonvertebral Fracture Incidence ALN vs. CAL RR=0.74(p=NS) ALN vs. CAL RR=0.75 (p=NS) RIS vs. CALRR=0.31(p<0.05) RIS vs. CALRR=0.25 (p<0.01) 4.0 3.0 25% Fracture incidence (%) 75% 2.0 26% 69% 1.0 0.0 6-months 12-months Nasal calcitonin Alendronate Risedronate *Adjusted for age, sex, HRT use, number of concomitant medications and fragility fractures in pre-treatment period Watts N, et al. J Manag Care Pharm 2004;10:142-151

  21. Effectiveness of Bisphosphonates on Nonvertebral and Hip Fractures in the First Year of Therapy: The Risedronate and Alendronate (REAL) Cohort Study Silverman SL, Watts NB, Delmas PD, Lange JL, Lindsay R Silverman L et al. Osteoporos Int. 2007;18:25-34

  22. Study Objective • To evaluate the onset of fracture reduction by bisphosphonate therapies in clinical medical practice by measuring the incidence of hip and nonvertebral fractures among women 65+ in the year following initiation of either once-a-week doing of risedronate or alendronate

  23. Fracture OutcomesFracture Sites and Analysis Methods

  24. Study Population • Inclusion Criteria • All women • > 65 years of age • Once-weekly bisphosphonate (BP) use between July 2002 and September 2004 • 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

  25. Baseline CharacteristicsDeterminants of Fracture Risk

  26. Cumulative Hip Fracture Incidence

  27. Cumulative Incidence of Hip Fractures During Therapy

  28. Cumulative Nonvertebral Fracture Incidence

  29. Cumulative Incidence of Nonvertebral Fractures During Therapy

  30. Conclusion • In an observational study of medical practice, patients using risedronate had a lower incidence of nonvertebral and of hip fractures in the first year of therapy than those using alendronate

  31. TheVIBEStudy:eValuation of IBandronateEfficacy • A retrospective cohort study comparing fracture rates for women receiving monthly ibandronate versus weekly bisphosphonates

  32. To investigate the efficacy of monthly ibandronate versus weekly BPs by comparing rates of incident clinical fractures over 12 months in a retrospective cohort study Objective BP = bisphosphonate

  33. Longitudinal patient data from health plans: eligibility, medical and pharmaceutical claims (anonymous, HIPAA-compliant) i3 Research database (single, large health plan with 14 million annual enrolment) i3 Innovus IMPACT database (multiple, unaffiliated health plans with over 70 million enrolled 1997–2007) Endpoints: new fractures hip non-vertebral (inclusive of hip) vertebral (clinical) any (inclusive of all the above) Analysis time to first incident fracture (Kaplan-Meier methods) relative risk (hazard ratio) from Cox regression, controlled for baseline covariates Methodology

  34. Women aged ≥45 years newly started on an oral BP received ≥1 prescription between 1 April and 31 December 2005 (index date) for ibandronate (Boniva/Bonviva) 150mg once monthly, alendronate (Fosamax) 35mg or 70mg weekly or risedronate (Actonel) 35mg weekly no BP in baseline period (6 months prior to index date) Continuous enrolment in health plan for ≥9 months 6 months before starting BP therapy ≥3 months after the first BP prescription Excluded women with Paget’s disease of bone or malignant neoplasm Study population

  35. Patient age at index date co-pay of index treatment GI diagnosis Osteoporosis fracture history bone densitometry procedure osteoporosis diagnosis osteopenia diagnosis Healthcare utilisation number of outpatient visits hospitalisation Medication use number of therapeutic classes Estrogen Non-estrogen anti-osteoporotics (calcitonin, SERMs) GI medication (PPI, H2B, CTP) corticosteroid Baseline characteristics GI = gastrointestinal; SERM = selective estrogen receptor modulatorPPI = proton pump inhibitor; H2B = H2B=H2 blocker; CTP = cytoprotective

  36. Each subject required to have a 6 month baseline period to examine medication use and medical history After starting BP therapy (index date) each subject was observed for fracture for up to 12 months, or until loss to follow-up (end of health plan enrolment) discontinue therapy (for primary analysis only) change in BP therapy switched to a different BP switched dosing regimen (e.g. weekly to daily) Further observations were then stopped (censored) Period of observation

  37. Study design: retrospective cohort study Patient intake period: start BP therapy (index date)1 April 2005 31 December 2005 Baseline period: 6 months1 October 2004 30 June 2005 Follow-up period: up to 12 months1 April 2005 31 December 2006

  38. Primary analysis: adherent patients “Head-to-Head” comparison of drug efficacy patients received minimum of 90 days therapy observed for fracture after 90 days, only while remaining on therapy Secondary analysis: all patients starting BP therapy patients required to have received ‘≥1 BP prescription’ observed for fracture after index prescription Sensitivity analyses exclude patients with clinically important baseline differences: use of oestrogen or other anti-osteoporotics, corticosteroids, GI medications, etc. definitions of adherence: refill gap for ibandronate* (30 days vs 45 days), requiring 90-day minimum adherence Overview of Analyses *Gaps for monthly ibandronate (always 30 days for weekly BPs)

