eugm 2011 | day | experiences with interim analyses and dm cs
TRANSCRIPT
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ExperienceswithInterimAnalysesandDataMonitoringCommi:ees
EASTUser‐GroupMeeAng14thOctober2011,Paris
SimonDay,PhD
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ExperienceswithInterimAnalysesandDataMonitoringCommi:ees
Or: I’d never be so stupid as to do that, would I?
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“plansordecisionsbasedonstaAsAcallyimpreciseinterimdatamayoKenbesubopAmal”
Section 6.5 “Sponsor access to interim data for planning purposes”
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Example–Afacogininseveresepsis
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DesignandobjecAves
• Doubleblind,placebo‐controlled,mulAcentre,phase3randomisedcontrolledclinicaltrial
• Primaryoutcome–allcause28daymortality
• Targetsamplesize1550(Increasedby400ataninterimanalysis)
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Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=?
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Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.
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Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.006
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Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.006
• “Tifacoginsignificantlya:enuatedprothrombinfragmentandthrombin:anA‐thrombincomplexlevels[secondaryendpoints]inpaAentswithhighandlowINR[pre‐specifiedsubgroups]”
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Whatshouldhappen?
• Pre‐specifiedinterimanalysisat¼,½and¾ofpaAentscompleAng28days
• Purpose:“safety,fuAlityandefficacy”
• Safetyandefficacy–kindofthesamething
• TifacoginiseffecAve–morepaAentsaredyingonplacebo
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Whatshouldhappen?
• Ifthistrialcon.nues,pa.entsrandomisedtothecontrolarmwillneedlesslydie
• Another1100paAentsduetoberandomised
• Weshouldorder160coffinsforpaAentswhowillbegiven.facogin
• Weshouldorder215coffinsforpaAentswhowillbegivenplacebo
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“Phew, I got the real stuff!”
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Example–MRCacutemyeloidleukemia
The MRC AML12 trial
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Thetrial
• 5coursesoftherapyversus4courses• Primaryendpoint–survival• 1078paAents• Yearlyinterimanalyses
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Interimanalysis(2)
• HazardraAo0.47(infavourof5courses)• 95%confidenceinterval0.29–0.77,P=0.003
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Interimanalysis(3)
• HazardraAo0.47(infavourof5courses)• 95%confidenceinterval0.29–0.77,P=0.003
• HazardraAo0.55(infavourof5courses)• 95%confidenceinterval0.38–0.80,P=0.002
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“That’ll be five courses for me,
please, waiter”
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Lancet 2001; 357:1385–90.
Example–theCAPRICORNstudy
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Primaryendpoint
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New(changed)endpoint
• All‐causemortality
• Ataninterimanalysis,changedto:– All‐causemortality (P<0.005)Or– All‐causemortalityorcardiovascularhospitalisaAon
(P<0.045)
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Results
Relative risk 0.77 (0.60 – 0.98) P=0.031
Relative risk 0.92 (0.80 – 1.07) P=0.296
All-cause mortality All-cause mortality or Cardiovascular hospitalisation
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Results
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Example–Afacogininseveresepsis
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Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.006
• “Tifacoginsignificantlya:enuatedprothrombinfragmentandthrombin:anA‐thrombincomplexlevels[secondaryendpoints]inpaAentswithhighandlowINR[pre‐specifiedsubgroups]”
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Whatdidhappen?
• Theykeptthetrialgoing(Yes,andpeopledied!)
• Howmanydied? HighINR LowINRplacebo 296(33.9%) 118(23%)Afacogin 301(34.2%) 83(12%) P=0.?
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Whatdidhappen?
• Theykeptthetrialgoing(Yes,andpeopledied!)
• Howmanydied? HighINR LowINRplacebo 296(33.9%) 118(23%)Afacogin 301(34.2%) 83(12%) P=0.051 Pearsonχ2
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Whatdidhappen?
• Theykeptthetrialgoing(Yes,andpeopledied!)
• Howmanydied? HighINR LowINRplacebo 296(33.9%) 118(23%)Afacogin 301(34.2%) 83(12%) P=0.03 logisAcregression
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Conclusion
“plans or decisions based on statistically imprecise interim data may often be suboptimal”
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Example–MRCacutemyeloidleukemia
The MRC AML12 trial
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Interimanalysis(3)
• HazardraAo0.47(infavourof5courses)• 95%confidenceinterval0.29–0.77,P=0.003
• HazardraAo0.55(infavourof5courses)• 95%confidenceinterval0.38–0.80,P=0.002
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Whatshouldhappen?
• Again,theDMEC(sic)keptthetrialgoing,despiteendpointbeingdeath
• Fromthepaper:“ThemainreasonfornotclosingtherandomisaAonwasthatthetreatmenteffects(53%and45%reducAoninoddsofdeath)wereconsideredtoolargetobeclinicallyplausible.”
• TheywereBayesians!
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Thesequenceofevents
“plans or decisions based on statistically imprecise interim data may often be suboptimal”
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SothequesAonstoaskyourselves
1. “Thattrialwestoppedearly…whatwouldhavehappenedifwehadkeptgoing?”
2. “Thatfixedsamplesizetrialthatwedid…whatwouldhavehappenedifitrecruitedmorepaAents?”
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ExperienceswithInterimAnalysesandDataMonitoringCommi:ees