eugm 2011 | day | experiences with interim analyses and dm cs
TRANSCRIPT
ExperienceswithInterimAnalysesandDataMonitoringCommi:ees
EASTUser‐GroupMeeAng14thOctober2011,Paris
SimonDay,PhD
ExperienceswithInterimAnalysesandDataMonitoringCommi:ees
Or: I’d never be so stupid as to do that, would I?
3
“plansordecisionsbasedonstaAsAcallyimpreciseinterimdatamayoKenbesubopAmal”
Section 6.5 “Sponsor access to interim data for planning purposes”
4
Example–Afacogininseveresepsis
5
DesignandobjecAves
• Doubleblind,placebo‐controlled,mulAcentre,phase3randomisedcontrolledclinicaltrial
• Primaryoutcome–allcause28daymortality
• Targetsamplesize1550(Increasedby400ataninterimanalysis)
6
Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=?
7
Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.
8
Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.006
9
Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.006
• “Tifacoginsignificantlya:enuatedprothrombinfragmentandthrombin:anA‐thrombincomplexlevels[secondaryendpoints]inpaAentswithhighandlowINR[pre‐specifiedsubgroups]”
10
Whatshouldhappen?
• Pre‐specifiedinterimanalysisat¼,½and¾ofpaAentscompleAng28days
• Purpose:“safety,fuAlityandefficacy”
• Safetyandefficacy–kindofthesamething
• TifacoginiseffecAve–morepaAentsaredyingonplacebo
11
Whatshouldhappen?
• Ifthistrialcon.nues,pa.entsrandomisedtothecontrolarmwillneedlesslydie
• Another1100paAentsduetoberandomised
• Weshouldorder160coffinsforpaAentswhowillbegiven.facogin
• Weshouldorder215coffinsforpaAentswhowillbegivenplacebo
12
“Phew, I got the real stuff!”
13
Example–MRCacutemyeloidleukemia
The MRC AML12 trial
14
Thetrial
• 5coursesoftherapyversus4courses• Primaryendpoint–survival• 1078paAents• Yearlyinterimanalyses
15
Interimanalysis(2)
• HazardraAo0.47(infavourof5courses)• 95%confidenceinterval0.29–0.77,P=0.003
16
Interimanalysis(3)
• HazardraAo0.47(infavourof5courses)• 95%confidenceinterval0.29–0.77,P=0.003
• HazardraAo0.55(infavourof5courses)• 95%confidenceinterval0.38–0.80,P=0.002
17
“That’ll be five courses for me,
please, waiter”
18
Lancet 2001; 357:1385–90.
Example–theCAPRICORNstudy
19
Primaryendpoint
20
New(changed)endpoint
• All‐causemortality
• Ataninterimanalysis,changedto:– All‐causemortality (P<0.005)Or– All‐causemortalityorcardiovascularhospitalisaAon
(P<0.045)
21
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
22
Results
23
Example–Afacogininseveresepsis
24
Interimanalysis,N=722
• Mortalityrates:placebo 38.9%Afacogin 29.1%
P=0.006
• “Tifacoginsignificantlya:enuatedprothrombinfragmentandthrombin:anA‐thrombincomplexlevels[secondaryendpoints]inpaAentswithhighandlowINR[pre‐specifiedsubgroups]”
25
Whatdidhappen?
• Theykeptthetrialgoing(Yes,andpeopledied!)
• Howmanydied? HighINR LowINRplacebo 296(33.9%) 118(23%)Afacogin 301(34.2%) 83(12%) P=0.?
26
Whatdidhappen?
• Theykeptthetrialgoing(Yes,andpeopledied!)
• Howmanydied? HighINR LowINRplacebo 296(33.9%) 118(23%)Afacogin 301(34.2%) 83(12%) P=0.051 Pearsonχ2
27
Whatdidhappen?
• Theykeptthetrialgoing(Yes,andpeopledied!)
• Howmanydied? HighINR LowINRplacebo 296(33.9%) 118(23%)Afacogin 301(34.2%) 83(12%) P=0.03 logisAcregression
28
Conclusion
“plans or decisions based on statistically imprecise interim data may often be suboptimal”
29
Example–MRCacutemyeloidleukemia
The MRC AML12 trial
30
Interimanalysis(3)
• HazardraAo0.47(infavourof5courses)• 95%confidenceinterval0.29–0.77,P=0.003
• HazardraAo0.55(infavourof5courses)• 95%confidenceinterval0.38–0.80,P=0.002
31
Whatshouldhappen?
• Again,theDMEC(sic)keptthetrialgoing,despiteendpointbeingdeath
• Fromthepaper:“ThemainreasonfornotclosingtherandomisaAonwasthatthetreatmenteffects(53%and45%reducAoninoddsofdeath)wereconsideredtoolargetobeclinicallyplausible.”
• TheywereBayesians!
32
Thesequenceofevents
“plans or decisions based on statistically imprecise interim data may often be suboptimal”
33
SothequesAonstoaskyourselves
1. “Thattrialwestoppedearly…whatwouldhavehappenedifwehadkeptgoing?”
2. “Thatfixedsamplesizetrialthatwedid…whatwouldhavehappenedifitrecruitedmorepaAents?”
ExperienceswithInterimAnalysesandDataMonitoringCommi:ees