non inferiority vs equivalence

they are planned and performed as equivalence trials or non-inferiority trials [3]. How does one make sense of something that is 'non-inferior' and also 'superior'. Non-inferiority (and equivalence) trial designs were developed to demonstrate similarity between an experimental treatment and an active control. In summary, superiority, non-inferiority, and equivalence studies are three study types with different assumptions about treatment effects 24 [ Table 1]. The margin of non-inferiority in this example is 7%. In non-inferiority trials, you want the effectiveness to be ___________ the measure of association (RR or OR) range. Methods of analysis and for estimating the numbers of participants to be recruited to such trials are given. This is a detailed animated video presentation on the three main types of clinical trials, namely superiority, non-inferiority and equivalence clinical trial. Equivalence and noninferiority designs are useful when the superiority of one intervention over another is neither expected nor required. Non-inferiority - Design Failure to include placebo can lead to lack of internal validity in non-inferiority trials, but is common Design flaws TEND TO BIAS RESULTS towards a finding of equivalence Ethical issues MJA 2009;190(6):326-330. . non-inferior) if the lower limit of the computed 95% ci around the difference between e/n and r/s does not extend beyond a pre-defined margin (shown as - in figure 1c), also known as the non-inferiority Analysis English to Polish translations [PRO] Medical - Medical (general) / clinical trials. The difference between equivalence and non-inferiority is rather simple. Also supported are one-sided versions (so-called non-inferiority or non-superiority tests). The upper boundary of an 11% increase in strokes is probably acceptable to clinicians and patients. These mathematical expressions have been given "lay names" by satisticians in an effort to describe the math to non-statisticians; these names are: Non-inferiority Superiority Bioequivalence Of these three comparisons, the non-inferiority has the largest range of successful trial outcomes (equivalence or superiority). 18:06 Aug 18, 2011. In equivalence trials the null hypothesis is that the treatments are significantly different, by a specified margin (the "equivalence margin"). All tests are on standardized (differences of) means theta: theta = (mu_x - mu) / sigma. The CONSORT extension for reporting noninferiority and equivalence trials was updated in 2012 to be in-line with CONSORT 2010, and can be downloaded below. In such cases, only one of the 2 one-sided tests described above in the TOST section needs to be performed. Sometimes the aim of an RCT is just to show that a new therapy is not superior but equivalent to or not inferior to an established therapy, i.e. In noninferiority studies, the objective is to demonstrate that a therapy is not inferior (i.e., equivalent or possibly superior) than another. The choice of equivalence margins should be justified clini-cally. What is the intent of non-inferiority trials? Equivalence trial 36. While the adaptation to the non-inferiority design is relatively straightforward, the equivalence design requires more effort. In this case this significance level is also 0.025. If the intent is to show that the differences between control and study treatments are not large in either direction the study is called an equivalence trial. If the intent of . Equivalence is claimed only if the treatment difference is concluded to be both significantly above the lower limit () and significantly below the upper limit (+) using a traditional one-sided test against a constant for each of the two components of H 1 (usually t tests if the outcome is continuous). Our choice of a non-inferiority trial design was based on the expectation that non-inferiority of capecitabine, given orally on an outpatient basis, would be sufficient to tip the risk-benefit ratio in its favour. The pros and cons of non-inferiority (equivalence) trials. Interchanging from superiority to non-inferiority and vice versa Switching from non-inferiority to superiority is feasible provided that the margin (with respect to the control) is predefined or can be justified during the analysis. One-Sided Noninferiority Tests In some cases, the goal of the analysis is not to show that a test and reference mean are "equivalent", but only to show that the test formulation is at least as good as the reference formulation. This trial was a non-inferiority (NI) trial, and in a subsequent re-analysis also concluded the superiority of high dose IV iron regimen over the low dose regimen. Pragmatic equivalence and non-inferiority trials are an important