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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. - PowerPoint PPT Presentation

Text of OsteoporosisWRAP SlideCAST

  • OsteoporosisWRAP SlideCASTComplexities and Challenges of Measuring Fracture End Points Interpreting the Results of Existing Trials Steven T Harris MD FACPClinical Professor of MedicineUniversity of California, San Francisco

  • Fracture EndpointsRegulatory approval of existing medications has been based on fracture reduction, rather than changes in surrogates such as bone mineral density (BMD) aloneThe most common fracture endpoint has been the reduction in vertebral fractureVertebral fracture has most often been defined on the basis of morphometric changes, including both new and worsening fracturesClinical vertebral fracturedefined as fracture associated with back painhas usually been identified as a secondary endpoint

  • Fracture Endpoints, contNon-vertebral fracture has most commonly been identified as a secondary endpoint as wellVarying definitions of non-vertebral fracture: all fractures vs fragility fractures vs a particular composite endpointHip fracture has sometimesbut not alwaysbeen identified as a separate endpoint of particular interest

  • Fracture Endpoints, contFracture reduction has most often been expressed both clinically and commerciallyas relative risk reduction, rather than absolute risk reductionThe rapidity with which fracture protection occurs has been of clinicaland commercialinterestThere are no head-to-head randomized trials with fracture as the primary endpointThe pivotal fracture trials recruited patients with a certain samenessbut there were notable differences in demographics, baseline fracture status and baseline BMDs neverthelessThere were obvious differences in observed fracture ratesboth vertebral and non-vertebral

  • % of Patients With New Vertebral FracturesOver 3-5 YearsVertebral Fracture Effects In Prospective TrialsDirect Comparisons Among Trials Cannot Be Made Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356:1809051015202530 PROOF MORE FIT-VFA VERT-NA VERT-MN BONE HORIZON MORE FIT-CFA With Prevalent Vertebral Fractures Vert Fx Without Vert Fx30%47%41%49%50%40%50%52%70%% = Relative Fracture Risk Reduction

  • % of Patients With New Nonvertebral FracturesOver 3-5 YearsNonvertebral Fracture Effects In Prospective TrialsDirect Comparisons Among Trials Cannot Be Made * Chesnut CH, et al. Am J Med. 2000;109:267 Ettinger B, et al. JAMA. 1999;282:637Black DM, et al. Lancet. 1996;348:1535 Cummings SR, et al. JAMA. 1998;280:2077Harris ST, et al. JAMA. 1999;282:1344 Reginster J, et al. Osteoporos Int. 2000;11:83Chesnut CH, et al. J Bone Miner Res. 2004;19:1241 Black DM, et al. N Engl J Med 2007:356:1809051015202530 PROOF MORE FIT-VFA FIT-CFA VERT-NA VERT-MN BONE HORIZON20%p = 0.0612%p = n.s.25%p < 0.00133%p = 0.06% = Relative Fracture Risk Reduction10%p = n.s.12%p = n.s.39%p < 0.05p = n.s.* Patient demographics and the definition of nonvertebral fracture varied among studies

  • Fracture EndpointsIf existing randomized clinical trials cannot reasonably address all issues of clinical relevance, then additional insights can be gleaned from:Additionalpost hocanalyses of existing trial dataMeta analyses of existing trial dataObservational data

  • Nonvertebral Fracture Reduction Post-hoc analyses0246810121461218243036% patients with nonvertebral fracture59%P=0.002***********Time (months)Harrington Calcif Tissue Int 2004;74:129Black JCEM 2000;85:4118n= 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
  • Ibandronate and the risk of non-vertebral and clinical fractures in women with postmenopausal osteoporosis (PMO): results of a meta-analysis of Phase III studiesHarris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  • 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 methodStudy Objectives1oral 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.

  • Pooled Fracture AnalysisMethodsCox regression analyses were adjusted for variables to allow for meaningful comparisons among trialsAgePrevious clinical fractureBaseline BMDLumbar spine BMD for models with all clinical fractures Hip BMD for models with nonvertebral fractures (NVFs) or key NVFsKaplan-Meier methods were used to: Plot survival curves for time to fractureCompare rates using a log-rank testHarris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  • Pooled Fracture Analysis Methods (cont.)Fracture rates were determined by tabulating the proportion of all ITT patients with at least 1 fractureDoses 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 0.006Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  • IV and oral ibandronate annual cumulative exposure across studies1. 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 071108 mg12 mg10.8 mg5.5 mg4 mg04812Annual cumulative exposure (mg)Quarterly IVQuarterly IVQuarterly IVOral daily Oral monthlyMF43801IRIS3DIVA5BONE2MOBILE4

  • Fracture risk reductions for high dose of ibandronate (10.8 mg/yr), by fracture type+/- 95% Confidence IntervalsRelative risk reduction adjusted for age, baseline BMD, and fracture history. *P
  • Pooled Ibandronate Fracture Analysis

    Cox regression analyses for difference in relative risk of fracture with ibandronate vs placebo. Kaplan-Meier plot (2-year data).Estimated Clinical Fracture Rate, %Days0501001502002503003504004505005506006507007501086420Relative Risk Reduction 28.8%P

  • Pooled Ibandronate Fracture Analysis, contEstimated Nonvertebral Fracture Rate, %Days050100150200250300350400450500550600650700750Relative Risk Reduction 29.9%P
  • LimitationsNot all studies were placebo-controlledA limited number of baseline patient characteristics (age, previous fracture, baseline BMD) were available for use in multivariable modelsThis was an exploratory, post hoc analysis with no adjustment for multiple comparisons Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  • ConclusionsIn this pooled analysis, doses of ibandronate resulting in an ACE of 10.8 mgwhich include the marketed doses of 150 mg monthly oral and 3 mg IV quarterlysignificantly reduced the risk of clinical fractures and non-vertebral fractures compared to placeboThe 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 Harris ST, Blumentals WA and Miller PD. Curr Med Res Opin. 2008;24:237-45

  • Observational StudiesStrengths and Limitations of Claims DataStrengthsTreatment patterns are those in real world clinical practice A large number of patients can be followed over timeLimitationsNo chart review available to validate the ICD-9 codesSelection bias is possibleif not probableCannot assess the use of samples or OTC productsExtraneous variables are not controlled

  • *Adjusted for age, sex, HRT use, number of concomitant medications and fragility fractures in pre-treatment period69%75%RIS vs. CAL RR=0.31 (p
  • Effectiveness of Bisphosphonates on Nonvertebral and Hip Fractures in the First Year of Therapy: The Risedronate and Alendronate (REAL) Cohort StudySilverman SL, Watts NB, Delmas PD, Lange JL, Lindsay RSilverman L et al. Osteoporos Int. 2007;18:25-34

  • Study ObjectiveTo 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

  • Fracture OutcomesFracture Sites and Analysis Methods

  • Study PopulationInclusion CriteriaAll women> 65 years of ageOnce-weekly bisphosphonate (BP) use between July 2002 and September 2004Exclusion criteria< 6 months of health plan enrollment before first BP use< 3 months of health plan enrollment after first BP useAny BP use during 6-month history periodDiagnosis of malignancy or Pagets diseaseDiscontinuation of BP therapy with first 3 months of exposure period

  • Baseline CharacteristicsDeterminants of Fracture Risk

  • Cumulative Hip Fracture Incidence

  • Cumulative Incidence of Hip Fractures During Therapy