In non-inferiority trials, where non-inferiority of a new experimental drug compared to an active control has to be shown, it may be advisable to use an additional placebo group for internal validation if ethically justifiable. The focus of this paper is on such designs. Assuming normality and homogeneity of variances we will derive a statistical test procedure which turns out to be equivalent to the assessment based on Fieller's confidence interval. Based on the power function of this test, sample size calculations are carried out to achieve a given power. Additionally, the optimal allocation of the total sample size is derived. As an alternative to this parametric procedure, the bootstrap percentile interval is discussed and finally compared with Fieller's confidence interval in a study on mildly asthmatic patients.
The treatment of metastatic melanoma is still undergoing a process of major change. The two most important novel therapeutic strategies, selective kinase inhibitors and immune checkpoint blockers, both significantly prolong survival times of patients with advanced metastatic disease. Different agents, dose regimens and combinations have been tested against each other vigorously within these two groups. However, results from prospective head-to-head comparative studies of both strategies are still lacking. We performed an exploratory analysis of survival data from selected clinical trials representative for the new treatment strategies in advanced metastatic melanoma. Eighty-three Kaplan-Meier survival curves from 25 trials were digitised and grouped by therapeutic strategy and treatment line. For each of these groups, mean survival curves were generated for progression-free (PFS) and overall survival (OS) by weighted averaging. Survival curves grouped together by therapeutic strategy revealed a high concordance, particularly in the first-line setting. For kinase inhibitors, the most favourable PFS and OS in all therapy lines were observed for combined BRAF plus MEK inhibition. For immune checkpoint inhibitors, combined PD-1 plus CTLA-4 inhibition demonstrated the best survival outcome in all categories except for OS in first-line therapy. For the latter, combined PD-1 plus CTLA-4 inhibition showed similar outcomes as single-agent PD-1 inhibition. Comparison of kinase inhibitors and checkpoint blockers revealed a superiority of combined BRAF plus MEK inhibition within the first 6 months, later changing to a superiority of PD-1 blockers alone or in combination with CTLA-4 blockers. These results need confirmation by prospective clinical trials.
This article reviews the most important reasons to include a placebo and a reference treatment group in a study to investigate the efficacy of a new experimental treatment. We argue that as a general rule the regulatory requirement is the proven superiority of the experimental treatment over placebo and the proven noninferiority of the experimental treatment as compared to the reference treatment. Whether or not the reference treatment can be shown to be superior to placebo may impact the formulation of the indication but should not, per se, question the usefulness of the experimental treatment or the credibility of the principal proof of efficacy. We argue that a mandatory requirement for the reference treatment to be superior to placebo is ill founded and especially difficult to justify in the situation where the experimental treatment can also prove its superiority over the reference treatment. For this latter situation, it is shown that no adjustment for multiple hypothesis testing is needed, if at the same time superiority of the reference over placebo and superiority of the experimental treatment over the reference are investigated.
Inferential test strategies for multi-arm trials are adapted or proposed for the special situation when more than one dose of a test treatment, placebo and active control(s) are compared. This includes between doses, dose-placebo and dose-active-control comparisons. The procedures refer to situations when detailed comparisons make sense only if the sensitivity of the trial has been shown, for example, if a dose-response relationship or a difference between active control and placebo has been established. Split strategies, hierarchical (assuming an order restriction among doses) or linked procedures are introduced. In linked procedures, equivalence to the active control will be established only if the dose is also shown to be effective as compared to placebo. All the inferential procedures control the experimentwise error rate in the strong sense for the respective sets of null hypotheses considered.
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