Ibuprofen versus pivmecillinam for uncomplicated urinary. In your example, the trial would be sized based on the primary endpoint noninferiority. The aim of the study was to investigate whether the delivery of therapy by telephone was as effective as face to face sessions, the standard mode of. Sessler, md equivalence and noninferiority designs are useful when the superiority of one.
Survival is an east module for planning, simulating, monitoring and communicating group sequential clinical trial designs with survival endpoints. Making sense of equivalence and noninferiority trials. Sealed envelope power calculator for binary outcome non. Bayes factors for superiority, noninferiority, and. Noninferiority versus superiority trial design for new antibiotics in an era of high antimicrobial resistance. Design of phase ii noninferiority trials sciencedirect. The following examples illustrate designing noninferiority studies and conducting noninferiority tests.
In an equivalence trial, the desired conclusion is that two products are the same or not unacceptably different from each other. A randomised controlled noninferiority trial study design was used. Power analyses for noninferiority tests can be performed on means for normal data, geometric means for lognormal data, or proportions for frequency data. Noninferiority randomized controlled trial of cognitive targeted biopsy versus software targeted biopsy full text view.
Noninferiority trials and 1sided confidence intervals duration. Noninferiority clinical trials scott evans, phd, ms, harvard university harvard catalyst april 4, 2016 outline concept, rationale, and examples assumptions constancy assay sensitivity design selecting the active control selecting the ni margin other issues and design alternatives trial conduct analyses itt vs. Noninferiority superiority bioequivalence of these three comparisons, the noninferiority has the largest range of successful trial outcomes equivalence or superiority. When planning a noninferiority trial, one should adequately understand its concept and the possible drawbacks. In assessing noninferiority trials the issues of trial design, such as randomisation, blinding and followup, are considered in the same way as they are in trials looking for superiority. Noninferiority trials usually require larger sample sizes than superiority trials because the noninferiority margin is smaller than the treatment effects assessed by superiority trials and study power needs to be higher usually 90% for a noninferiority trial, to minimise the risk that a noninferior treatment is missed due to chance. Design and analysis of noninferiority trials crc press book. Noninferiority trials are intended to show that the effect of a new treatment is not worse than that of an active control by more than a specified margin. This calculator is designed for continuous outcomes such as walking distance, blood pressure, white blood cell count in parallel group noninferiority trials. Noninferiority trials presentation linkedin slideshare.
Noninferiority trials, on the other hand, aim to show that an experimental treatment is not worse than an active control by more than the equivalence margin. A binary outcome has two categories, such as deadalive, hospitalisation yesno, therapeutic successfailure and so on. In an equivalence trial, if the effects of the two treatments differ by more than the equivalence margin in either direction, then equivalence does not hold. Julious1 march24,2016 abstract a sample size justi. It is also important to note, as has been inferred from the above, that a noninferiority trial is essentially a one sided equivalence trial or conversely an equivalence trial can be described as two one sided tests tost. Using examples from real clinical trials, design and analysis of noninferiority trials brings together this body of research and confronts the issues involved in the design of a noninferiority trial. However, there are other considerations when assessing noninferiority trials. Thus a calculated sample size for a noninferiority trial is usually the smallest of the three hypothesis. As a result, we often fail to open a noninferiority phase iii trial and a large number of. The mean outcome is compared between the experimental and standard treatment groups.
Two wrongs dont make a right, but three rights do make a left. Furthermore, due to lack of phase ii noninferiority trial design methods, we do not have an opportunity to investigate the efficacy of the experimental therapy through a phase ii trial. Oral fexinidazole for latestage african trypanosoma. A noninferiority phase iii trial requires a roughly four times larger sample size than that of a similar standard superiority trial.
Typically, evidence in each of these paradigms is quantified with a variant of the null hypothesis significance test. Twosample ttest for noninferiority statistical software. Superiority, equivalence, and noninferiority trial designs. Noninferiority randomized controlled trial of cognitive.
Further indepth discussion of noninferiority and equivalence testing, and several examples, can be found in castelloe and watts 2015 example 1. Statistical grand rounds equivalence and noninferiority testing in regression models and repeatedmeasures designs edward j. This calculator is useful for the types of tests known as noninferiority and superiority tests. Even in this case, however, the possibility of bias can not be ruled out, and it can be awkward to have different analytic strategies for superiority and noninferiority. This calculator is designed for binary outcomes in parallel group non inferiority trials. Sample size calculation for non inferiority study with two. Which hypothesis you use depends entirely on the question your trial is addressing. Who protects participants in noninferiority trials when. Sealed envelope power calculator for continuous outcome. Noninferiority versus superiority trial design for new. However, estimating the number of participants required to give a meaningful result is not always straightforward.
