Venita DePuy, PhD Bowden Analytics } Pr Pre-pl planned (a d (and - PowerPoint PPT Presentation

Venita DePuy, PhD Bowden Analytics

} Pr Pre-pl planned (a d (and pr d pre-speci cified!) looks at the da data a at s spe pecific i interva vals } If If da data i is o ove verwhelmingl gly go good (o d (or ba bad), i d), it ma may w warra rrant nt st stopping ng t the he t tri rial } Many Many different erent ap appro roac aches hes: O’Bri Brien en-Fl Fleming, Po Pocock, La , Lan-De DeMets ap appro roac aches hes to tho hose, e, and and many any others hers } We We w will u use L Lan-De DeMets ap appro roac ach h to O’B O’B-F PhUSE Connect 05June2018 Bowden Analytics

} Sa Sample e Si Size e Calculations } In Interim A Analysis De Design gn } Pe Performing the Interim Analysis ◦ Analysi sis s (PROC LI LIFETEST, , PH PHREG EG) ◦ Interim Analysi sis } Ca Can be perfor ormed in SAS, EAST, T, PASS, and oth others PhUSE Connect 05June2018 Bowden Analytics

} SAS ◦ Calculate sample size & boundaries for interim: Proc Seqdesign ◦ Survival calculation: Proc Lifetest or PHReg ◦ Interim analysis in Proc Seqtest (bring in data from Seqdesign and Lifetest/PHReg) } EAST ◦ Point & click interfaces ◦ Many options for sample size & boundary calculations ◦ Perform survival analysis ◦ Enter parameter estimates ( δ ) calculated earlier to perform interim analysis ◦ Many output options (graphs) } PASS ◦ Point & click interface for sample size & boundaries ◦ Separate software required for interim analysis PhUSE Connect 05June2018 Bowden Analytics

} Treatment Arms A (active) and B (control) ◦ Randomized 1:1 } Primary Endpoint is Increase in Lab X Value past a predetermined threshold ◦ Expect median time to hit threshold to be 20 days in treatment A and 30 days in treatment B } Slow enrollment: 50 subjects every 6 months } 6 month duration of study (censored after) } Testing whether duration differs between treatments ◦ H 0 : θ = 0 against H a : θ ≠ 0 where θ = - ln ( λ ), and λ is the hazard ratio PhUSE Connect 05June2018 Bowden Analytics

proc power; twosamplesurvival test=logrank alpha=0.05 groupmedsurvtimes=(20 30) npergroup=. accrualtime=730 followuptime=180 power=.80; run; 6 month f/up = 180 days PhUSE Connect 05June2018 Bowden Analytics

proc seqdesign boundaryscale=StdZ; Default is standardized Z scale OverallStudy: Design nstages=1 1 stage = no alpha=0.05 beta=.2; interim analysis Samplesize model=TWOSAMPLESURVIVAL (medsurvtime=20 nullmedsurvtime=30 ref= hazard accrual=uniform acctime=730 foltime=180); run; PhUSE Connect 05June2018 Bowden Analytics

Sa Sample e Si Size e Su Summary Sample Sa e Si Size e Su Summary Test Te Two-Sample Accrual Rate Ac 0.261731 Survival Accrual Time Ac 730 Null Hazard Rate Nu 0.023105 Follow-up Fo up Time 180 Ha Haza zard Rate (Group A) A) 0.034657 910 Tot Total Ti Time Ha Haza zard Rate (Group B) 0.023105 Max Number er of f Even ents 190.968 Haza Ha zard Ratio 1.5 -θ 1 = Max Sa Sample e Si Size 191.0639 lo log(H (Hazard R Ratio io) 0.405465 Expected Sample Size (Null Re Ex Ref) 191.0639 Re Reference Hazards Alt Ref Ex Expected Sample Size (Alt Re Ref) 191.0639 Uniform Accrual Ac Boundary In Bo Information (St Standardized ed Z Sca Scale) e) vs. 198 Null Reference = 0 Nu from Proc Alternative Boundary Values _Stage_ _S Power Information Level Reference Lower Upper Proportion Actual Events Lower Upper Alpha Alpha 1 1.0000 47.74201 190.968 -2.80159 2.80159 -1.95996 1.95996 ±1.96 ± θ 1 Ö I 0 I 0 is based on PhUSE Connect 05June2018 α , β , θ 1 Bowden Analytics

θ 1 = -ln (30/20) proc seqdesign boundaryscale=stdz = -0.40547 ALTREF = -0.40547; TwoSidedOBF_Lan: design nstages=2 Analyses at 85 & 198 subjects alpha=0.05 beta=.2 method=errfuncOBF info=cum(85 198) stop=both (betaboundary=nonbinding); ods output Boundary=BoundZ; run; PhUSE Connect 05June2018 Bowden Analytics

