Alfonso Iorio Health Information Research Unit amp HamiltonNiagara Hemophilia Program McMaster University Hemophilia Research Study Update Berlin 1214 march 2015 Overview Removable risk factors ID: 1003579
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1. Balancing risk factors for inhibitors development in clinical practiceAlfonso IorioHealth Information Research Unit & Hamilton-Niagara Hemophilia ProgramMcMaster UniversityHemophilia Research Study UpdateBerlin, 12-14 march 2015
2. Overview - Removable risk factors - Risks profiles for treatment selectionConsiderations on available dataStepping back: what is the problem?Implication for practiceImplications for research
3. OverviewConsiderations on available dataStepping back: what is the problem?Implication for practiceImplications for research
4. Inhibitors, inhibitors, inhibitors….StudyDesignYear, patientsCRRDinterpretationContributionRODINP, R, IC, MC2000-2010340 (574)28.29.0Post hocHypothesis generationUKHCDOR, IC, SC2000-2010300 (407)23.811.3Time effect, B-DD f-VIII,RODIN effectGenerate alternative hypothesisFrance CR, IC, SC2000-2010234 (303)30.015.0Strong “center” effectRODIN effect ??Generate a second alternative hypothesisVezinaS, SC2005-201086 (99)36.06.0Higher rate with AdvateYou cannot “export” results?EUHASSP, DC, MC2009-2013284 (417)26.24.5RODIN effectNon-confirmatoryEAHAD IPDMA, MC1994-200380 (761)40.06.6Any of the previousNon confirmatoryDirection of effectInconsistencyP = prospective; R = registry; MC = multiple centers/countries, IC = inception cohort, SC = single country; S = survey; DC = dynamic cohort; MA = meta-analysis
5. Systematic review? Meta-analysis? Pooled analysis?Di Minno et al, accepted, Blood
6. Kreuz W, Gill JC, Rothchild C et al.Thrombosis and Haemostasis 2005; 93:457-467 15% inhibitor rate with Kogenate (1997-2001)
7. KogenateAdvateRODIN = DashedNot RODIN = SolidAdvate 3/1226/11713/43Kogenate 24/6516/315/32UKHCDO cohort: effect of time and … RODIN?RODIN vs not RODINP = 0.08
8. EUHASSEUHASS without RODIN NP95% CIN95% CIPlasma D510.220.110.350.210.100.37Recomb3660.260.220.310.240.190.29Advate1410.260.190.340.260.180.36Helixate370.320.180.500.330.180.52Kogenate1060.300.220.400.220.130.34Refacto AF520.290.170.430.270.150.431.67 (CI 0.95–2.95)0.99 (CI 0.62–1.61)1.17 (CI 0.81–1.70)Relative risk, Kogenate vs Advate18 RODIN ctrs (94)39 Non RODIN (190)57 centers (284 pts)
9. EUHASS subgroups - unpublishedGroup / SubgroupAdvate%KogenateHelixate%RREUHASS - all37/14126.244/14230.81.17(0.81 – 1.70)RODIN centers15/5626.817/3844.7FranceC centers5/1338.57/2133.3UKDCDO ctrs4/1330.82/922.2EUHASS only13/5922.018/7524.01.09(0.58 – 2.04)EUHASS only (HR)7/5911.914/7518.71.57(0.68 – 3.60)OR (EUHASS only): All 1.12 (0.49 – 2.52) HR 1.70 (0.64 – 4.52)Courtesy of Kathelijn FIscher
10. Take home messages - IKogenate has been associated with a higher rate of inhibitor (and so Refacto/Xyntha)The size and strength of the association is still unclearThere is not robust evidence for causation
11. OverviewConsiderations on available dataStepping back: what is the problem?Implication for practiceImplications for research
12. Two critical conceptsAssociation versus causationResidual confoundingBradford Hill criteriaAssessing adverse effectsRare/CommonAnticipated/Unexpected/AnticipatedUnlinked to efficacy mechanism/Linked??? Almost never comparative assessment
13. Family historyGene mutationBrandMULTIVARIABLEANALYSIS
14. Gene mutationFamily historyBrandMULTIVARIABLEANALYSIS??Unknown???
15. Gene mutationFamily historyBrandMULTIVARIABLEANALYSIS??Unknown??Kogenate/Advate?
16. Unmeasured confoundingSelection by indicationThe ideal patient profile for molecule x….Center effectThe effect of center is a proxy for what you cannot measureit is constantly checked even in randomized trialsMethods exists for small centersCenter effect and “center size” effect ARE NOT the sameMcGilchrist, CA et al. Regression with frailty in survival analysis. Biometrics, 1991 47, 461-6.Hougaard, P. Frailty models for survival data. Lifetime Data Analysis, 1995, 1, 255-273.