Outpatient versus inpatient treatment for patients with acute pulmonary embolism. A clinical trial that shows that a new treatment is equivalent to standard treatment. If this can be established, the new treatment can be considered. The desiderata of trial conduct may work against you. Because of the large required sample size, we often face. In a noninferiority trial, by contrast, the aim is to show that a new product is not unacceptably worse than an older one. The noninferiority trial is a useful alternative in such situations. Design and analysis of noninferiority trials chapman. That is, the non inferiority margin is 20% of 550 which is 110.
Test statistics many different test statistics have been proposed for non inferiority tests of a single proportion. If the whole confidence interval ci for the difference in treatment. Provides a wide variety of options for normal and binomial endpoints in superiority, noninferiority, and equivalence studies. You may follow along here by making the appropriate entries or load the completed template example 1 by clicking on open example template from the file menu of the twosample ttest for noninferiority window. The most widely used design is a noninferiority trial. Sequential is an east module for planning, simulating, monitoring and communicating group sequential clinical trial designs. In november 2016 the fda released final guidance on noninferiority clinical trials to establish effectiveness providing researchers guidance on when to use noninferiority trials to demonstrate effectiveness along with how to choose the noninferiority margin, test the noninferiority hypothesis, and provide interpretable results.
This article provides background on a noninferiority trial design along with assumptions and advantages and disadvantages of the trial design. Calculate sample size needed to compare 2 proportions. Each chapter begins with a nontechnical introduction, making the text easily understood by those without prior knowledge of this type of trial. As the name suggests, the aim is to show that the new treatment is not inferior to the existing one that is, it is either equally effective or better.
Whether the null hypothesis represents noninferiority or superiority depends on the context and whether the non. These trials have a number of inherent weaknesses that superiority trials do not. This calculator is designed for binary outcomes in parallel group noninferiority trials. Noninferiority trials are more complex to design, conduct, and interpret than conventional superiority trials. The challenges faced throughout the design of a noninferiority trial compared with superiority trials include the selection of an appropriate and clinically relevant margin, the primary population for analysis, and the choice of comparator treatment e. Equivalence trials are two distinctly different kinds of trials, with noninferiority trials as a sortof hybrid between the two. All patients received oral and written information about the trial and signed an informed consent form. In a trial intending to show that there is a difference less than a specific amount between control and experimental treatments, a noninferiority design statistically tests the null hypothesis that the experimental treatment is inferior by the equivalence margin. Choice of the noninferiority margin is critical in designing noninferiority trials.
In clinical trials, study designs may focus on assessment of superiority, equivalence, or noninferiority, of a new medicine or treatment as compared to a control. The intervention was 10 weekly sessions of exposure therapy and response prevention delivered by telephone or face to face. Therefore, noninferiority trials are often analyzed using itt and perprotocol approaches, and only if both approaches support noninferiority is the trial considered positive. Additionally, if a clear superiority or inferiority exists, a properly executed noninferiority trial will spot it. A null hypothesis is assumed null effect, inferior by a specific amount, inferior by a specific amount and. Noninferiority comparator active comparator drug should ideally be widely used with established efficacy via superiority trial and identical indication noninferiority trial should mimic design of superiority trial primary variables, doses of comparator, inclusionexclusion criteria, etc. Background a noninferiority trial is used to demonstrate a test drug is not clinically worse than an active treatment active control by more than a prespecified margin noninferiority margin. Lenient significance boundaries can result in a statistical finding of noninferiority without showing substantive clinical noninferiority flacco et al. In this multicentre, randomised, openlabel, active control, parallelgroup, pivotal phase 23, noninferiority trial, we recruited patients aged 15 years or older with parasitologically confirmed latestage ghat infection from nine ghat treatment centres in the democratic republic of the congo and one in the central african republic. The only difference is that for noninferiority tests o0 1. Design and analysis tools for noninferiority tests you can use proc power to analyze power and determine sample size for a variety of noninferiority tests. On thursday, october 4, 2012, niemierko, andrzej wrote.
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