  39. Time-to-event analysis of fracture incidence with Kaplan-Meier methods Cox regression used to estimate RR (hazard ratio) of fracture comparing monthly versus weekly cohorts, adjusted for covariates results shown are from stepwise regression models with all baseline characteristics entered as candidate variables, retaining statistically significant variables age, osteoporosis diagnosis, use of DXA, fracture history number of medication classes used, oestrogen use number of outpatient visits Conclusions were unchanged in models that included other clinically important variables use of other anti-osteoporotics (calcitonin, SERMs) use of glucocorticosteroids Statistical Analysis RR = relative risk; DXA = dual energy X-ray absorptiometry

  40. Patient disposition:primaryand secondary analyses Candidate patients ≥1 prescription for BP* (n=445,430) 1 • Aged <45 years or male (n=13,217) • >1 study drug (n=19) Females aged ≥45 years (n=338,872) 2 • BP pre-index (n=237,480) • Cancer pre-index (n=9,681) • Paget’s disease (n=81) Eligible patients First treatment, no cancer or Paget’s disease (n=91,630) 3 • Invalid data: negative costs (n=32) Secondary analysis population: all patients starting BPs (n=91,598) 4 • Discontinue BP <90 days (n=27,416) Primary analysis population: adherent patients (n=64,182) *Alendronate, ibandronate or risedronate

  41. Baseline Characteristics: Primary Analysis

  42. RR=0.82 p=0.052 RR=0.88 p=0.26 Weekly oral BPs(n=56,837) Monthly oral ibandronate(n=7,345) 1.6 1.2 0.8 0.4 0 1.51 1.40 1.30 1.29 Fracture incidence (%) RR=1.06 p=0.84 RR=0.36 p<0.01 0.24 0.20 0.19 0.11 Fx=95 Fx=106 Fx=15 Fx=858 Fx=103 Fx=738 Fx=135 Fx=8 Non-vertebral Hip Vertebral Any Fractures Primary analysis: monthlyibandronatevsweekly bisphosphonates at 12 months RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

  43. Weekly oral alendronate(n=35,865) Monthly oral ibandronate(n=7,345) Primary analysis: monthlyibandronateversus weekly alendronate at 12 months RR=0.80 p<0.05 RR=0.88 p=0.26 1.6 1.2 0.8 0.4 0 1.51 1.40 1.29 1.29 Fracture incidence (%) RR=1.00 p=1.00 RR=0.34 p<0.01 0.24 0.20 0.19 0.11 Fx=542 Fx=103 Fx=464 Fx=95 Fx=68 Fx=15 Fx=86 Fx=8 Non-vertebral Hip Vertebral Any Fractures RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

  44. Monthly oral ibandronate(n=7,345) Weekly oral risedronate(n=20,972) Primary analysis: monthlyibandronateversus weekly risedronate at 12 months RR=0.85 p=0.14 RR=0.91 p=0.42 1.6 1.2 0.8 0.4 0 1.51 1.40 1.31 1.29 Fracture incidence (%) RR=1.19 p=0.57 RR=0.39 p<0.01 0.23 0.20 0.18 0.11 Fx=274 Fx=95 Fx=38 Fx=15 Fx=49 Fx=316 Fx=103 Fx=8 Non-vertebral Hip Vertebral Any Fractures RR = adjusted RR (hazard ratio) using Cox regression controlling for potentialconfounding variables; Persistent patient cohort with no refill gap >45 days(monthly) or 30 days (weekly); Fx = absolute number of fractures

  45. In order to understand whether the results were due to baseline differences in the populations, sensitivity analyses were performed which excluded patients with the following during baseline Estrogen or other anti-osteoporotic medication use (SERMS, calcitonin) corticosteroid use fracture GI medication use corticosteroid use and/or osteopenia The conclusions regarding fracture endpoints remained unchanged in the analyses Sensitivity analyses: exclude patients with clinically important baseline differences

  46. Observational studies are subject to potential confounding (not randomised) there may be residual confounding that was not adequately controlled for but this was also evaluated with multiple sensitivity analyses Diagnosis data was collected for billing purposes, not for research a diagnosis code on a medical claim is not necessarily confirmation of a fracture vertebral fracture may be coded on basis of patient symptoms, rather than X-ray it is unlikely that fracture misclassification is differential and clinical fractures are the most important There is no perfect measure of patient compliance a filled prescription does not mean the medication was taken, and medication samples are not recorded in prescription claims data the above would underestimate antifracture benefit (and unlikely to be differential) Duration of follow-up period was limited to 12 months by the available data P values were not adjusted for multiple comparisons Limitations

  47. Large observational study in a real-world population findings more appropriate for generalisation and representative than clinical trials learnings from other observational studies considered in study design All potential confounders were entered into the Cox-regression model and results were unchanged Results consistent across a broad range of sensitivity analyses Strengths

  48. Risk of hip and non-vertebral fractures was the same with monthly ibandronate and weekly bisphosphonates Suggests efficacy of ibandronate on non vertebral fractures, consistent with data obtained in a recent meta-analysis1 The rates of vertebral fractures were significantly lower with monthly ibandronate versus weekly bisphosphonates in the primary analysis, but the number of patients with vertebral fracture with monthly ibandronate was limited (n=8) Discussion 1Adachi R, et al. J Bone Miner Res 2007;S221:S210–11 (Abstract M428)

More Related