title: Effect of a misspecification of response rates on type I and type II errors, in a phase II Simon design.
abstract: Phase-II trials are a key stage in the clinical development of a new treatment. Their main objective is to provide the required information for a go/no-go decision regarding a subsequent phase-III trial. In single arm phase-II trials, widely used in oncology, this decision relies on the comparison of efficacy outcomes observed in the trial to historical controls. The false positive rate generally accepted in phase-II trials, around 10%, contrasts with the very high attrition rate of new compounds tested in phase-III trials, estimated at about 60%. We assumed that this gap could partly be explained by the misspecification of the response rate expected with standard treatment, leading to erroneous hypotheses tested in the phase-II trial. We computed the false positive probability of a defined design under various hypotheses of expected efficacy probability. Similarly we calculated the power of the trial to detect the efficacy of a new compound for different expected efficacy rates. Calculations were done considering a binary outcome, such as the response rate, with a decision rule based on a Simon two-stage design. When analysing a single-arm phase-II trial, based on a design with a pre-specified null hypothesis, a 5% absolute error in the expected response rate leads to a false positive rate of about 30% when it is supposed to be 10%. This inflation of type-I error varies only slightly according to the hypotheses of the initial design. Single-arm phase-II trials poorly control for the false positive rate. Randomised phase-II trials should, therefore, be more often considered.
authors.affiliation: Service de Biostatistique et d'Épidémiologie, Institut Gustave Roussy, 114 rue Edouard Vaillant, 94805 Villejuif, France.
authors.forename: Charlotte
authors.initials: C
authors.lastname: Baey
authors.forename: Marie-Cécile
authors.initials: MC
authors.lastname: Le Deley
mesh_terms: D017322:Clinical Trials, Phase II as Topic; D035061:Control Groups; D005189:False Positive Reactions; D006801:Humans; D010361:Patients; D011336:Probability; D015203:Reproducibility of Results; D012107:Research Design; D018401:Sample Size; D013223:Statistics as Topic; D016896:Treatment Outcome