ABSTRACT
Noninferioritylequivalence designs are often used in vaccine clinical trials. The goal of these designs is to demonstrate that a new vaccine, or new formulation or regimen of an existing vaccine, is similar in terms of effectiveness to the existing vaccine, while offering such advantages as easier manufacturing, easier administration, lower cost, or improved safety profile. These noninferioritylequivalence designs are particularly useful in four common types of immunogenicity trials: vaccine bridging trials, combination vaccine trials, vaccine concomitant use trials, and vaccine consistency lot trials. In this paper, we give an overview of the key statistical issues and recent developments for noninferioritylequivalence vaccine trials. Specifically, we cover the following topics: (i) selection of study endpoints; (ii) formulation of the null and alternative hypotheses; (iii) determination of the noninferioritylequivalence margin; (iv) selection of efficient statistical methods for the statistical analysis of noninferioritylequivalence vaccine trials, with particular emphasis on adjustment for stratification factors and missing pre-or post-vaccination data; and (v) the calculation of sample size and power.
Subject(s)
Models, Statistical , Randomized Controlled Trials as Topic/statistics & numerical data , Vaccines/pharmacokinetics , Endpoint Determination/methods , Endpoint Determination/statistics & numerical data , Humans , Randomized Controlled Trials as Topic/methods , Therapeutic Equivalency , Vaccines/adverse effects , Vaccines/immunology , Vaccines/therapeutic useABSTRACT
BACKGROUND: The incidence and severity of herpes zoster and postherpetic neuralgia increase with age in association with a progressive decline in cell-mediated immunity to varicella-zoster virus (VZV). We tested the hypothesis that vaccination against VZV would decrease the incidence, severity, or both of herpes zoster and postherpetic neuralgia among older adults. METHODS: We enrolled 38,546 adults 60 years of age or older in a randomized, double-blind, placebo-controlled trial of an investigational live attenuated Oka/Merck VZV vaccine ("zoster vaccine"). Herpes zoster was diagnosed according to clinical and laboratory criteria. The pain and discomfort associated with herpes zoster were measured repeatedly for six months. The primary end point was the burden of illness due to herpes zoster, a measure affected by the incidence, severity, and duration of the associated pain and discomfort. The secondary end point was the incidence of postherpetic neuralgia. RESULTS: More than 95 percent of the subjects continued in the study to its completion, with a median of 3.12 years of surveillance for herpes zoster. A total of 957 confirmed cases of herpes zoster (315 among vaccine recipients and 642 among placebo recipients) and 107 cases of postherpetic neuralgia (27 among vaccine recipients and 80 among placebo recipients) were included in the efficacy analysis. The use of the zoster vaccine reduced the burden of illness due to herpes zoster by 61.1 percent (P<0.001), reduced the incidence of postherpetic neuralgia by 66.5 percent (P<0.001), and reduced the incidence of herpes zoster by 51.3 percent (P<0.001). Reactions at the injection site were more frequent among vaccine recipients but were generally mild. CONCLUSIONS: The zoster vaccine markedly reduced morbidity from herpes zoster and postherpetic neuralgia among older adults.
