title: Adapting the sample size planning of a phase III trial based on phase II data.
abstract: Traditionally, in clinical development plan, phase II trials are relatively small and can be expected to result in a large degree of uncertainty in the estimates based on which Phase III trials are planned. Phase II trials are also to explore appropriate primary efficacy endpoint(s) or patient populations. When the biology of the disease and pathogenesis of disease progression are well understood, the phase II and phase III studies may be performed in the same patient population with the same primary endpoint, e.g. efficacy measured by HbA1c in non-insulin dependent diabetes mellitus trials with treatment duration of at least three months. In the disease areas that molecular pathways are not well established or the clinical outcome endpoint may not be observed in a short-term study, e.g. mortality in cancer or AIDS trials, the treatment effect may be postulated through use of intermediate surrogate endpoint in phase II trials. However, in many cases, we generally explore the appropriate clinical endpoint in the phase II trials. An important question is how much of the effect observed in the surrogate endpoint in the phase II study can be translated into the clinical effect in the phase III trial. Another question is how much of the uncertainty remains in phase III trials. In this work, we study the utility of adaptation by design (not by statistical test) in the sense of adapting the phase II information for planning the phase III trials. That is, we investigate the impact of using various phase II effect size estimates on the sample size planning for phase III trials. In general, if the point estimate of the phase II trial is used for planning, it is advisable to size the phase III trial by choosing a smaller alpha level or a higher power level. The adaptation via using the lower limit of the one standard deviation confidence interval from the phase II trial appears to be a reasonable choice since it balances well between the empirical power of the launched trials and the proportion of trials not launched if a threshold lower than the true effect size of phase III trial can be chosen for determining whether the phase III trial is to be launched.
authors.affiliation: Office of Biostatistics, Office of Pharmacoepidemiology and Statistical Science, Center for Drug Evaluation and Research, US Food and Drug Administration, Silver Spring, MD 20993, USA. suejane.wang@cder.fda.gov
authors.forename: Sue-Jane
authors.initials: SJ
authors.lastname: Wang
authors.forename: H M James
authors.initials: HM
authors.lastname: Hung
authors.forename: Robert T
authors.initials: RT
authors.lastname: O'Neill
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D003627:Data Interpretation, Statistical; D006801:Humans; D011336:Probability; D018401:Sample Size