example of non inferiority trial

Warfarin has been the standard anticoagulant therapy for over 60 years but has some disadvantages including the requirement for routine monitoring of the international normalized ratio (INR). method for non-inferiority phase III trials. Hypothetical scenarios of a clinical study revealing non-inferiority and superiority, non-inferiority alone, non-inferiority and inferiority, inconclusive, and inferiority. Non-inferiority testing is a common hypothesis test in the development of generic medicine and medical devices. 1). The one-sided zone of non-inferiority is defined by − Ψ, i.e., the difference in population means between . Generally, equivalence trials and non-inferiority trials will require larger sample sizes than superiority trials. The term 'non-inferiority' is now well established, but if taken literally could be misleading. 2. 2. PDF Interpreting Non-inferiority Clinical Trials The uncertainty about treatment effects should be less when planning sample sizes for non-inferiority trials. 3. Does the design of the trial enhance the risk of type I errors? 5 for the ratio of the antibody GMTs in survivors of cancer versus general population comparisons, chosen to be consistent with the general population comparator trials at the time that our trial was initiated. The most common design compares the proposed non-inferior treatment to the standard treatment alone but this leaves uncertain if the treatment effect is the same as from previous studies. Those results can then be treated equally for a balanced conclusion, or the more pessimistic results can be used for a conservative interpretation. However, only a superiority trial can demonstrate this. However, it seems that this principle is most applicable to superiority trials. A number of components are required to facilitate a suitable sample size calculation. Under the assumption that the new treatment is a little better, as is often the case for a new product, the required sample size decreases considerably. Determination of an appropriate non-inferiority margin is critical to the demonstration of non-inferiority. Therefore, the investigator cannot claim non-inferiority of the experimental therapy to the active control. For example, although effective interventions existed for stroke prevention in atrial fibrillation and for valvular disease, the use of these therapies was compromised by burdensome logistics, or safety and tolerability concerns. Power Analysis using StudySize 3.0. Alvine wrote: Dear all, I'd like to estimate the sample size for a non inferiority clinical trial. 2020; 382(5):405-415. a non-inferiority trial is the current. The sample size required for a non-inferiority clinical trial can be calculated using the formula in Figure 1 [5],[6]. StudySize - Software for Sample Size Calculation and Power ... Non-inferiority trials that evaluate whether a new therapy is not inferior to the standard therapy, are becoming more common in the last two decades. None of SAS Examples 7.7-7.9 accounted for withdrawals. Sample Size for Non-Inferiority Tests for One Proportion ... Critically evaluate results of superiority and non-inferiority trials. PDF Reporting of Noninferiority and Equivalence Randomized Trials D'Agostino,3 the use of such non-inferiority trials has increased considerably over the last decades. Non-inferiority is shown if the lower side of a two-sided (1-2α)×100% CI is above -Δ. What is a non-inferiority trial? | The BMJ A Phase 3, randomized, double-blind, non-inferiority trial was conducted to determine the Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs. 10-day Oral Linezolid Therapy (ESTABLISH-1). The Non-adherence in non-inferiority trials: pitfalls and ... PDF Practical guide to sample size calculations: non ... Non-Inferiority Clinical Trials to Establish Effectiveness ... A good example of the appropriate use of a non-inferiority trial is the current research programmes to develop new drugs for treatment of drug-sensitive tuberculosis. Examples of equivalence and non-inferiority trials Example 2. 1. Noninferiority trials should USE and REPORT THE RESULTS from Both Methods. When designing a non-inferiority trial with a binary primary outcome, the choice of effect measure for the non-inferiority margin (e.g. Assuming an event-free survival rate of 90% with COPP, the expected sample size would need to provide 80% power to show non-inferiority, as long as COPDAC was less than 2% inferior to COPP. 3. Critically evaluate results of superiority and non-inferiority trials. mens are highly eﬀ ective . mens are highly eﬀ ective . 