Optimal planning of phase II/III programs for clinical trials with multiple endpoints.

Owing to increased costs and competition pressure, drug development becomes more and more challenging. Therefore, there is a strong need for improving efficiency of clinical research by developing and applying methods for quantitative decision making. In this context, the integrated planning for phase II/III programs plays an important role as numerous quantities can be varied that are crucial for cost, benefit, and program success. Recently, a utility-based framework has been proposed for an optimal planning of phase II/III programs that puts the choice of decision boundaries and phase II sample sizes on a quantitative basis. However, this method is restricted to studies with a single time-to-event endpoint. We generalize this procedure to the setting of clinical trials with multiple endpoints and (asymptotically) normally distributed test statistics. Optimal phase II sample sizes and go/no-go decision rules are provided for both the "all-or-none" and "at-least-one" win criteria. Application of the proposed method is illustrated by drug development programs in the fields of Alzheimer disease and oncology.

A systematic review and meta-analysis of the utility of repeated versus single hepatic resection for colorectal cancer liver metastases.

BACKGROUND: Recurrence of colorectal liver metastases after a first hepatectomy is common (4-48% of patients). This review investigates the utility of repeated hepatic resection of colorectal liver metastases. METHODS: A systematic search of the literature was performed in the Cochrane Library, MEDLINE, EMBASE, and trial registers. All studies comparing repeated hepatic resection for colorectal liver metastases with patients who underwent only one hepatectomy were eligible. Outcome criteria were safety parameters and survival rates. Data were analyzed using the random-effects model. RESULTS: In eight observational clinical studies, 450 patients with repeated hepatic resection were compared with 2669 single hepatic resections. Morbidity such as hepatic insufficiency (OR [95% CI] 1.46 [0.69; 3.08], p = 0.32) and biliary leakage and fistula (OR [95% CI] 1.22 [0.80; 1.85], p = 0.35) was comparable between the two groups. Mortality (OR [95% CI] 1.13 [0.46; 2.74], p = 0.79) and overall survival (HR [95% CI] 1.00 [0.63; 1.60], p = 0.99) were not significantly different between the two groups. DISCUSSION: Repeated hepatic resection for colorectal liver metastases is safe in selected patients. A prospective, multicenter high-quality trial or register study of repeated hepatic resection will be required to clarify patient-oriented outcomes such as overall survival and quality of life.