De Design In Information (sel elec ect rows) Bo Boundary Sca Scale Standardized Z Ea Early Stop op Accept (Nonbinding)/ Reject Null Met ethod Error Spending Nu Number of Stages 2 Al Alpha (Binding Beta Boundary) 0.04712 Alpha (Nonbinding Beta Boundary) Al 0.05 Max Info formation (Per ercen cent of f Fixed ed Sa Sample) e) 104.9799 Max Info formation 50.1183 Nu Null Ref ASN N (Percent of Fixe xed Sample) 88.39329 Al Alt Ref AS ASN (Percent of Fixed Sample) 96.62317 Bo Boundary In Information (St Standardized ed Z Sca Scale) e) Very stringent tage_ No Nonbinding Beta Boundary, Nu Null Reference = 0 at interim _Sta Alternative Boundary Values _S Information Level Reference Lower Upper Actual Lower Upper Alpha Beta Beta Alpha Proportion 1 0.4293 21.5154 -1.8808 1.8808 -3.2276 -0.3526 0.3526 3.2276 2 1.0000 50.118 -2.8705 2.8705 -1.9636 -1.9636 1.9636 1.9636 PhUSE Connect 05June2018 Bowden Analytics Almost 1.96

Stage 1: Stage 2: Interim Final Analysis Analysis (I=50.12) (I=21.52) PhUSE Connect 05June2018 Bowden Analytics

Randomly generated data N=85 proc lifetest data=samp; Exponential distributions 20% censored at mean 14d time mTIME*CENSOR(1); Subjects on study censored at 180d test TRT; ods output logunichisq=PARMS; run; Results 38 in Trt A (1), 47 in Trt B (2) 5 & 8 censored respectively PA PARMS da dataset: Mean time in uncensored=22.4, 28.5d Var ariab able Statistic St StdErr St ChiSq Ch Pr ProbChiS iSq trt tr 4.6995 4.0794 1.3271 0.2493 PhUSE Connect 05June2018 Bowden Analytics

} Proc Seqdesign with output in correct units ◦ Score statistic for Proc Lifetest ◦ MLE for Proc PHReg } Perform survival analysis (Lifetest or PHReg) } Proc Seqtest to combine results from both PhUSE Connect 05June2018 Bowden Analytics

proc seqdesign boundaryscale=SCORE altref = -0.40547; TwoSidedOBF_Lan: design nstages=2 alpha=0.05 beta=.2 method=errfuncOBF info=cum(85 198) stop=both (betaboundary=nonbinding); ods output Boundary=BoundS; run; Pr Proc Li Lifetest Pa Parameter Out Output ut Mani nipul ulation data PARMSs (keep = VARIABLE _SCALE_ _STAGE_ STDERR ESTIMATE) ; set PARMS (rename=(Statistic=Estimate)); if VARIABLE='TRT'; If If using Proc PH PHReg… Limit to PARAMETER=‘TRT’, _SCALE_='Score'; no rename statement, _STAGE_=1; _SCALE_=‘MLE’ run; PhUSE Connect 05June2018 Bowden Analytics

proc seqtest boundary=BoundS parms(Testvar=trt) = parmsS infoadj=prop boundaryscale=Score; ods output test=testS; run; PhUSE Connect 05June2018 Bowden Analytics

Te Test Inf nformation n (Score Scale) Nu Null Reference = 0 Alternative Boundary Values Test _Stage_ _S Information Level Reference Lower Upper TRT Proportion Actual Lower Upper Alpha Beta Beta Alpha Estimate Action e_ 1 0.3320 16.6411 -6.74747 6.74747 -13.4636 . . 13.46356 4.69946 Continue 2 1.0000 50.1183 -20.3215 20.3215 -14.0831 -14.0831 14.0831 14.0831 . PhUSE Connect 05June2018 Bowden Analytics

Bo Boundary Information (S (Score Sc Scale le) _Stage_ Non Nonbinding g Beta ta Bou oundary, Nu Null Reference = 0 Alternative Boundary Values _S Information Level Reference Lower Upper Proportion Actual Lower Upper Alpha Beta Beta Alpha 1 0.4293 21.51543 -8.72386 8.72386 -14.97129 -1.63544 1.63544 14.97129 2 1.0000 50.1183 -20.32147 20.32147 -13.90099 -13.90099 13.90099 13.90099 Plan anned Actual Ac al Test In Te Informa mation (Score Scale) Null Reference = 0 Nu Alternative Boundary Values Test _S _Stage_ Information Level Reference Lower Upper TRT Actual Lower Upper Alpha Beta Beta Alpha Estimate Action Proportion 1 0.3320 16.6411 -6.74747 6.74747 -13.4636 . . 13.46356 4.69946 Continue 2 1.0000 50.1183 -20.3215 20.3215 -14.0831 -14.0831 14.0831 14.0831 . PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics

Default values (not yet changed) PhUSE Connect 05June2018 Bowden Analytics

PhUSE Connect 05June2018 Bowden Analytics