1981;34(9-10):469-479. Subsequently, we propose three diﬀerent designs . Lower cost and sample size also makes it a more convenient endeavour! Practical advice and examples are provided that illustrate how to carry out the calculations by hand and using the app SampSize. Example 1 - Non-Inferiority Test for Two Independent Samples This section presents an example of how to test non-inferiority. In other words, a poorly designed non-inferiority trial can lead to the adoption of a useless treatment. References: Brown SG, Ball EL, Perrin K, et al. The 4% non -inferiority margin was extrapolated References: Brown SG, Ball EL, Perrin K, et al. Non-inferiority trials are increasingly used to evaluate new treatments that are expected to have secondary advantages over standard of care, but similar efficacy on the primary outcome. Compare purpose, sample size, margin, null hypothesis, and statistical analysis plan between superiority and non-inferiority trials. If they are better in other words doctors are worse this would still be a positive outcome. drugs for treatment of drug-sensitive. Internationally recommended regimens are highly effective, curing 95% or more of patients in clinical trials in a wide variety of settings. It is well known that the size of the margin strongly influences the required sample size. 1. If the whole confidence interval (CI) for the difference in treatment . In the 12 prostate cancer studies, 5 were designed as non-inferiority trials, 4 as superiority trials and 3 did not report the design of the trial Among the 13 studies designed as non-inferiority . A real example of a non-inferiority trial is the VALIANT trial in patients with myocardial infarction and heart failure . Thus, a non-inferiority trial is one-sided, whereas an equivalence trial is two-sided. Both single-sided & two-sided intervals are valid. Equivalence and non-inferiority trials typically compare the effects of a treatment of interest with the current gold-standard treatment as the comparator. Non-inferiority trials incorporate the process of statistical hypothesis testing, although the approach is an adaptation of the traditional one used in superiority trials. There is no placebo arm in non-inferiority trials. The one-sided zone of non-inferiority is defined by − Ψ, i.e., the difference in population means between . Effect size estimation for non-inferiority trial. Clearly the outcome of a non-inferiority trial depends critically on the non-inferiority margin. Of these three comparisons, the non-inferiority has the largest range of successful trial outcomes (equivalence or superiority). "NI" is non-inferiority. Fox W. Second, non-inferiority trials typically have large and equal sample sizes above 30 in each group where the coverage probabilities of different CI statistical methods were shown to be more similar to one another . Second, we show that several arguments for different approaches to the design, analysis and . Assessing non-inferiority is actually more complex . The 95% lower confidence limit for $\mu_E - \mu_A$ is -6.0, which does not lie within $\left(-4, +∞\right)$. Different possible scenarios of the results of a non-inferiority clinical trial. For example . trials. In this case this significance level is also 0.025. When a non-inferiority or equivalence trial is designed to compare Poisson or negative binomial rates, an appropriate method is needed to estimate the sample size to ensure the trial is properly . Superiority. It is a widespread practice that a However, with a non-inferiority trial, we would only wish to show that nurse practitioners are as good as doctors. Thus a calculated sample size for a non-inferiority trial is usually the smallest of the three hypothesis. A non-inferiority trial is used to demonstrate a test drug is not clinically worse than an active treatment (active control) by more than a pre-specified margin (non-inferiority margin). impossible, a prestated margin of non-inferiority ( ) for the treatment effect in a primary patient outcome is defined. [4,6] Conceptually, it is calculated what sample size is needed to prove, with statistical significance and a certain power, that the loss of therapeutic effect of the new therapy compared to the standard . 2. Within these parameters of the non-inferiority trials, it is unclear if there are still significant differences in CI widths by . 2020; 382(5):405-415. Sample size for a non-inferiority trial is usually calculated under the assumption that the experimental agent and control treatment have equal effects, that is, when γ is assumed to be zero. An adaptation of previously developed formulae for the superiority framework is presented that specifically allows for effect reversal under the non-inferiority setting, and its consequent effect on variance. A study set out to show that once-daily dosing with mesalazine granules was as good as three-times-daily dosing at inducing remission during first episodes of ulcerative colitis. Compare purpose, sample size, margin, null hypothesis, and statistical analysis plan between superiority and non-inferiority trials. Equivalence trials are very similar, except that equivalence is defined as the treatment effect being between and . The superiority comparison is a subset of the non-inferiority . Suppose the current (control) fertilizer has an undesirable impact on the ground water so a replacement (treatment) fertilizer has been developed that does not Let's define non-inferiority margin as 3 points, and test if T is non-inferior than C by 3 points or less. A non-inferiority trial design is chosen when