means of conducting postmarketing surveillance of existing therapy choices. Based on observed single pregnancy rates 52% for IVF-SET, 43% for IVF-MNC and 47% for IUI-COH respectively, both IVF-SET and IVF-MNC arms were shown to be non-inferior to IUI-COH. 20% 3. Equivalence was defined as a CI range of [ 0.5 days, + 0.5 days]. The overall quality of results obtained from equivalence and noninferiority trials depends on trial design and the manner in which an investigator reports the results. In a non-inferiority trial, by contrast, the aim is to show that a new product is not unacceptably worse than an older one. Non-inferiority testing is a common hypothesis test in the development of generic medicine and medical devices. . 1. Please have a look at the following video introducing equivalence and non-inferiority: Useful Links. In this case, there are two null hypotheses: Making sense of equivalence, non-inferiority and active control trials as non-inferior. 40% 5. A non-inferiority trial is different as it is designed not to show that treatments are equal, or 'not different', but that the new treatment is not unacceptably worse than, or 'non-inferior' to, an active control. Equivalence trials test whether a difference between groups falls within a prespecified equivalence region, whereas noninferiority trials test whether a preferred intervention is either better or at least not worse than the comparator, with worse being . Equivalence vs. Non-Inferiority Regulator's View BMWP / EMA Workshop on Biosimilar MAbs 24 October 2011, London Martina Weise, MD Federal Institute for Drugs and Medical Devices (BfArM), Germany. The top of the output displays summary statistics for each sample. Which hypothesis you use depends entirely on the question your trial is addressing. That is, there is an equivalence interval above and below the mean of the standard therapy, as shown in Figure 27-1. sylwenos. Statistically, such a study differs from an equivalence trial because the is only one-sided towards . Bundesinstitut fr Arzneimittel und Medizinprodukte General Guideline: (Non)Clinical Issues The observed data are statistically compared against the . As it turned out, dabigatran 110 mg dose reduced the relative risk to 0.91 (95% confidence interval 0.74-1.11). 30% 4. B v C 0.4460 Equivalence has not been demonstrated. 37. The largest possible choice for the non-inferiority margin is the entire known effect of the active control compared to placebo, called M1. Using the two one-sided test (TOST) procedure, equivalence is tested using a (1-2)100% CI. Sometimes the aim of an RCT is just to show that a new therapy is not superior but equivalent to or not inferior to an established therapy, i.e. Contrasts are made between trials designed to detect superiority, with those to demonstrate Non-inferiority or equivalence. The non-inferiority trial, which is related to the equivalence trial, aims not at showing equivalence but only at showing that the new therapy is no worse than the reference therapy. After choosing an interval of "clinical equivalence," the therapeutic equivalence between the two drugs can be affirmed if the observed effect of A and its 95% CI vs B fall within the equivalence margins. Equivalence tests are a variety of hypothesis tests used to draw statistical inferences from observed data. The main CONSORT Statement provides recommendations for reporting randomized controlled trials, which aim to determine whether one intervention is . The ICH E10 guidance has the following statement [23]: Since the types of trials have different aims, they differ significantly in various methodological aspects. Demonstrating similarity between compared groupsthat is, equivalence or noninferiority of the outcome of one group to the outcome of another grouprequires a different analytic approach than determining the difference between groupsthat is, superiority of one group over another. Summary - Determining Non-inferiority Equivalence requires that the difference control - new intervention is both > - and < , the new treatment must be neither worse nor better than the control by a fixed amount. An equivalence boundary should be set before the trial. Testing for Equivalence or Non -inferiority Level : Intermediate Version No: 1 Version Date: June 2013 Nurun Nisa de Souza, MD, MPH Associate Duke-NUS Graduate Medical School The awareness of the methodological dierences is generally quite limited. 