Trial Design Issues

Endpoints and Sample Size

Phase III trial design begins with specification of a primary endpoint, which is typically a simple binary event such as survived/died or recurred/remained recurrence free, but usually with one important difference relative to Phase II trials; for each patient the time from randomization until occurrence of this event will be recorded, rather than the event status at some fixed time landmark. These time-to-event endpoints are particularly suited for adjuvant therapy trials, where because the number of patients participating is appreciably larger than in Phase II trials, recruitment takes place over a lengthy interval and each patient will have a different follow-up duration at any given time from trial initiation. Use of follow-up time per patient is more efficient than waiting until all patients have reached some fixed time. The treatment effect measure is usually specified in terms of hazards, which can be thought of as failure probabilities or failure rates per unit of time, between two treatment groups. Hypotheses are thus usually formulated in terms of the hazard ratio (HR) as H0:1A/1B = HR = 1.0 where 1A and 1B are the hazards for treatments A and B, versus alternative HA: HR < 1.0, for some value of the HR that represents a clinically material difference in outcomes. In the case of an equivalence trial, one might test a null hypothesis that the HR does not differ from 1.0 by more than some specified amount such that the two treatments would be considered equivalent (hence, this difference must be small) versus the alternative that a greater difference exists (see References 1, 2 for more on equivalence trials). Under the assumption that this ratio is relatively constant over time, a given HR can be converted to an absolute difference between groups in proportions remaining event free at a given follow-up time. For example, a new/standard HR equal to 0.75, or a 25% reduction in failure rate in the new relative to the standard group, may translate into an absolute difference in the proportion of patients remaining free of the event between groups of 4.6% at 5 years, given that the standard group 5-year survival percentage is 80% (Table 8.4).

TABLE 8.4. Absolute difference in 5-year survival and number of events required for a two-arm Phase III trial.

Reduction in hazard of failure for new treatment

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