using a placebo arm would not be ethical because an available . The goal of a non-inferiority trial is to evaluate whether the effect of an experimental treatment is not inferior to that of the active control. These trials answer whether we are willing to accept a new intervention that may be clinically worse, yet still be beneficial for patients while having another advantage, such as less-intensive treatment, lower cost or fewer side effects.1 Non-inferiority and . Internationally recommended regi-. The rate of non-remission at eight weeks was 24.3% in the three-times-daily group, but only 20.9% in the . a non-inferiority trial is the current. Examples of trials from the literature are discussed along with a computer simulation of a simple non-inferiority monitoring rule. Keywords: Clinical trial, non-inferiority trials, odds ratio, power, sample size Introduction In clinical trials, the aim is to display whether the use of a novel drug or a novel medical instrument will be efficient and reliable. Does the design of the trial enhance the risk of type I errors? "CI" is the 95% confidence interval. 4,5 Consequently, pivotal noninferiority trials led to the approval of non-vitamin K antagonist oral . (For non-inferiority, we want experimental therapy to be not inferior to the active control.) This article discusses the implications of different patterns of non-adherence in non-inferiority trials and offers practical recommendations for trial design, alternative analysis strategies, and outcome . practitioners. Non-inferiority. First, using two examples from infectious disease research, we show that the classification of superiority or non-inferiority trials is not always straightforward. Non-inferiority trials aim to demonstrate that the difference between the effectiveness of a new drug and an active control is small—small The plan is to show that the new treatment is clinically at least as good as the existing. Conservative versus Interventional Treatment for Spontaneous Pneumothorax N Engl J Med. In other words, a poorly designed non-inferiority trial can lead to the adoption of a useless treatment. Choosing the non-inferiority margin, which defines what we consider 'not unacceptably worse', is a pivotal step in designing non-inferiority trials. In these trials, therapeutic equivalence of the two interventions is claimed when the intervention effect and its CI lies between − Δ and + Δ. In the visualization superiority . The most widely used design is a non-inferiority trial; 3,4 two key design choices are the new duration of therapy and the non-inferiority margin, that is, the maximum difference in efficacy of the new versus standard treatment duration that investigators will tolerate. The magic is in the margin. 1983;39(2):499-503. risk ratio or risk difference) has an important effect on sample size . For therapeutic or prophylactic trials the noninferior-ity approach is much more common than a true (2-sided . 2018 ). At ﬁrst, we review a design. For example a trial is being designed to compare two treatments with an outcome of Response to Treatment. If they are better in other words doctors are worse this would still be a positive outcome. Non-inferiority trials incorporate the process of statistical hypothesis testing, although the approach is an adaptation of the traditional one used in superiority trials. Example "The PROUD trial is designed as a randomised, controlled, observer, surgeon and patient blinded multicenter superiority trial with two parallel groups and a primary . [1,2] An important reason for conducting a non-inferiority trial is when a new therapy is expected to have advantages over the standard therapy, other than the main therapeutic effect. J Chronic Dis. In the example above, if the non-inferiority margin had been, say, 2 months, non-inferiority would also have been demonstrated in scenario D. Given this importance, it is important to set the non-inferiority margin in advance and to do so in an . Schoenfeld D. Sample-Size Formula for the Proportional-Hazards Regression-Model. Each chapter begins with a non-technical introduction, making the text easily understood by those without prior knowledge of this type of trial. If this is not the expectation put the values you expect to observe in (a) and (b). research programmes to develop new. One can also declare superiority in a non - inferiority trial if the lower limit of CI of the new treatment is above the non - inferiority margin and above zero. This guidance finalizes the draft guidance for industry, Non-Inferiority Clinical Trials, published in 2010. A commonly used method is called the fixed-margin approach recommended by the FDA. Item 8: Description of trial design including type of trial (e.g., parallel group, crossover, factorial, single group), allocation ratio, and framework (e.g., superiority, equivalence, non-inferiority, exploratory). Planning the duration of a comparative clinical trial with loss to follow-up and a period of continued observation. tuberculosis. in non-inferiority trials for one proportion via Monte Carlo simulations. ∆ is the