For example, if a superiority trial of the active control demonstrated to be 15% better than placebo, a clinician may set the noninferiority margin to. First, one might argue that the 2% margin was unreasonably generous and potentially biased toward noninferiority, given the. A virtualsimulated case study comparing equivalence and noninferiority. Ni trials compare a new drug with a proven drug to determine whether the new drug is less effective by an unacceptable margin. However, details on how such a margin should be determined are not clearly specified, with the exception of the recently drafted guideline on noninferiority trials issued by the fda. Examples of equivalence and noninferiority trials example 2. Selection of the noninferiority margin and establishment of assay sensitivity are two major issues in the design, analysis and interpretation for twoarm non. Noninferiority trials in surgical oncology springerlink.
Bayesian approach to noninferiority trials for normal means. Noninferiority clinical trials to establish effectiveness guidance for. Noninferiority trial inferiority trial example noninferiority. The corresponding treatment effect estimate for nitrofurantoin was 26. If it was not, equivalence or noninferiority conclusions are meaningless the noninferior drug could have no effect at all. Department of biostatistics, uab school of public health. Imi, eu 7th framework program fp7, the dutch medicines evaluation. Emergency preparedness international programs news and events training and continuing.
This document provides guidance to sponsors and applicants submitting. Consider a standard treatment called drug x that has efficacy in some disease called a. The noninferiority margin may also be determined by the socalled. Noninferiority tests for binary endpoints with variable. Main concepts the fda has publicly expressed its expectations regarding the choice of noninferiority margins for some time, for example, in a presentation from february 2002 4. Suppose it is of interest to establish noninferiority of the test drug as compared to the active control agent. A noninferiority trial intends to demonstrate that the new drug is not. In general, fdas guidance documents do not establish legally enforceable. These study designs are useful in situations where a placebo or no. The noninferiority trial is a useful alternative in such situations. In the current example, a difference of one month, say, might be. Most noninferiority trials mention this non inferiority margin. Emmanuel lesaffre department of biostatistics, erasmus mc, rotterdam, the netherlands. The ich e10 also points out that the selection of the noninferiority margin should be based on historical experience in placebocontrolled trials, and be.
For example, in the 2008 draft fda guidance for diabetes mellitus, a noninferiority margin in hba1c reduction is suggested of 0. Noninferiority trials are experimental models designed to determine whether a. Now given that the true mean cure rates of the treatment agents and the active control are. Fda guidance on noninferiority clinical trials to establish. In march 2010, the centers for drug evaluation and research cder and biologics evaluation and research cber of the us fda issued a draft guidance for industry on noninferiority trials. The case of epidemiological data beyond clinical trials. Fda issues first draft guidance on noninferiority trials. Compare 2 means 2sample noninferiority or superiority. Most of the guidelines on noninferiority trials 4 6 state that a margin should account for both clinical and statistical considerations.
Noninferiority versus superiority trial design for new. Regulatory scientific advice on noninferiority drug trials ncbi. Noninferiority trials in breast and nonsmall cell lung. A twoarm noninferiority trial without a placebo is usually adopted to demonstrate that an experimental treatment is not worse than a reference treatment by a small prespecified noninferiority margin due to ethical concerns. This is typically derived from the results of prior clinical trials, using meta analysis. The fda has proposed the first draft guidance on noninferiority ni clinical trials, which may help increase the availability of comparative information on drugs. Most of the trials used rd to define the noninferiority margin, which ranged from 2. Assay sensitivityassumptions in noninferiority trials. The choice of noninferiority margin, initial sample size or desired width of the ci in a benchmarking study are all subjective decisions and can only be chosen by balancing the risk of incorrectly awarding a benchmarking standard to an implant with a failure rate beyond the noninferiority margin versus benchmark inflation where all devices. Determining the sample size required to establish whether. Even though we may assume that this difference is small enough to conclude noninferiority, this is where the noninferiority margin comes in. In fact, it has been pointed out that determining the noninferiority margin is the single greatest challenge in the design, conduct, and interpretation of non.
The draft fda guideline on noninferiority clinical trials. Bayesian approach to noninferiority trials for normal. Exploring how noninferiority and equivalence are assessed. Besides a great deal of recent publications in specialized journals, guidance.