17. Evidence suggesting RCTs are superior to observational studiesObservational study resultsRCT resultsExtracranial to intracranial bypass: > 200 case series showed benefitRCT (n=1377) RR increase of 14% for strokeHRT for post-menopausal women: M-A of 16 cohort and 3 X-sectional studies: RRR of 0.5 for CADRCT (n=16,608): HRT increased risk of CAD HR=1.29Cohort study (n=5133): signif decrease in CAD death with vit ERCT (n=9541): no effect of vit E (harm from hi doses)
18. CART ANALYSIS
19. Take home messages - IICarrying matches does not cause cancerMultivariable analysis (and so propensity score analysis) are not a cure (neither a resuscitation measure) for fatally flawed studiesRandomization might be necessary
20. OverviewConsiderations on available dataStepping back: what is the problem?Implication for practiceImplications for research
21. Courtesy ofJenny Goudemand
22. EPIC: another learning lessonCourtesy ofGunther AuerswaldAccepted on Hemophilia
23. Take home messages - IIIClear: type of concentrate is a weak risk factorClear: if you can, don’t use KogenateLess clear: what do I do then? what do I use then?Plasma derived?Human cell line recombinant factor VIII?Advate?Long acting factor VIII?Investigational molecules?
24. ARS - QuestionWhat will I use to treat my next PUP?KogenatePlasma derived FVIIIHuman cell line recombinant factor VIIIAdvateLong acting factor VIIIInvestigational molecules
25. OverviewConsiderations on available dataStepping back: what is the problem?Implication for practiceImplications for research
26. FactsRODIN, FranceCoag, UKHCDO showed that you can measure differences in immunogenicity with about 300 PUPsEUHASS showed you can accrue a similar number in half the time
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28. PCI cases enrolled in administrative registryRandomized within registryNumber of patientsYear
29. The randomized trial design - hemophilia1234
30. ARS - QuestionIf such a trial was available, would you participate?YESNO
31. Barriers to such a studyNeed to use the “best possible product to match the unique individual profile”OTHERS REASONSPhysician preferencePatient preferenceEnrollment in studies on investigational molecules“Relationships” with manufactures
32. ARS - QuestionIf such a trial was available, what would be the main barrier to your participation?I have only one recombinant in my centerI don’t trust the factor-related inhibitor riskI don’t like randomly choosing (among equivalent products)Other barriers
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34. Paired availabilityRequirementCriteriaStable populationSingle hospital serves the areaNo in- out- migrationConstant eligibility criteriaNo change in prognosisStable treatment1. Rest of management stableStable evaluation1. No change in criteriaStable preferenceNo publicized credible reportNo direct-to-consumer advertisingStable treatment effectIntervention effect independent on disease stageNo learning curve required
35. Take home messages - IVWe’d better focus on important risk factors, not molecule-related riskAs to concentrate related riskIt is not a matter of better or larger data collection, we need a different way for data collection and analysis….. together we can
36. Thank you !!!Download these slides at:Hemophilia.mcmaster.caJoin the Web Application for Population PharmacokineticService (WAPPS) network at:www.wapps-hemo.org
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38. Evaluation of Safety and Effectiveness of factor VIII treatment in Hemophilia A patients with low titer inhibitors or a personal history of inhibitor. Patient Data Meta-analysis of rAFH-PFM Post-Authorization Safety Studies V. Romanov , M. Marcucci, J. Cheng,L. Thabane, A. Iorio Thrombosis and Haemostasis 2015, accepted
39. Inhibitors in hemophilia A patients with low titer inhibitors or a personal history of inhibitorV. Romanov et al. Thrombosis and Haemostasis 2015, accepted
40. Thank you !!!Download these slides at:Hemophilia.mcmaster.caJoin the Web Application for Population PharmacokineticService (WAPPS) network at:www.wapps-hemo.org
41. EUHASS – PTPsAdvate 0.11 (0.03 – 0.25)Kogenate 0.17 (0.06 - 0.37)OR = 1.54 (0.24 – 12)Xi, PTP meta-analysisAdvate 0.10 (0.05 – 0.18)Kogenate 0.26 (0.16 - 0.44)Kogenate 0.11 (0.05 - 0.23)OR = 2.6 (0.88 – 8.8)Aledort BDD meta-analysisKogenate vs AdvateHigh titerHR = 1.75 (0.05 – 65.5)All inhibitorsHR, 2.43 (0.31–19.2)KogenateAdvate