Non-inferiority clinical trial. Features and practical considerations

Serra-Aracil, Xavier; Fradera, Marc
doi:10.1016/j.cireng.2024.07.008
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0005">Prospective&#44; controlled randomised studies&#46; When are they non-inferiority studies &#40;NIS&#41;&#63;</span><p id="par0005" class="elsevierStylePara elsevierViewall">Most prospective&#44; controlled&#44; randomized studies &#40;PCRS&#41; are so-called superiority studies&#44; which aim to determine whether one intervention is superior to another&#46; The fact that no statistically significant differences are found between two interventions does not mean that they are similar or equivalent&#46; For this reason&#44; there are equivalence trials&#44; which aim to determine whether a new intervention is therapeutically similar to another existing one&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">Non-inferiority studies &#40;NISs&#41; assess whether a new treatment is not considered worse&#44; or inferior&#44; compared to the regular treatment&#46; These studies provide an answer as to whether we are willing to accept a new intervention that may be clinically inferior&#44; up to a certain point&#44; but that is still beneficial for patients and has some additional advantage&#44; such as a less aggressive&#44; safer and more cost-effective treatment&#8211;efficiency&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The original CONSORT &#40;CONsolidated Standards of Reporting Trials&#41; statement was developed to help address the problem of inadequate submission of PCRSs&#46; To facilitate the development and quality of the NISs&#44; an extension of the CONSORT 2010<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> guide was published&#46;</p><p id="par0015" class="elsevierStylePara elsevierViewall">Non-inferiority and equivalence are sometimes mistakenly used in the same way&#46; Equivalence trials are defined as the treatment effect being within both non-inferiority margins &#40;NIM&#41;&#44; above and below &#40;&#8722;&#916; and &#43;&#916;&#41;&#46;</p><p id="par0020" class="elsevierStylePara elsevierViewall">The low quality of these studies can bias their results and produce false positives for non-inferiority&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> The objective of this article is to address the presentation form of NISs&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0010">Main NIS characteristics</span><p id="par0025" class="elsevierStylePara elsevierViewall">NISs must follow the checklist proposed by the CONSORT guide adapted for this type of study&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> A series of characteristics mark their identity and all of them must clearly reflect these to ensure the NIS quality&#58;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a><ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">1</span><p id="par0030" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The non-inferiority margin &#40;NIM&#41;&#46; This is the value that allows a new treatment to be considered &#34;</span>acceptably worse&#46;&#34;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">2</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The types of population group analysis must be defined</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">3</span><p id="par0040" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The consistency of the confidence intervals &#40;CI&#41; must be defined</span>&#46;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">4</span><p id="par0045" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Missing data management</span>&#46; Some missing data are inevitable&#44; but in the NISs the missing data may be biased towards demonstrating inferiority&#46;</p></li></ul></p></span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0015">How NIS results should be reported</span><p id="par0050" class="elsevierStylePara elsevierViewall">Superiority PCRSs can be classified as positive or negative depending on whether the null hypothesis is rejected &#40;i&#46;e&#46;&#44; p&#8201;&#60;&#8201;&#46;05&#41;&#46; In contrast&#44; the NISs can be interpreted as non-inferior&#44; inconclusive&#44; inferior or superior&#44; depending on the location of the 95&#37; CI&#46;<a class="elsevierStyleCrossRef" href="#bib0020"><span class="elsevierStyleSup">4</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall"><a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a> describes all the possibilities of the results of an NIS depending on where the 95&#37; CI is located&#46; In the literature&#44; the term non-inferiority has sometimes been used when the difference between two treatments is inconclusive without reference to a non-inferiority margin&#46; This use is inappropriate&#46; If the trial was underpowered&#44; the actual difference could still be substantial&#46;</p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0060" class="elsevierStylePara elsevierViewall">In the NIS&#44; creating a figure with the position of the 95&#37; CI &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41; with the NIM helps readers interpret the result&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> Thus&#44; as seen in <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#44; cases C&#44; E and F were statistically significantly lower&#44; but nevertheless in terms of a NIS&#44; C was non-inferior&#44; E inconclusive and F lower&#44; in relation to the NIM&#46;<a class="elsevierStyleCrossRef" href="#bib0025"><span class="elsevierStyleSup">5</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">Non-inferiority can be assessed as either a relative or absolute difference&#46; Both have their advantages and disadvantages&#46; The absolute difference is often the most relevant to patient outcomes&#44; as it reflects a change in reduction or improvement associated with standard surgical treatment&#46; It can be more easily compared to other treatment effects&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">The relative difference may be particularly useful in understanding how the new treatment compares to the conventional treatment in terms of the total effect of treatment versus no treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0020">How to define the non-inferiority margin &#40;&#916;&#41;</span><p id="par0075" class="elsevierStylePara elsevierViewall">Determining the NIM&#44; also called delta &#40;&#916;&#41;&#44; is the main challenge in designing an NIS&#46; Choice is essential to reach appropriate conclusions&#46; The NIM should depend on the importance of the final result and the magnitude of the new treatment&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0080" class="elsevierStylePara