non-inferiority margin Full size image In this study, the authors claimed the superiority of the lactate strategy over the ScvO 2 strategy because the lactate group had a significantly lower mortality compared with the ScvO 2 group (18.3 versus 27.9%, P . This plays a huge role in lowering the cost of a trial. The sample size of a non-inferiority trial is calculated based on the non-inferiority margin, the intended power, and the significance level. I need your help calculating the estimated effect size for a non-inferiority hypothesis. Bioequivalence. The authors reported an intention to treat and per protocol analysis. In a non-inferiority trial, the focus is on the lower bound margin, what happens at the upper end is not of primary concern in this type of trial design. Non-inferiority (or equivalence) trial designs do not prohibit the conduct of conventional trial-based economic evaluations reporting cost-effectiveness. The focus of our article is non-regulatory trials with a public health objective. However, many unanswered questions remain regarding the application of non-inferiority margins to costs and QALYs. (For non-inferiority, we want experimental therapy to be not inferior to the active control.) In fact a non-inferiority trial aims to . Assume that the larger response is the better response. However, with a non-inferiority trial, we would only wish to show that nurse practitioners are as good as doctors. In this trial the most common adverse effects reported with tedizolid were nausea, headache and diarrhea. Empirical performance is assessed through a small simulation study, and an example based on an ongoing trial is presented. tuberculosis. EXAMPLE #2: Non-Inferiority There still might be some clinical benefit if T is worse than C only by some acceptable margin. 2-Sample, 2-Sided Equality 2-Sample, 1-Sided 2-Sample Non-Inferiority or Superiority 2-Sample Equivalence Compare k Means 1-Way ANOVA Pairwise, 2-Sided Equality 1-Way ANOVA Pairwise, 1-Sided Non-inferiority for proportions. In addition, it supersedes the guidance for industry, Antibacterial Drug Products: Use For surgery A, the score is 180 (the max for this score level is 200) We would like that the score with . Non-inferiority trials assess whether a new intervention is not much worse when compared to a standard treatment or care. Define superiority, non-inferiority, and equivalence trials. The sample size required for a non-inferiority clinical trial can be calculated using the formula in Figure 1 [5],[6]. A typical example is the non-inferiority trial, where it is tested whether a new experimental treatment is practically not inferior to an active comparator with a pre-specified margin $\delta$. Kenneth Schulz and David Grimes (Apr 9, p 1348)1 propose that it is ethical to enrol patients in "underpowered" trials given the uncertainty involved in estimating sample size. For example, sample size calculation is based solely on statistical methods of non-inferiority trials. The two communities were split into zones, which were randomly assigned (1:1:1) to the three treatment strategies: 35 zones to the SoC group, 35 zones to the HBD group, and 34 zones to the AC group. For this approach, the definition of equivalence or non-inferiority margins (NIM) is crucial, as we had noted earlier (Rief and Hofmann, Reference Rief and Hofmann. In the non-inferiority trial above, the null hypothesis started at the position of inferiority, with telephone delivery being inferior to the standard delivery of face to . Results: Using the European Polyp Surveillance non-inferiority trial as an example, our decision analytic approach suggests an appropriate non-inferiority margin, defined here as the difference between the two study arms in the 10-year risk of being diagnosed with colorectal cancer, of 0.42% rather than the 0.50% used to design the trial. If a withdrawal rate of $\gamma$ is anticipated, then the sample size should be increased by the factor $\dfrac{1}{\left(1 - \gamma\right)}$. example, superiority trials may show that a new drug is more effective than an active control—a drug known to be effective. 10 We considered a response to be non-inferior if the lower bound of the two-sided multiplicity . Finally, non-inferiority trial design usually requires a smaller sample size as compared to a superiority trial and hence fewer resources. A Phase 3, randomized, double-blind, non-inferiority trial was conducted to determine the Efficacy and Safety of 6-day Oral Tedizolid in Acute Bacterial Skin and Skin Structure Infections vs. 10-day Oral Linezolid Therapy (ESTABLISH-1). Interpreting superiority claims from a non-inferiority trial: The entire ITT 95% CI for the primary or co-primary endpoint: Does not cross/touch the pre-determined margin of non-inferiority (M 1 in the figure above) Interim monitoring for non-inferiority trials is shown to substantially reduce the exposure of patients to inferior therapies when, in fact, the experimental treatment is inferior to the standard treatment. These advantages however are not included in the classic frequentist approach of