37. In the current example, a difference of one month, say, might be the maximum that can be considered equal, so the non-inferiority margin would be one month. percentages is called the margin of non-inferiority. Th ese procedures compute both asymptotic and exact confidence intervals and hypothesis tests for the difference, ratio, and odds ratio of two proportions. Non-inferiority is shown if the lower side of a two-sided (1-2)100% CI is above -. The non-inferiority of the treatment to the control can be easily understood form the alternative hypothesis. In this paper, we review exact methods available for proving non-inferiority or equivalence of two treatments with a dichotomous endpoint. The developers must design an experiment to test the hypothesis that the response rate of the new treatment is at least 0.63. An important consideration for non-inferiority trials is that proving the margin may be difficult. This functions implements uniformly most powerful invariant equivalence tests for one-sample and (paired or unpaired) two-sample problems. This is followed by an Equivalence Analysis which compares each pair of sample standard deviations. If it was not, equivalence or non-inferiority conclusions are meaningless (The non-inferior drug could have no effect at all). contrastingly, in non-inferiority trials, while the e/n strategy is definitely not better than the r/s, it is not unacceptably worse (i.e. Since the types of trials have dierent aims, they dier signicantly in various methodological aspects. The upper margin (+2) is irrelevant in this case since it only separates equivalence from superiority. Also one-sided alternatives (non-inferiority and non-superiority tests) are supported. A non-inferiority test can be thought of as a superiority test + equivalence test, as its alternative hypothesis covers the equivalence test alternative and the superiority test alternative. Non-inferiority trials reduce to a simple one-sided hypothesis test. In an equivalence trial, we say that the new drug is equivalent to the standard if it falls within the range of to where I 1 is the lower equivalence interval and I 2 the upper one. Non-inferiority trial a trial with the primary objective of showing that the response to the investigational product is not clinically inferior (or not unacceptably inferior) to a comparative agent (active or placebo control but usually active) very common in the regulatory setting either for a new treatment or for a new label indication. In non-inferiority trials the null hypothesis is that the experimental treatment is worse than the standard treatment - and the equivalence margin determines how much worse . Such trial types are termed as Non-inferiority trials and although the basic design may appear to be the . A v C 0.1302 Equivalence has not been demonstrated. Equivalence testing is thus referred to as "two one-sided tests" (or TOST).4If . 19. The hypotheses of non-inferiority clinical trials are H 0 : 1- 0- vs. H 1 : 1- 0> -, (5) where 0 and is also called the margin of clinical significance which is usually small. In a non-inferiority trial, the calculation is conventionally based on achieving adequate power to demonstrate that the relevant confidence limit excludes the specified non-inferiority margin, assuming that the two treatments are equally effective [ 5, 11 ]; these problems are symmetrical, given these assumptions [ 11 ]. Non-inferiority is different from equivalence. Superiority of the new therapy is show as the difference of the mean between new and standard is greater than 0. In equivalence tests, the null hypothesis is defined as an effect large enough to be deemed interesting, specified by an equivalence bound. The selection of the non-inferiority margin is based upon a combination of statistical reasoning and clinical judgement. The statistical hypothesis to be tested is 0: 121: 12> 0.07 A three-armed trial with test, reference and placebo allows some within-trial validation of the choice of non-inferiority margin and is therefore the recommended design; it should be used wherever possible. A v B 0.3906 Equivalence has not been demonstrated. Slide 4. Cautious though their conclusions were (e.g., "preliminary support"), this study was not powered or designed specifically to conduct equivalence or non-inferiority analyses, relying instead on traditional analyses for significance testing. In order to fill this gap, we adapt three approaches used for superiority settings to non-inferiority and equivalence designs: the two-trials rule, the sceptical p-value approach and the meta-analysis criterion. In terms of the equivalence margin, the research hypothesis is that the efficacy of the new therapy is no more than units lower than that of the current therapy (when higher is better). a standard non-inferiority test is performed nowadays at a one-sided 0.025 level. Selecting a non-inferiority margin in a trial is challenging but also critical to a successful trial.

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