Balancing a deficit in hba1c against potential benefits of a product could be done in a health care evaluation in terms of. The choice of the noninferiority margin is a key step. This is a complex area, and we recommend downloading our freely available 1page summary to help assess issues with equivalence and noninferiority trials. Us fda draft guidance on noninferiority clinical trials states that in. The efficacy of the active control was preserved in the noninferiority study i. Thus a calculated sample size for a noninferiority trial is usually the smallest of the three hypothesis. Noninferiority tests for the odds ratio of two proportions. If you have the appropriate software installed, you can download article citation data to the citation manager of your choice. Thus, the pharmaceutical industry was eagerly awaiting the draft guidance on non. There is no consensus on the preferred method for defining the noninferiority margin in noninferiority trials, and previous studies showed that the rationale for its choice is often not reported. The superiority comparison is a subset of the noninferiority and will have a sample size that is similar to the noninferiority or a sample size that is much larger. These and other noninferiority bayes factors for proportions can be obtained by providing values for the sample size n, mortality count k, and the noninferiority margin to the script.
The noninferiority margin should preferably be no greater than half of the lower limit of the 95% ci of the standard treatment effect. It implies that the interest is onesided, and new treatment could be even better superior than control. Objectives explore superiority, equivalence, and noninferiority ni trial designs compare critical differences between superiority and ni trials and stumbling blocks involving issues such as the noninferiority margin examine potential issues with noninferiority studies. Several points are worthy of consideration with respect to the noninferiority margin in the sportif trials. If the test is significant margin then can should we conclude similarly to what we do for a superiority trial. Strong predictors of effectiveness, such as adherence, can make the margin more precise. Noninferiority trials in stroke, cardiovascular disease, infectious disease and diabetes were searched and screened for inclusion on clinicaltrials. One trial stated that an independent expert committee determined the margin. The noninferioirty margin in diabetes trials 20nov2008 slide no 20 the noninferiority margin recently the fda issued a draft guidance on diabetes trials, in which a noninferiority margin was provided typically, we accept a noninferiority margin of 0. Considering of the difference less than 10% is of no clinical importance. For noninferiority is replaced by where is the noninferiority margin and is the expected difference in the treatment means 1 1 2 2 2 2 n z a z b d s. Testing noninferiority of a new treatment in threearm. Bayesian approach to noninferiority trials for normal means show all authors. This is a trial with the primary objective of showing that the response to two or more treatments differs by an amount which is clinically unimportant.
The noninferioirty margin in diabetes trials 20nov2008 slide no 18. Sample size estimation two parallelsample proportions. Pdf defining the noninferiority margin and analyzing non. Fda guidance documents represent the agencys current thinking on a wide variety of topics in the drug development process, including clinical issues, statistics, manufacturing, safety, and labelling. The noninferiority margin is the maximum difference between the treatments for which the outcomes can be considered to be equal. Bayes factors for superiority, noninferiority, and. As mentioned earlier, it is impossible to prove the exact equality, hence, a margin. Indeed, the ich guidance ref 1 requires that the noninferiority margin is. The selection of the noninferiority margin is based upon a combination of statistical reasoning and clinical judgement. To me the possibility that the new drug could lead to a 45% increased risk of stroke would be unacceptable. Superiority trials versus noninferiority trials to.
In both noninferiority and equivalence trials, the largest difference between arms that would be clinically acceptable, namely the margin, is formulated according to earlier knowledge and clinical relevance,12 is a critical point in designing those trials and influenced the sample size calculation. Evaluating equivalence and noninferiority trials medscape. Testing superiority, equivalence, and noninferiority. An openlabel, pragmatic equivalence trial was conducted to compare dihydrocodeine and methadone for opioid maintenance treatment. This study investigated how the noninferiority margin is defined in the published literature, and whether its reporting has changed over time. The challenges of determining noninferiority margins. Clinical noninferiority trails aim to demonstrate that new treatment is not worse equivalent or better than the control with an acceptable level to be worse called margin of noninferiority mni. Adaptive designs for noninferiority trials with multiple. Making sense of equivalence and noninferiority trials.
It is demonstrated that the noninferiority margin proposed by the fda has some undesirable features, and that the cpmp guidance may need further interpretation with respect to a statement that. The increase in the popularity of noninferiority clinical trials represents the increasing need to search for substitutes for some reference standard treatments. These procedures compute both asymptotic and exact confidence intervals and hypothesis tests for the difference, ratio, and odds ratio of two proportions. This chapter documents four closely related procedures. Regulatory scientific advice on noninferiority drug trials. Superiority, noninferiority, equivalence studies what.
Three trials used rr, setting the noninferiority margin at 1. A threearmed trial with test, reference and placebo allows some withintrial validation of the choice of noninferiority margin and is therefore the recommended design. This is usually demonstrated by showing that the true treatment difference is likely to lie between a lower and an upper equivalence margin of clinically acceptable differences. Noninferiority, superiority, equivalence, and twosided tests vs. E10 choice of control group and related issues in clinical trials, section 1.
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