Table A3.

Probability of Detecting Adverse Events Under Random Subsampling Methods for Adjuvant Disease Studies

CALGB 89803 (n = 1,264), Adverse Event, Active Arm Rate Excess in Full Study	Sampling Method	Subsample Size (total No. of patients)
		200	300	400	500	600
Grade 3+ events
Thrombosis embolism, 4.2%	Random by patient	78	84	88	92	94
	Random by center*	NA	NA	NA	NA	NA
Grade 1 to 2 events
Sweating (diaphoresis), 5.8%	Random by patient	68	63	73	71	77
	Random by center*	NA	NA	NA	NA	NA
Constipation, 6.9%	Random by patient	68	69	74	73	83
	Random by center*	NA	NA	NA	NA	NA
HERA (n = 3,386), Adverse Event, Active Arm Rate Excess in Full Study	Sampling Method	Subsample Size (total No. of patients)
		600	900	1,200	1,500	1,800
Grade 3+ events
Ejection fraction decreased,†‡ 2.4%	Random by patient	75	77	84	85	92
	Random by center*	62	70	74	79	82
Grade 1 to 2 events
Fatigue,5.1%	Random by patient	55	55	56	54	54
	Random by center*	51	50	54	54	53
Headache,† 6.8%	Random by patient	86	91	96	97	99.1
	Random by center*	84	89	92	96	98
BIG 1-98 (n = 7,963), Adverse Event, Active Arm Rate Excess in Full Study	Sampling Method	Subsample Size (total No. of patients)
		600	1,200	2,000	4,000	6,000
Grade 1 to 2 events: Hypercholesterolemia,21.2%	Random by patient	100	100	100	100	100
	Random by center*	99.9	100	100	100	100

NOTE. To account for their substantially larger safety databases, the HERA study (n = 3,386) and BIG 1-98 study (n = 7,963) were evaluated using larger subsamples. Adverse events in italics could be missed under patient subsampling. The other events are known events but are included here because the magnitude of the active arm rate excess versus the control arm illustrates the properties of adverse event subsampling. From the HERA trial, known adverse events ejection fraction decreased (grade 3 to 4) and headache (grade 1 to 2) were included to demonstrate trends of finding adverse events as the rates of incidence increase from the cutoff rate. Grade 3+ events are detected in a simulation when they appear in 2% excess over the control arm; grade 1 to 2 events are detected when they appear in 5% excess over the control arm. Rates of detection in bold are ≥ 75%.

Abbreviations: CALGB, Cancer and Leukemia Group B; NA, not applicable; HERA, HERceptin Adjuvant; BIG, Breast International Group.

^*Sample sizes are approximate. No. of centers selected at random was determined to achieve an average No. of patients at or above the target level.

^†Known from previous trials.

^‡Identified as known in candidate trial from analysis of adverse events to be collected in all patients (see Methods).