Impact of lack-of-benefit stopping rules on treatment effect estimates of two-arm multi-stage (TAMS) trials with time to event outcome

Table 5 Simulation results for the trials that reach the final stage

Design	Under-	$H R_{D}^{1} = 0.75$			$H R_{D}^{1} = 0.85$
	lying	Estimated H R _Dfor trials reached final stage			Estimated H R _Dfor trials reached final stage
	H R _D	%Pass^a	Mean (centiles^b)	%Bias	%Pass^a	Mean (centiles^b)	%Bias
I outcome: OS^c
1	1.10	7	0.97(0.85,1.11)	− 12	2	1.01(0.94,1.10)	− 8
	1.00	21	0.92(0.80,1.05)	− 8	22	0.95(0.88,1.03)	− 5
	0.88	61	0.85(0.73,0.98)	− 3	84	0.87(0.79,0.95)	− 1
	0.75	94	0.74(0.62,0.88)	− 1	99.9	0.75(0.68,0.83)	0
2	1.10	1	0.90(0.78,1.01)	− 18	0	−	−
	1.00	10	0.86(0.79,0.98)	− 14	9	0.92(0.87,0.97)	− 8
	0.88	48	0.82(0.71,0.92)	− 7	81	0.87(0.79,0.93)	− 1
	0.75	93	0.74(0.62,0.86)	− 1	99.9	0.75(0.68,0.83)	0
I outcome: PFS^d
1	1.10	7	1.01(0.86,1.17)	− 8	2	1.04(0.96,1.13)	− 5
	1.00	22	0.94(0.80,1.09)	− 6	23	0.97(0.88,1.05)	− 3
	0.88	61	0.85(0.73,0.99)	− 3	84	0.87(0.79,0.96)	− 1
	0.75	93	0.74(0.62,0.88)	− 1	99.8	0.75(0.68,0.83)	0
2	1.10	1	0.97(0.82,1.11)	− 12	0	−	−
	1.00	9	0.91(0.79,1.05)	− 9	9	0.95(0.86,1.03)	− 5
	0.88	47	0.84(0.72,0.98)	− 5	82	0.87(0.79,0.95)	− 1
	0.75	93	0.74(0.62,0.88)	− 1	100	0.75(0.68,0.83)	0

^aPercentages of trials that pass interim stages 1 and 2 and continue accrual to the final stage;
^bthe 2.5th and 97.5th centiles of the estimated OS hazard ratios;
^coverall survival;
^dprogression-free survival.

ISSN: 1745-6215