sample size . The usual assumption of non-inferiority is that the two groups would have the same response rate, in this case put the same value in (a) and (b). drugs for treatment of drug-sensitive. Conservative versus Interventional Treatment for Spontaneous Pneumothorax N Engl J Med. I need to calculate the possible effect size on a different binary outcome considering . Results are stated as CI. Based on that the sample size should be 2655 in each arm. In the non-inferiority trial above, the null hypothesis started at the position of inferiority, with telephone delivery being inferior to the standard delivery of face to . A clinical trial is planned to compare the effect of a new treatment with the existing treatment. Thus, a non-inferiority trial is one-sided, whereas an equivalence trial is two-sided. This was a three-arm, cluster-randomised, non-inferiority trial, done in two urban communities in Lusaka, Zambia included in the HPTN 071 trial. In general, health economic evaluations require a larger number of cases to create better heterogeneity among patients. with PE and a non-inferiority margin of 4%, the sample size of 160 patients per treatment group would have 80% power to detect 4% non -inferiority margin with one-sided α 0.05 assuming a 5% drop out rate. Internationally recommended regi-. For example, in a trial where an outcome of higher values is desirable, if the upper limit of the 95% CI for the treatment difference by the experimental treatment is less than the equivalence margin, then the null hypothesis of inferiority can be rejected at the 5% significance level (Fig. practitioners. In this paper, the steps for conducting sample size calculations for non-inferiority and equivalence trials are summarised. research programmes to develop new. Background: Non-inferiority trials are performed when the main therapeutic effect of the new therapy is expected to be not unacceptably worse than that of the standard therapy, and the new therapy is expected to have advantages over the standard therapy in costs or other (health) consequences. Introduction. margin of non-inferiority. Using the two one-sided test (TOST) procedure, equivalence is tested using a (1-2α)×100% CI. Rubinstein LV, Gail MH, Santner TJ. The objective of a non-inferiority trial is sometimes stated as being to demonstrate that the test product is not inferior to the comparator. st: R: Sample size for non inferiority trial. Shift in research and development strategy from developing follow-on or 'me-too' drugs to differentiated medical products with potentially better efficacy than the standard of care (e.g., first-in-class, best-in-class, and bio-betters) highlights the scientific and commercial interests in establishing superiority even when a non-inferiority design, adequately powered for a pre-specified non . Using examples from real clinical trials, Design and Analysis of Non-Inferiority Trials brings together this body of research and confronts the issues involved in the design of a non-inferiority trial. An example where a non-inferiority trial would be adequate in a pharmacologic trial is the comparison between warfarin and new anticoagulant drugs. 29 A calculated sample size of n=84 presumes sufficient heterogeneity of patients for the health economic evaluation. Biometrics. In this non-inferiority trial, involving 436 young survivors of cancer, we noted that antibody responses against HPV types 16 and 18 were non-inferior to general population comparisons, except against HPV type 18 in older females (ie, aged 16-26 years) receiving nonavalent vaccine. Assume that the larger response is the better response. We have 2 surgery techniques, A and B, and we compare quality of life score after surgery. In this case that means a 95 % CI, so the significance level is 0.025. In this trial the most common adverse effects reported with tedizolid were nausea, headache and diarrhea. To claim non-inferiority of COPDAC versus COPP, we aimed to exclude a difference of 8% from the two-sided 95% CI for the event-free survival rate at 5 years. Define superiority, non-inferiority, and equivalence trials. Now I have the secondary hypothesis that is a non-inferiority. Non-adherence in non-inferiority trials can affect treatment effect estimates and often increases the chance of claiming non-inferiority under the standard intention-to-treat analysis. H 0: µ t - µ c = -3 => H 0: µ t - µ c + 3 = 0 H a: µ t - µ c non-inferiority randomized phase II trials with feasible sample sizes. Trial outcomes ( equivalence or superiority ) the BMJ < /a > Introduction //www.quantics.co.uk/blog/what-is-a-non-inferiority-clinical-trial/ '' Understanding... On sample size for a balanced conclusion, or the more pessimistic results can then be treated for. Eight weeks was 24.3 % in the classic frequentist approach of sample,. Therapeutic or prophylactic trials the noninferior-ity approach is much more common than a true ( 2-sided period of continued.... This would still be a positive outcome 21 ) 00470-8/fulltext '' > Making sense of and! 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