elsevierViewall">Despite being a key component in the design and interpretation of NISs&#44; recommendations for the selection of NIM are unclear&#46; A frequently used statement in some articles is&#44; &#8220;the choice of margin when it is clinically acceptable&#46;&#8221; This is not sufficiently consistent to justify the MNI&#46; In general&#44; the margin should be chosen on a clinical basis&#44; incorporating statistical evidence from meta-analyses or other quality clinical studies&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> If the choice of margin is based on a group of clinical experts&#44; information should be provided on how many experts were involved and how many considered acceptable the choice of margin &#40;as in Delphi processes&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">How should the sample estimation be made&#63;</span><p id="par0085" class="elsevierStylePara elsevierViewall">It differs considerably from superiority studies&#44; as they are directly defined by the NIM &#40;&#916;&#41;&#46; If &#916; is too large&#44; the risk of accepting both truly inferior and non-inferior treatment will be very high&#46; This situation is especially relevant for important outcomes such as mortality&#46; On the other hand&#44; setting &#916; as too small can produce inconclusive results&#44; requiring an extremely large trial&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The value of the statistical power &#40;1-&#946;&#41; must be known and this is assigned to the study&#46; Most researchers assign a &#946;&#8201;&#61;&#8201;&#46;2 value so the power is &#46;8&#46; This may be higher if it is assumed that the new treatment is more effective than the reference treatment or lower if it is assumed that it is less effective&#46; Also&#44; the type I risk alpha &#40;&#945;&#41; must be related as specified in the non-inferiority hypothesis&#46; The bilateral contrast type provides additional information&#44; particularly for the situation where the new treatment is superior to the regular one&#46;</p><p id="par0095" class="elsevierStylePara elsevierViewall">Sample size calculation formulas for non-inferiority studies for a primary variable with two categories &#40;2A&#41; or a continuous variable &#40;2B&#41; are shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46; In the following links the online calculators for NISs with both types of variables may be accessed&#58;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0100" class="elsevierStylePara elsevierViewall"><a href="https://www.sealedenvelope.com/power/continuous-noninferior/">https&#58;&#47;&#47;www&#46;sealedenvelope&#46;com&#47;power&#47;continuous-noninferior&#47;</a><a class="elsevierStyleCrossRef" href="#bib0035"><span class="elsevierStyleSup">7</span></a> and <a href="https://www.sealedenvelope.com/power/binary-noninferior">https&#58;&#47;&#47;www&#46;sealedenvelope&#46;com&#47;power&#47;binary-noninferior</a>&#46;<a class="elsevierStyleCrossRef" href="#bib0040"><span class="elsevierStyleSup">8</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Specify the type of population group analysis that is being assessed</span><p id="par0105" class="elsevierStylePara elsevierViewall">Both intention-to-treat &#40;ITT&#41; and per-protocol analyses should be considered to meet non-inferiority&#46; Generally&#44; the ITT analysis population is the most appropriate&#44; but as previously mentioned&#44; this may underestimate the real difference between treatments&#44; and it is important to also describe compliance with treatment in both groups&#46;<a class="elsevierStyleCrossRef" href="#bib0015"><span class="elsevierStyleSup">3</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Should an interim analysis be performed&#63; Study detention</span><p id="par0110" class="elsevierStylePara elsevierViewall">In superiority trials&#44; when an interim analysis shows clear evidence of the efficacy of the new treatment&#44; it may be considered ethically incorrect to continue the trial and deny the effective new treatment to the control group&#46; In contrast&#44; in an NIS&#44; if non-inferiority is demonstrated for the primary outcome before completion of the trial&#44; there is less ethical need to stop the trial because the control group is already receiving standard treatment&#46; It is therefore suggested to finalise the NIS and be able to specifically define where the CI is located&#46;</p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Final comment</span><p id="par0115" class="elsevierStylePara elsevierViewall">The main characteristics of the NISs that we have described must be clearly described&#46; Any absence in their definition can lead to false conclusions&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> This is particularly the case of those NISs with inconclusive results&#44; which can misinterpret the true results of the trial&#46;</p></span></span>"
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          "en" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Location of the possible results of the 95&#37; confidence intervals&#46; The solid line is 0&#44; which indicates statistical significance when the entire interval is on one side or the other of 0&#46; The dashed line is the one that indicates the non-inferiority margin &#40;&#916;&#61; &#8722;10&#41;&#46; The shaded area to the left indicates the non-inferiority area&#46; &#40;A&#41; If the CI is completely to the left of zero&#44; the new treatment is superior and of course&#44; not inferior&#46; &#40;B&#41; If the CI lies to the left of &#916; and includes zero&#44; the new treatment is not inferior but has not been shown to be superior&#46; &#40;C&#41; If the CI is completely to the left of &#916; and completely to the right of zero&#44; the new treatment is not inferior in the sense already defined&#44; but it is also inferior in the sense that a zero-treatment difference is excluded&#44; so it will be statistically lower&#46; This puzzling circumstance is rare because it requires a very large sample size&#46; It may also be due to a non-inferiority margin that is too wide&#46; &#40;D&#41; If the CI includes &#916; and zero&#44; the difference is not significant but the result on non-inferiority is inconclusive&#46; &#40;E&#41; If the CI includes &#916; and is completely to the right of zero&#44; the difference is statistically significant but the result is inconclusive with respect to a possible inferiority of magnitude &#916; or worse&#46; &#40;F&#41; If the CI is completely to the right of &#916;&#44; the new treatment is inferior&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p>"
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